@article {pmid39019674,
year = {2024},
author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C},
title = {[Proposals from a French expert panel for respiratory care in ALS patients].},
journal = {Revue des maladies respiratoires},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.rmr.2024.06.006},
pmid = {39019674},
issn = {1776-2588},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.

METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel.

RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients.

CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.},
}

@article {pmid39019479,
year = {2024},
author = {Nurmammadova, L and Yozgat, Y and Yozgat, CY and Babayeva, T and Bayramova, N and Talebazadeh, F and Koç, E and Kahraman, FU and Erenberk, U},
title = {[Rolle von Parametern bei der Vollblutanalyse als Indikator für systemische Entzündungen bei Kindern mit rheumatischen Klappenerkrankungen].},
journal = {Klinische Padiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2367-9190},
pmid = {39019479},
issn = {1439-3824},
}

@article {pmid39019135,
year = {2024},
author = {Cao, M and Yi, L and Xu, Y and Tian, Y and Li, Z and Bi, Y and Guo, M and Li, Y and Liu, Y and Xu, X and Sun, J and Li, C and Duan, W},
title = {Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.},
journal = {Brain research},
volume = {1843},
number = {},
pages = {149124},
doi = {10.1016/j.brainres.2024.149124},
pmid = {39019135},
issn = {1872-6240},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear.

METHODS: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.We treated age-matched SOD1-G93A mice with B022 (a NIK inhibitor) to investigate the role of NIK in the ALS animal model. We also established a new mice model by crossing SOD1-G93A mice with NIK[+/-] mice to further evaluate the interrelationship between the NIK and the disease progression in ALS animal model.

RESULTS: In this study, we found the ncNF-κB pathway was activated in SOD1-G93A animal model and TBK1 deletion model. Inhibition of NIK activity by small molecule B022 significantly improved the motor performance of the ALS animal model. However, NIK deletion enhanced the mutant SOD1 toxicity by inflammatory infiltration.

CONCLUSION: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.},
}

@article {pmid39017978,
year = {2024},
author = {Vinceti, M and Urbano, T and Filippini, T and Bedin, R and Simonini, C and Sorarù, G and Trojsi, F and Michalke, B and Mandrioli, J},
title = {Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {39017978},
issn = {1559-0720},
support = {"PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.},
}

@article {pmid39017652,
year = {2024},
author = {Ranta-Aho, J and Johari, M and Udd, B},
title = {Current advance on distal myopathy genetics.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WCO.0000000000001299},
pmid = {39017652},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Distal myopathies are a clinically heterogenous group of rare, genetic muscle diseases, that present with weakness in hands and/or feet at onset. Some of these diseases remain accentuated in the distal muscles whereas others may later progress to the proximal muscles. In this review, the latest findings related to genetic and clinical features of distal myopathies are summarized.

RECENT FINDINGS: Variants in SMPX, DNAJB2, and HSPB6 have been identified as a novel cause of late-onset distal myopathy and neuromyopathy. In oculopharyngodistal myopathies, repeat expansions were identified in two novel disease-causing genes, RILPL1 and ABCD3. In multisystem proteinopathies, variants in HNRNPA1 and TARDBP, genes previously associated with amyotrophic lateral sclerosis, have been shown to cause late-onset distal myopathy without ALS. In ACTN2-related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present.

SUMMARY: The identification of novel distal myopathy genes and pathogenic variants contribute to our ability to provide a final molecular diagnosis to a larger number of patients and increase our overall understanding of distal myopathy genetics and pathology.},
}

@article {pmid39015513,
year = {2024},
author = {Barahim Bastani, P and Saber Tehrani, AS and Badihian, S and Rieiro, H and Rastall, D and Farrell, N and Parker, M and Otero-Millan, J and Hassoon, A and Newman-Toker, D and Clawson, LL and Uchil, A and Riley, K and Zeiler, SR},
title = {Self-Recording of Eye Movements in Amyotrophic Lateral Sclerosis Patients Using a Smartphone Eye-Tracking App.},
journal = {Digital biomarkers},
volume = {8},
number = {1},
pages = {111-119},
pmid = {39015513},
issn = {2504-110X},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) can affect various eye movements, making eye tracking a potential means for disease monitoring. In this study, we evaluated the feasibility of ALS patients self-recording their eye movements using the "EyePhone," a smartphone eye-tracking application.

METHODS: We prospectively enrolled ten participants and provided them with an iPhone equipped with the EyePhone app and a PowerPoint presentation with step-by-step recording instructions. The goal was for the participants to record their eye movements (saccades and smooth pursuit) without the help of the study team. Afterward, a trained physician administered the same tests using video-oculography (VOG) goggles and asked the participants to complete a questionnaire regarding their self-recording experience.

RESULTS: All participants successfully completed the self-recording process without assistance from the study team. Questionnaire data indicated that participants viewed self-recording with EyePhone favorably, considering it easy and comfortable. Moreover, 70% indicated that they prefer self-recording to being recorded by VOG goggles.

CONCLUSION: With proper instruction, ALS patients can effectively use the EyePhone to record their eye movements, potentially even in a home environment. These results demonstrate the potential for smartphone eye-tracking technology as a viable and self-administered tool for monitoring disease progression in ALS, reducing the need for frequent clinic visits.},
}

@article {pmid39015316,
year = {2024},
author = {Liu, Y and Chen, Y and Gao, M and Luo, J and Wang, Y and Wang, Y and Gao, Y and Yang, L and Wang, J and Wang, N},
title = {Association between glioma and neurodegenerative diseases risk: a two-sample bi-directional Mendelian randomization analysis.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1413015},
pmid = {39015316},
issn = {1664-2295},
abstract = {BACKGROUND: Earlier observational studies have demonstrated a correlation between glioma and the risk of neurodegenerative diseases (NDs), but the causality and direction of their associations remain unclear. The objective of this study was to ascertain the causal link between glioma and NDs using Mendelian randomization (MR) methodology.

METHODS: Genome-wide association study (GWAS) data were used in a two-sample bi-directional MR analysis. From the largest meta-analysis GWAS, encompassing 18,169 controls and 12,488 cases, summary statistics data on gliomas was extracted. Summarized statistics for NDs, including Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) were obtained from the GWAS of European ancestry. Inverse variance weighted (IVW) method was elected as the core MR approach with weighted median (WM) method and MR-Egger method as complementary methods. In addition, sensitivity analyses were performed. A Bonferroni correction was used to correct the results.

RESULTS: Genetically predicted glioma had been related to decreased risk of AD. Specifically, for all glioma (IVW: OR = 0.93, 95% CI = 0.90-0.96, p = 4.88 × 10[-6]) and glioblastoma (GBM) (IVW: OR = 0.93, 95% CI = 0.91-0.95, p = 5.11 × 10[-9]). We also found that genetically predicted all glioma has a suggestive causative association with MS (IVW: OR = 0.90, 95% CI = 0.81-1.00, p = 0.045). There was no evidence of causal association between glioma and ALS or PD. According to the results of reverse MR analysis, no discernible causal connection of NDs was found on glioma. Sensitivity analyses validated the robustness of the above associations.

CONCLUSION: We report evidence in support of potential causal associations of different glioma subtypes with AD and MS. More studies are required to uncover the underlying mechanisms of these findings.},
}

@article {pmid39010704,
year = {2024},
author = {Liu, J and Shi, X and Shao, Y},
title = {Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.},
journal = {Brain and behavior},
volume = {14},
number = {7},
pages = {e3624},
pmid = {39010704},
issn = {2162-3279},
mesh = {Humans ; *Mendelian Randomization Analysis ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; *Polymorphism, Single Nucleotide ; *Neurodegenerative Diseases/genetics ; *Glycated Hemoglobin/metabolism ; *Sodium-Glucose Transporter 1/genetics ; Diabetes Mellitus, Type 2/drug therapy/genetics ; Sodium-Glucose Transporter 2/genetics/metabolism ; Parkinson Disease/genetics/drug therapy ; Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Alzheimer Disease/genetics/drug therapy ; Multiple Sclerosis/drug therapy/genetics ; },
abstract = {INTRODUCTION: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels.

METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders.

RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings.

CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.},
}

Humans
*Mendelian Randomization Analysis
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
*Polymorphism, Single Nucleotide
*Neurodegenerative Diseases/genetics
*Glycated Hemoglobin/metabolism
*Sodium-Glucose Transporter 1/genetics
Diabetes Mellitus, Type 2/drug therapy/genetics
Sodium-Glucose Transporter 2/genetics/metabolism
Parkinson Disease/genetics/drug therapy
Amyotrophic Lateral Sclerosis/genetics/drug therapy
Alzheimer Disease/genetics/drug therapy
Multiple Sclerosis/drug therapy/genetics

@article {pmid39009686,
year = {2024},
author = {Neupane, K and Narayan, A and Sen Mojumdar, S and Adhikari, G and Garen, CR and Woodside, MT},
title = {Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants.},
journal = {Nature chemical biology},
volume = {},
number = {},
pages = {},
pmid = {39009686},
issn = {1552-4469},
support = {N/A//Gouvernement du Canada | National Research Council Canada (Conseil national de recherches Canada)/ ; RGPIN-2018-04673//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; N/A//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; PJT-185931//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; N/A//Alberta Innovates | Alberta Innovates - Health Solutions (AIHS)/ ; N/A//Alberta Innovates | Alberta Innovates - Health Solutions (AIHS)/ ; },
abstract = {Many neurodegenerative diseases feature misfolded proteins that propagate via templated conversion of natively folded molecules. However, crucial questions about how such prion-like conversion occurs and what drives it remain unsolved, partly because technical challenges have prevented direct observation of conversion for any protein. We observed prion-like conversion in single molecules of superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis. Tethering pathogenic misfolded SOD1 mutants to wild-type molecules held in optical tweezers, we found that the mutants vastly increased misfolding of the wild-type molecule, inducing multiple misfolded isoforms. Crucially, the pattern of misfolding was the same in the mutant and converted wild-type domains and varied when the misfolded mutant was changed, reflecting the templating effect expected for prion-like conversion. Ensemble measurements showed decreased enzymatic activity in tethered heterodimers as conversion progressed, mirroring the single-molecule results. Antibodies sensitive to disease-specific epitopes bound to the converted protein, implying that conversion produced disease-relevant misfolded conformers.},
}

@article {pmid39009447,
year = {2024},
author = {Akter, M and Sepehrimanesh, M and Xu, W and Ding, B},
title = {Assembling a coculture system to prepare highly pure induced pluripotent stem cell-derived neurons at late maturation stages.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0165-24.2024},
pmid = {39009447},
issn = {2373-2822},
abstract = {Generation of human induced pluripotent stem cell (hiPSC)-derived motor neurons (MNs) offers an unprecedented approach to modeling movement disorders such as dystonia and amyotrophic lateral sclerosis. However, achieving survival poses a significant challenge when culturing induced MNs, especially when aiming to reach late maturation stages. Utilizing hiPSC-derived motor neurons and primary mouse astrocytes, we assembled two types of coculture systems: direct coculturing of neurons with astrocytes, and indirect coculture using culture inserts that physically separate neurons and astrocytes. Both systems significantly enhance neuron survival. Compared with these two systems, no significant differences in neurodevelopment, maturation, and survival within 3 weeks, allowing to prepare neurons at maturation stages. Using the indirect coculture system, we obtained highly pure MNs at the late mature stage from hiPSCs. Transcriptomic studies of hiPSC-derived MNs showed a typical neurodevelopmental switch in gene expression from the early immature stage to late maturation stages. Mature genes associated with neurodevelopment and synaptogenesis are highly enriched in MNs at late stages, demonstrating that these neurons achieve maturation. This study introduces a novel tool for the preparation of highly pure hiPSC-derived neurons, enabling the determination of neurological disease pathogenesis in neurons at late disease onset stages through biochemical approaches, which typically necessitate highly pure neurons. This advancement is particularly significant in modeling age-related neurodegeneration.Significance Statement Achieving survival poses a significant challenge for long-term neural cell cultures. Utilizing hiPSC-derived motor neurons and primary mouse astrocytes, we established an indirect coculture system using culture inserts that physically separate neurons and astrocytes, thereby facilitating neuronal maturation. Transcriptomic studies revealed the typical neurodevelopmental switch in gene expression from the early immature stage to late maturation stages, indicating the high quality and maturation of neurons prepared with culture inserts. This study introduces a novel tool for the preparation of highly pure hiPSC-derived neurons, enabling the determination of neurological disease pathogenesis in neurons at late disease onset stages through biochemical approaches, which typically necessitate highly pure neurons. This advancement is particularly significant in modeling age-related neurodegeneration.},
}

@article {pmid39008674,
year = {2024},
author = {Mason, AH and Motta, A and Kratish, Y and Marks, TJ},
title = {Demystifying group-4 polyolefin hydrogenolysis catalysis. Gaseous propane hydrogenolysis mechanism over the same catalysts.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {121},
number = {30},
pages = {e2406133121},
doi = {10.1073/pnas.2406133121},
pmid = {39008674},
issn = {1091-6490},
support = {DE-FG02-03ER15457//DOE | Office of Science (SC)/ ; DOE DE-SC0024448//Dow Chemical Company (Dow)/ ; ECCS-2025633//National Science Foundation (NSF)/ ; NNA04CC36G//NASA | Ames Research Center (ARC)/ ; DOE DE-SC0001329//Dow Chemical Company (Dow)/ ; HP10CPXHA1 2023//CINECA HPC/ ; },
abstract = {A kinetic/mechanistic investigation of gaseous propane hydrogenolysis over the single-site heterogeneous polyolefin depolymerization catalysts AlS/ZrNp2 and AlS/HfNp2 (AlS = sulfated alumina, Np = neopentyl), is use to probe intrinsic catalyst properties without the complexities introduced by time- and viscosity-dependent polymer medium effects. In a polymer-free automated plug-flow catalytic reactor, propane hydrogenolysis turnover frequencies approach 3,000 h[-1] at 150 °C. Both catalysts exhibit approximately linear relationships between rate and [H2] at substoichiometric [H2] with rate law orders of 0.66 ± 0.09 and 0.48 ± 0.07 for Hf and Zr, respectively; at higher [H2], the rates approach zero-order in [H2]. Reaction orders in [C3H8] and [catalyst] are essentially zero-order under all conditions, with the former implying rapid, irreversible alkane binding/activation. This rate law, activation parameter, and DFT energy span analysis support a scenario in which [H2] is pivotal in one of two plausible and competing rate-determining transition states-bimolecular metal-alkyl bond hydrogenolysis vs. unimolecular β-alkyl elimination. The Zr and Hf catalyst activation parameters, ΔH[‡] = 16.8 ± 0.2 kcal mol[-1] and 18.2 ± 0.6 kcal mol[-1], respectively, track the relative turnover frequencies, while ΔS[‡] = -19.1 ± 0.8 and -16.7 ± 1.4 cal mol[-1] K[-1], respectively, imply highly organized transition states. These catalysts maintain activity up to 200 °C, while time-on-stream data indicate multiday activities with an extrapolated turnover number ~92,000 at 150 °C for the Zr catalyst. This methodology is attractive for depolymerization catalyst discovery and process optimization.},
}

@article {pmid39008617,
year = {2024},
author = {Tsitkanou, S and Lindsay, A and Abbott, G and Foletta, V and Walker, AK and Russell, AP and Della Gatta, PA},
title = {Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model.},
journal = {Journal of applied physiology (Bethesda, Md. : 1985)},
volume = {},
number = {},
pages = {},
doi = {10.1152/japplphysiol.00192.2023},
pmid = {39008617},
issn = {1522-1601},
support = {//Deakin University | Institute for Physical Activity and Nutrition (IPAN)/ ; //Onassis Foundation Greece/ ; //Deakin University, Alfread Deakin PostDoc Fellowship/ ; //Neurological Foundation of New Zealand/ ; 1124005//Australian National Health and Medical Research Council/ ; //Ross Maclean Fellowship/ ; //Bill Guest FightMND Mid-Career Development Fellowship/ ; //Brazil Family Program for Neurology/ ; },
abstract = {Exercise training is considered a non-pharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with Amyotrophic Lateral Sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete four weeks of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimes need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.},
}

@article {pmid39007704,
year = {2024},
author = {Gandhi, P and Waito, AA and Peladeau-Pigeon, M and Plowman, EK and Steele, CM},
title = {How Do Quantitative Videofluoroscopy Measures Differ Between People With Amyotrophic Lateral Sclerosis and Age-Matched Healthy Adults?.},
journal = {Journal of speech, language, and hearing research : JSLHR},
volume = {},
number = {},
pages = {1-21},
doi = {10.1044/2024_JSLHR-24-00106},
pmid = {39007704},
issn = {1558-9102},
abstract = {PURPOSE: Dysphagia is a leading cause of morbidity in people with amyotrophic lateral sclerosis (PwALS). Previous videofluoroscopic swallowing studies (VFSS) in PwALS do not account for the influence of senescence. We aimed to compare swallowing in PwALS and an age- and sex-matched control group using healthy reference data to define typical and atypical values.

METHOD: We conducted retrospective analysis of VFSS data from 19 PwALS (10 male, Mage = 63 years, range: 47-82) compared to control data from a cohort of healthy adults. Participants swallowed 20% w/v liquid barium from thin to extremely thick consistency. Blinded duplicate VFSS analysis using the ASPEKT (Analysis of Swallowing Physiology: Events, Kinematics and Timing) method yielded descriptive statistics for 16 quantitative VFSS parameters by consistency. Mann-Whitney U tests were used to identify significant cohort differences. Additionally, the frequencies of atypical values (in the 25% tails of the reference distribution) were tabulated by cohort and compared using odds ratios.

RESULTS: PwALS showed increased frequencies of multiple swallows per bolus, incomplete laryngeal vestibule closure, and reduced hyoid speed across consistencies. By contrast, similar frequencies of atypical values for pharyngeal constriction and residue in both cohorts suggest that age-related changes may contribute to the presence of these features in PwALS.

CONCLUSIONS: This analysis builds on previous descriptions of swallowing pathophysiology in amyotrophic lateral sclerosis (ALS) by clarifying the extent to which aging may account for some of the atypical findings seen in this patient population. Longitudinal studies are recommended to further differentiate the effects of ALS from age-related changes in swallowing over the course of disease progression.},
}

@article {pmid39007446,
year = {2024},
author = {Torra, J and Mora, G and Montull, JM and Royo-Esnal, A and Notter, JS and Salas, M},
title = {A 4-year field study monitoring the evolution of Trp574Leu-resistant plants in an Echinochloa crus-galli population under different crop rotation and herbicide programs in maize.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.8315},
pmid = {39007446},
issn = {1526-4998},
support = {//Corteva Agriscience/ ; RYC2018-023866-I//Spanish Ministry of Science, Innovation, and Universities/ ; //Spanish State Research Agency/ ; PID2020-113229RB-C42//European Regional Development Fund (ERDF)/ ; },
abstract = {BACKGROUND: A 4-year experiment evaluated the effects of different integrated weed management (IWM) programs on the evolution of a Echinochloa crus-galli population resistant to acetolactate synthase (ALS) inhibitors in a maize cropping system. The programs included the continued use of ALS inhibitors, mixing them with alternative herbicides, or without ALS-inhibitors, in all cases under maize monocrop or a biennial crop rotation.

RESULTS: IWM programs that relied solely on non-ALS-inhibitors usually achieved high control levels across years (> 90%). Additionally, Trp574Leu-resistant plants became prevalent (> 90%) in programs only using ALS inhibitors, while in the rest the frequency of susceptible plants did not substantially decrease below 40%. Regarding the other monitored grass weeds, Digitaria sanguinalis and Panicum dichotomiflorum were effectively controlled in programs using ALS-inhibitors without soybean rotation or in programs without ALS-inhibitors altogether, excepting the program relying on an 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibitor under maize monocrop for the latter species (0%).

CONCLUSION: At the end of the experiment, the only IWM programs that reduced infestation levels were the one without ALS-inhibitors under soybean rotation, and the one with standard pre-emergence treatments. These findings highlight the effectiveness of crop rotation and alternative herbicides both pre- or post-emergence in controlling E. crus-galli. ALS-inhibitors, while challenged by resistance in E. crus-galli, remain valuable tools for managing other grass weed species in maize. It is crucial to adapt IWM strategies for herbicide-resistant E. crus-galli and other grass weed populations to mitigate the further evolution of resistance. © 2024 Corteva Agriscience. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid39007083,
year = {2024},
author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM},
title = {Superoxide dismutase and neurological disorders.},
journal = {IBRO neuroscience reports},
volume = {16},
number = {},
pages = {373-394},
pmid = {39007083},
issn = {2667-2421},
abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.},
}

@article {pmid39006832,
year = {2023},
author = {Neumann, M and Kothare, H and Ramanarayanan, V},
title = {Combining Multiple Multimodal Speech Features into an Interpretable Index Score for Capturing Disease Progression in Amyotrophic Lateral Sclerosis.},
journal = {Interspeech},
volume = {2023},
number = {},
pages = {2353-2357},
pmid = {39006832},
issn = {2308-457X},
support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; },
abstract = {Multiple speech biomarkers have been shown to carry useful information regarding Amyotrophic Lateral Sclerosis (ALS) pathology. We propose a two-step framework to compute optimal linear combinations (indexes) of these biomarkers that are more discriminative and noise-robust than the individual markers, which is important for clinical care and pharmaceutical trial applications. First, we use a hierarchical clustering based method to select representative speech metrics from a dataset comprising 143 people with ALS and 135 age- and sex-matched healthy controls. Second, we analyze three methods of index computation that optimize linear discriminability, Youden Index, and sparsity of logistic regression model weights, respectively, and evaluate their performance with 5-fold cross validation. We find that the proposed indexes are generally more discriminative of bulbar vs non-bulbar onset in ALS than their individual component metrics as well as an equally-weighted baseline.},
}

@article {pmid39006831,
year = {2023},
author = {Kothare, H and Neumann, M and Liscombe, J and Green, J and Ramanarayanan, V},
title = {Responsiveness, Sensitivity and Clinical Utility of Timing-Related Speech Biomarkers for Remote Monitoring of ALS Disease Progression.},
journal = {Interspeech},
volume = {2023},
number = {},
pages = {2323-2327},
pmid = {39006831},
issn = {2308-457X},
support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; },
abstract = {In this study, we describe the responsiveness of timing-related measures extracted from read speech in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We found that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt is the most responsive measure, of the ones considered in this study, at detecting such change in both pALS with bulbar (n = 35) and non-bulbar onset (n = 94). We further evaluated the sensitivity of speech metrics in tracking disease progression in pALS while their ALSFRS-R speech score remained unchanged at 3 out of a total possible score of 4. We observed that timing-related speech metrics showed significant longitudinal changes even after accounting for learning effects. The findings of this study have the potential to inform disease prognosis and functional outcomes of clinical trials.},
}

@article {pmid39006764,
year = {2024},
author = {Yang, C and Liu, G and Chen, X and Le, W},
title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.},
journal = {MedComm},
volume = {5},
number = {7},
pages = {e638},
pmid = {39006764},
issn = {2688-2663},
abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.},
}

@article {pmid39006715,
year = {2024},
author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J},
title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.},
journal = {Cureus},
volume = {16},
number = {6},
pages = {e62310},
pmid = {39006715},
issn = {2168-8184},
abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.},
}

@article {pmid39006307,
year = {2023},
author = {Ayoubi, R and Alshafie, W and Shlaifer, I and Southern, K and McPherson, PS and Laflamme, C and , },
title = {The identification of high-performing antibodies for Sequestosome-1 for use in Western blot, immunoprecipitation and immunofluorescence.},
journal = {F1000Research},
volume = {12},
number = {},
pages = {324},
pmid = {39006307},
issn = {2046-1402},
mesh = {*Sequestosome-1 Protein/immunology/metabolism ; Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western ; Antibodies/immunology ; },
abstract = {Sequestosome-1, encoded by the gene SQSTM1, functions as a bridge between ubiquitinated proteins and the proteasome or autophagosome, thereby regulating protein degradation pathways. Loss of Sequestosome-1 is hypothesized to enhance neurodegeneration progression in several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal disorders (FTD). Sequestosome-1 reproducible research would be facilitated with the availability of well-characterized anti-Sequestosome-1 antibodies. In this study, we characterized seventeen Sequestosome-1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.},
}

*Sequestosome-1 Protein/immunology/metabolism
Humans
*Fluorescent Antibody Technique/methods
*Immunoprecipitation/methods
*Blotting, Western
Antibodies/immunology

@article {pmid39005475,
year = {2024},
author = {Xie, M and Miller, AS and Pallegar, PN and Umpierre, A and Liang, Y and Wang, N and Zhang, S and Nagaraj, NK and Fogarty, ZC and Ghayal, NB and Oskarsson, B and Zhao, S and Zheng, J and Qi, F and Nguyen, A and Dickson, DW and Wu, LJ},
title = {Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.06.30.601396},
pmid = {39005475},
issn = {2692-8205},
abstract = {Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.},
}

@article {pmid39005384,
year = {2024},
author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Bai, J and Shahzad, S and Nedumaran, J and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, P and Ward, M and Todd, P and Barmada, SJ},
title = {TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39005384},
issn = {2692-8205},
abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, highly prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a byproduct of TDP43 autoregulation and cleared by nonsense mediated RNA decay (NMD). The sTDP43-encoding transcripts that escape NMD can lead to toxicity but are rapidly degraded post-translationally. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration in vitro and in vivo via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and provide insight into the consequences of aberrant sTDP43 accumulation in disease.},
}

@article {pmid39005345,
year = {2024},
author = {Rizuan, A and Shenoy, J and Mohanty, P and Dos Passos, PMS and Mercado Ortiz, JF and Bai, L and Viswanathan, R and Wang, SH and Johnson, V and Mamede, LD and Ayala, YM and Ghirlando, R and Mittal, J and Fawzi, NL},
title = {Structural details of helix-mediated TDP-43 C-terminal domain multimerization.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39005345},
issn = {2692-8205},
support = {R01 NS116176/NS/NINDS NIH HHS/United States ; },
abstract = {The primarily disordered C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43), a key nuclear protein in RNA metabolism, forms neuronal inclusions in several neurodegenerative diseases. A conserved region (CR, spanning residues 319-341) in CTD forms transient helix-helix contacts important for its higher-order oligomerization and function that are disrupted by ALS-associated mutations. However, the structural details of CR assembly and the explanation for several ALS-associated variants' impact on phase separation and function remain unclear due to challenges in analyzing the dynamic association of TDP-43 CTD using traditional structural biology approaches. By employing an integrative approach, combining biophysical experiments, biochemical assays, AlphaFold2-Multimer (AF2-Multimer), and atomistic simulations, we generated structural models of helical oligomerization of TDP-43 CR. Using NMR, we first established that the native state of TDP-43 CR under physiological conditions is α-helical. Next, alanine scanning mutagenesis revealed that while hydrophobic residues in the CR are important for CR assembly, phase separation and TDP-43 nuclear retention function, polar residues down regulate these processes. Finally, pairing AF2-Multimer modeling with AAMD simulations indicated that dynamic, oligomeric assemblies of TDP-43 that are stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. In conclusion, our results advance the structural understanding of the mechanisms driving TDP-43 function and provide a window into the initial stages of its conversion into pathogenic aggregates.},
}

@article {pmid39005286,
year = {2024},
author = {Krattli, RP and Do, AH and El-Khatib, SM and Alikhani, L and Markarian, M and Vagadia, AR and Usmani, MT and Madan, S and Baulch, JE and Clark, RJ and Woodruff, TM and Tenner, AJ and Acharya, MM},
title = {Complement C5a receptor 1 blockade reverses cognitive deficits following cranial radiation therapy for brain cancer.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.02.601806},
pmid = {39005286},
issn = {2692-8205},
abstract = {Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are particularly a pressing problem for the survivors of pediatric and low grade glioma (LGG) patients who often live long post-RT. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205, to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. C5aR1 inhibition reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 inhibition in the syngeneic, orthotopic astrocytoma, and glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 is currently in clinical trials for amyotrophic lateral sclerosis (ALS). Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.},
}

@article {pmid39005258,
year = {2024},
author = {Feringa, FM and Koppes-den Hertog, SJ and Wang, L and Derks, RJE and Kruijff, I and Erlebach, L and Heijneman, J and Miramontes, R and Pömpner, N and Blomberg, N and Olivier-Jimenez, D and Johansen, LE and Cammack, AJ and Giblin, A and Toomey, CE and Rose, IVL and Yuan, H and Ward, M and Isaacs, AM and Kampmann, M and Kronenberg-Versteeg, D and Lashley, T and Thompson, LM and Ori, A and Mohammed, Y and Giera, M and van der Kant, R},
title = {The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.01.601474},
pmid = {39005258},
issn = {2692-8205},
abstract = {Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.},
}

@article {pmid39004530,
year = {2024},
author = {Vacchiano, V and Di Stasi, V and Bruni, S and Rizzo, G and Liguori, R},
title = {Thoracic paraspinal muscles denervation assessment in amyotrophic lateral sclerosis: Clinical-neurophysiological correlations and prognostic value.},
journal = {Journal of the neurological sciences},
volume = {},
number = {},
pages = {123133},
doi = {10.1016/j.jns.2024.123133},
pmid = {39004530},
issn = {1878-5883},
}

@article {pmid39004370,
year = {2024},
author = {Hajdukiewicz, H and Hajdukiewicz, M and Ruiz-Villanueva, V and Radecki-Pawlik, A and Zawiejska, J},
title = {Exploring historical changes in mountain river hydrodynamics induced by human impact.},
journal = {The Science of the total environment},
volume = {},
number = {},
pages = {174742},
doi = {10.1016/j.scitotenv.2024.174742},
pmid = {39004370},
issn = {1879-1026},
abstract = {During the 20th-century many mountain rivers in Europe were subjected to intensive human impacts which substantially modified their channel morphology. How these changes affected river hydrodynamics and response to floods remains uncertain. In this work, we perform hydraulic modelling using data from archival aerial photos to explore relations between hydraulic parameters of floods and human-induced channel incision occurring on the Czarny Dunajec River (Polish Carpathians) between 1964 and 2012. Data on vertical position of the channel used for two-dimensional modelling of flood flows were extracted (as Digital Elevation Models DEMs) from archival aerial photos from 1964 and 1983 and ALS (Airborne Laser Skanning)-derived DEM from 2012. Water depth, flow velocity, bed shear stress, and sediment critical diameter were modelled for four flood scenarios (2-year, 5-year, 20-year, and 50-year floods) as well as the extent of flooded area and additionally the grain size of channel sediment was calculated. The values of water depth, flow velocity, bed shear stress and sediment critical diameter increased significantly between 1964 and 1983, especially for 20-year and 50-year floods. Only the flow velocity within the floodplain zone did not increase for the two largest flood scenarios due to the expansion of riparian forest in the second half of the twentieth century. The increase in flow rate was accompanied by a progressive reduction of the extent of flooded area, especially between 1964 and 1983, as well as by increase in mean grain size of channel sediment. Between 1983 and 2012 changes in hydraulic parameters were less pronounced, and coarser and well packed channel sediment dominated on the river bed. Our work demonstrates that reconstruction of past river hydrodynamics, rather than river state at time horizons, can give essential insights into functioning of the river channel and floodplain during the intensification of human impacts after 1950s.},
}

@article {pmid39003629,
year = {2024},
author = {Yao, S and Yin, H and Li, Y and Yang, Q and Yuan, S and Deng, W},
title = {Cytochrome P450 CYP81A104 in Eleusine indica confers resistance to multiherbicide with different modes of action.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.8310},
pmid = {39003629},
issn = {1526-4998},
support = {32372569//National Natural Science Foundation of China/ ; 137050535//Qing Lan Project of Yangzhou University/ ; },
abstract = {BACKGROUND: Developing herbicide-resistant (HR) crop cultivars is an efficient way to control weeds and minimize crop yield losses. However, widespread and long-term herbicide application has led to the evolution of resistant weeds. Here, we established a resistant (R) E. indica population, collected from imidazolinone-resistant rice cultivar fields.

RESULTS: The R population evolved 4.5-fold resistance to imazamox. Acetolactate synthase (ALS) gene sequencing and ALS activity assays excluded the effect of target-site resistance in this population. P450 inhibitor malathion pretreatment significantly reversed resistance to imazamox. RNA sequencing showed that a P450 gene CYP81A104 was expressed higher in R versus susceptible (S) plants. Arabidopsis overexpressing CYP81A104 showed resistance to ALS inhibitors (imazamox, tribenuron-methyl, penoxsulam and flucarbazone-sodium), PSII inhibitor (bentazone), hydroxyphenyl pyruvate dioxygenase inhibitor (mesotrione) and auxin mimics (MCPA), which was generally consistent with the results presented in the R population.

CONCLUSION: This study confirmed that the CYP81A104 gene endowed resistance to multiherbicides with different modes-of-action. Our findings provide an insight into the molecular characteristics of resistance and contribute to formulating an appropriate strategy for weed management in HR crops. © 2024 Society of Chemical Industry.},
}

@article {pmid39002811,
year = {2024},
author = {Huin, V and Blum, D and Delforge, V and Cailliau, E and Djeziri, S and Dujardin, K and Genet, A and Viard, R and Attarian, S and Bruneteau, G and Cassereau, J and Genestet, S and Kaminsky, AL and Soriani, MH and Lefilliatre, M and Couratier, P and Pittion-Vouyovitch, S and Esselin, F and De La Cruz, E and Guy, N and Kolev, I and Corcia, P and Cintas, P and Desnuelle, C and Buée, L and Danel-Brunaud, V and Devos, D and Rolland, AS},
title = {Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.},
journal = {Neurobiology of disease},
volume = {199},
number = {},
pages = {106603},
doi = {10.1016/j.nbd.2024.106603},
pmid = {39002811},
issn = {1095-953X},
abstract = {Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.},
}

@article {pmid39001793,
year = {2024},
author = {Gao, J and Okolo, O and Siedlak, SL and Friedland, RP and Wang, X},
title = {Ferritin is closely associated with microglia in amyotrophic lateral sclerosis.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlae074},
pmid = {39001793},
issn = {1554-6578},
support = {RF1AG066578/NH/NIH HHS/United States ; AARG-22-923849/ALZ/Alzheimer's Association/United States ; },
abstract = {Iron deposition is a hallmark of amyotrophic lateral sclerosis (ALS) and has been strongly implicated in its pathogenesis. As a byproduct of cellular oxidative stress, iron dysregulation modifies basal levels of the regulatory iron-binding protein ferritin. Examination of thoracic and lumbar spinal cord tissues found increased ferritin immunostaining in white matter axons that corresponded to areas of increased microgliosis in 8 ALS patients versus 8 normal subjects. Gray matter areas containing the motor neurons also demonstrated increased ferritin and microglia in ALS compared to controls but at lower levels than in the white matter. Motor neurons with or without TDP-43 inclusions did not demonstrate either increased ferritin or associated microglial activation. We also observed an association of ferritin with microglia in cerebral cortical tissue samples of ALS cases and in the spinal cord tissues of transgenic mice expressing the SOD1G93A mutation. Elevated ferritin levels were detected in the insoluble fraction from spinal cord tissues of individuals with ALS. These findings suggest that activated microglia and increased ferritin may play significant roles in ALS progression since they are found closely associated in areas of axonal and cortical degeneration.},
}

@article {pmid39000814,
year = {2024},
author = {Fan, S and Jing, S and Xu, W and Wu, B and Li, M and Jing, H},
title = {Extraction of Moso Bamboo Parameters Based on the Combination of ALS and TLS Point Cloud Data.},
journal = {Sensors (Basel, Switzerland)},
volume = {24},
number = {13},
pages = {},
pmid = {39000814},
issn = {1424-8220},
support = {LTGC23C160002//Zhejiang Provincial Natural Science Foundation of China/ ; 2021LFR057//Research Fund of Zhejiang A&F University/ ; 2023LFK141//Research Fund of Zhejiang A&F University/ ; },
mesh = {*Algorithms ; Sasa ; Lasers ; Poaceae ; },
abstract = {Extracting moso bamboo parameters from single-source point cloud data has limitations. In this article, a new approach for extracting moso bamboo parameters using airborne laser scanning (ALS) and terrestrial laser scanning (TLS) point cloud data is proposed. Using the field-surveyed coordinates of plot corner points and the Iterative Closest Point (ICP) algorithm, the ALS and TLS point clouds were aligned. Considering the difference in point distribution of ALS, TLS, and the merged point cloud, individual bamboo plants were segmented from the ALS point cloud using the point cloud segmentation (PCS) algorithm, and individual bamboo plants were segmented from the TLS and the merged point cloud using the comparative shortest-path (CSP) method. The cylinder fitting method was used to estimate the diameter at breast height (DBH) of the segmented bamboo plants. The accuracy was calculated by comparing the bamboo parameter values extracted by the above methods with reference data in three sample plots. The comparison results showed that by using the merged data, the detection rate of moso bamboo plants could reach up to 97.30%; the R[2] of the estimated bamboo height was increased to above 0.96, and the root mean square error (RMSE) decreased from 1.14 m at most to a range of 0.35-0.48 m, while the R[2] of the DBH fit was increased to a range of 0.97-0.99, and the RMSE decreased from 0.004 m at most to a range of 0.001-0.003 m. The accuracy of moso bamboo parameter extraction was significantly improved by using the merged point cloud data.},
}

*Algorithms
Sasa
Lasers
Poaceae

@article {pmid39000336,
year = {2024},
author = {Bodai, L and Borosta, R and Ferencz, Á and Kovács, M and Zsindely, N},
title = {The Role of miR-137 in Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {25},
number = {13},
pages = {},
pmid = {39000336},
issn = {1422-0067},
support = {OTKA 145898//National Research, Development and Innovation Office [Hungary]/ ; },
mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; Gene Expression Regulation ; },
abstract = {Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.},
}

*MicroRNAs/genetics/metabolism
Humans
*Neurodegenerative Diseases/genetics/metabolism
Animals
Gene Expression Regulation

@article {pmid39000168,
year = {2024},
author = {Ciuro, M and Sangiorgio, M and Cacciato, V and Cantone, G and Fichera, C and Salvatorelli, L and Magro, G and Leanza, G and Vecchio, M and Valle, MS and Gulino, R},
title = {Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.},
journal = {International journal of molecular sciences},
volume = {25},
number = {13},
pages = {},
pmid = {39000168},
issn = {1422-0067},
support = {2015MJBEM2_006//the Italian "Ministero dell'Istruzione, dell'Università e della Ricerca"/ ; },
mesh = {Animals ; *Motor Neurons/drug effects/metabolism/pathology ; *Mitochondrial Dynamics/drug effects ; Mice ; *Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Cholera Toxin/metabolism ; Saporins ; Quinazolinones/pharmacology ; Neuronal Plasticity/drug effects ; Male ; Mitochondria/drug effects/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.},
}

Animals
*Motor Neurons/drug effects/metabolism/pathology
*Mitochondrial Dynamics/drug effects
Mice
*Disease Models, Animal
*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology
Cholera Toxin/metabolism
Saporins
Quinazolinones/pharmacology
Neuronal Plasticity/drug effects
Male
Mitochondria/drug effects/metabolism

@article {pmid38999592,
year = {2024},
author = {Li, Q and Wang, H and Yu, J and Zhang, W and Guo, W and Liu, Y},
title = {Metabolism-Based Herbicide Resistance to Mesosulfuron-methyl and Identification of Candidate Genes in Bromus japonicus.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {13},
pages = {},
pmid = {38999592},
issn = {2223-7747},
support = {23JCQNJC00450//Tianjin Natural Science Foundation/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; },
abstract = {The evolved resistance of Bromus japonicus Houtt. to ALS-inhibiting herbicides is well established. Previous studies have primarily focused on target-site resistance; however, non-target-site resistance has not been well characterized. This investigation demonstrated that ALS gene sequencing did not detect any previously known resistance mutations in a mesosulfuron-methyl-resistant (MR) population, and notably, treatment with the P450 monooxygenase (P450) inhibitor malathion markedly heightened susceptibility to mesosulfuron-methyl. Utilizing UPLC-MS/MS analysis confirmed elevated mesosulfuron-methyl metabolism in MR plants. The integration of Isoform Sequencing (Iso-Seq) and RNA Sequencing (RNA-Seq) facilitated the identification of candidate genes associated with non-target sites in a subpopulation with two generations of herbicide selection. Through qRT-PCR analysis, 21 differentially expressed genes were characterized, and among these, 10 genes (comprising three P450s, two glutathione S-transferases, one glycosyltransferase, two ATP-binding cassette transporters, one oxidase, and one hydrolase) exhibited constitutive upregulation in resistant plants. Our findings substantiated that increased herbicide metabolism is a driving force behind mesosulfuron-methyl resistance in this B. japonicus population.},
}

@article {pmid37214833,
year = {2024},
author = {Stains, EL and Kennalley, AL and Tian, M and Boehnke, KF and Kraus, CK and Piper, BJ},
title = {United States' qualifying conditions compared to evidence of the 2017 National Academy of Sciences Report.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.05.01.23289286},
pmid = {37214833},
abstract = {OBJECTIVE: To compare the 2017 National Academies of Sciences, Engineering, and Medicine (NAS) report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 to 2024 and to determine if there exist gaps in evidence-based decision making.

METHODS: The 2017 NAS report assessed therapeutic evidence for over twenty medical conditions treated with MC. We identified the QCs of 38 states (including Washington, D.C.) where MC was legal in 2024. We also identified the QCs that these states used in 2017. QCs were then categorized based on NAS-established level of evidence: substantial/conclusive evidence of effectiveness, moderate evidence of effectiveness, limited evidence of effectiveness, limited evidence of ineffectiveness, and no/insufficient evidence to support or refute effectiveness. This study was completed between January 31, 2023 through May 20, 2024.

RESULTS: Most states listed at least one QC with substantial evidence-80.0% of states in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states' QC lists met the standard of substantial evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (chronic pain) was categorized by the NAS as having substantial evidence for effectiveness. However, seven (ALS, Alzheimer's disease, epilepsy, glaucoma, Huntington's disease, Parkinson's disease, spastic spinal cord damage) were rated as either ineffective or insufficient evidence.

CONCLUSION: Most QCs lack evidence for use based on the 2017 NAS report. Many states recommend QCs with little evidence, such as amyotrophic lateral sclerosis (ALS), or even those for which MC is ineffective, like depression. There have been insufficient updates to QCs since the NAS report. These findings highlight a disparity between state-level MC recommendations and the evidence to support them.},
}

@article {pmid38999371,
year = {2024},
author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV},
title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.},
journal = {Journal of clinical medicine},
volume = {13},
number = {13},
pages = {},
pmid = {38999371},
issn = {2077-0383},
abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.},
}

@article {pmid38997748,
year = {2024},
author = {Kato, C and Ueda, K and Morimoto, S and Takahashi, S and Nakamura, S and Ozawa, F and Ito, D and Daté, Y and Okada, K and Kobayashi, N and Nakahara, J and Okano, H},
title = {Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.},
journal = {Inflammation and regeneration},
volume = {44},
number = {1},
pages = {32},
pmid = {38997748},
issn = {1880-9693},
support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; },
abstract = {BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.

METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.

RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.

CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.},
}

@article {pmid38997636,
year = {2024},
author = {Karagianni, K and Dafou, D and Xanthopoulos, K and Sklaviadis, T and Kanata, E},
title = {RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {30},
number = {1},
pages = {101},
pmid = {38997636},
issn = {1528-3658},
support = {01146//Hellenic Foundation for Research and Innovation (H.F.R.I.) under the "2nd Call for H.F.R.I. Research Projects to support Post-Doctoral Researchers"/ ; 10829//Hellenic Foundation for Research and Innovation (H.F.R.I.) under the 4th Call for H.F.R.I. PhD Fellowships/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *RNA Editing ; Humans ; *Frontal Lobe/metabolism ; *Synapses/metabolism/genetics ; Transcriptome ; Gene Expression Profiling ; Glutamic Acid/metabolism ; Computational Biology/methods ; Male ; Female ; Gene Expression Regulation ; Middle Aged ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis.

METHODS: We aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group).

RESULTS: We identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study.

CONCLUSIONS: We provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism
*RNA Editing
Humans
*Frontal Lobe/metabolism
*Synapses/metabolism/genetics
Transcriptome
Gene Expression Profiling
Glutamic Acid/metabolism
Computational Biology/methods
Male
Female
Gene Expression Regulation
Middle Aged

@article {pmid38997630,
year = {2024},
author = {Staderini, T and Bigi, A and Lagrève, C and Marzi, I and Bemporad, F and Chiti, F},
title = {Biophysical characterization of the phase separation of TDP-43 devoid of the C-terminal domain.},
journal = {Cellular & molecular biology letters},
volume = {29},
number = {1},
pages = {104},
pmid = {38997630},
issn = {1689-1392},
support = {AriSLA//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; project TDP-43-STRUCT//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; PRIN Project 2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; Fondi di Ateneo 2021//Università degli studi di Firenze/ ; },
mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *Protein Domains ; Fluorescence Recovery After Photobleaching ; Phase Separation ; },
abstract = {BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are associated with deposition of cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons. One complexity of this process lies in the ability of TDP-43 to form liquid-phase membraneless organelles in cells. Previous work has shown that the recombinant, purified, prion-like domain (PrLD) forms liquid droplets in vitro, but the behaviour of the complementary fragment is uncertain.

METHODS: We have purified such a construct without the PrLD (PrLD-less TDP-43) and have induced its phase separation using a solution-jump method and an array of biophysical techniques to study the morphology, state of matter and structure of the TDP-43 assemblies.

RESULTS: The fluorescent TMR-labelled protein construct, imaged using confocal fluorescence, formed rapidly (< 1 min) round, homogeneous and 0.5-1.0 µm wide assemblies which then coalesced into larger, yet round, species. When labelled with AlexaFluor488, they initially exhibited fluorescence recovery after photobleaching (FRAP), showing a liquid behaviour distinct from full-length TDP-43 and similar to PrLD. The protein molecules did not undergo major structural changes, as determined with circular dichroism and intrinsic fluorescence spectroscopies. This process had a pH and salt dependence distinct from those of full-length TDP-43 and its PrLD, which can be rationalized on the grounds of electrostatic forces.

CONCLUSIONS: Similarly to PrLD, PrLD-less TDP-43 forms liquid droplets in vitro through liquid-liquid phase separation (LLPS), unlike the full-length protein that rather undergoes liquid-solid phase separation (LSPS). These results offer a rationale of the complex electrostatic forces governing phase separation of full-length TDP-43 and its fragments. On the one hand, PrLD-less TDP-43 has a low pI and oppositively charged domains, and LLPS is inhibited by salts, which attenuate inter-domain electrostatic attractions. On the other hand, PrLD is positively charged due to a high isoionic point (pI) and LLPS is therefore promoted by salts and pH increases as they both reduce electrostatic repulsions. By contrast, full-length TDP-43 undergoes LSPS most favourably at its pI, with positive and negative salt dependences at lower and higher pH, respectively, depending on whether repulsive or attractive forces dominate, respectively.},
}

*DNA-Binding Proteins/metabolism/chemistry
Humans
*Protein Domains
Fluorescence Recovery After Photobleaching
Phase Separation

@article {pmid38996790,
year = {2024},
author = {Alqahtani, A and Alsubai, S and Sha, M and Dutta, AK and Zhang, YD},
title = {Intellectual assessment of amyotrophic lateral sclerosis using deep resemble forward neural network.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {178},
number = {},
pages = {106478},
doi = {10.1016/j.neunet.2024.106478},
pmid = {38996790},
issn = {1879-2782},
abstract = {ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disorder causing profound physical disability that severely impairs a patient's life expectancy and quality of life. It also leads to muscular atrophy and progressive weakness of muscles due to insufficient nutrition in the body. At present, there are no disease-modifying therapies to cure ALS, and there is a lack of preventive tools. The general clinical assessments are based on symptom reports, neurophysiological tests, neurological examinations, and neuroimaging. But, these techniques possess various limitations of low reliability, lack of standardized protocols, and lack of sensitivity, especially in the early stages of disease. So, effective methods are required to detect the progression of the disease and minimize the suffering of patients. Extensive studies concentrated on investigating the causes of neurological disease, which creates a barrier to precise identification and classification of genes accompanied with ALS disease. Hence, the proposed system implements a deep RSFFNNCNN (Resemble Single Feed Forward Neural Network-Convolutional Neural Network) algorithm to effectively classify the clinical associations of ALS. It involves the addition of custom weights to the kernel initializer and neutralizer 'k' parameter to each hidden layer in the network. This is done to increase the stability and learning ability of the classifier. Additionally, the comparison of the proposed approach is performed with SFNN (Single Feed NN) and ML (Machine Learning) based algorithms, namely, NB (Naïve Bayes), XGBoost (Extreme Gradient Boosting) and RF (Random Forest), to estimate the efficacy of the proposed model. The reliability of the proposed algorithm is measured by deploying performance metrics such as precision, recall, F1 score, and accuracy.},
}

@article {pmid38996764,
year = {2024},
author = {Montero, AS and Aliouat, I and Ribon, M and Canney, M and Goldwirt, L and Mourah, S and Berriat, F and Lobsiger, CS and Pradat, PF and Salachas, F and Bruneteau, G and Carpentier, A and Boillée, S},
title = {Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.},
journal = {EBioMedicine},
volume = {106},
number = {},
pages = {105235},
doi = {10.1016/j.ebiom.2024.105235},
pmid = {38996764},
issn = {2352-3964},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).

METHODS: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.

FINDINGS: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.

INTERPRETATION: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.

FUNDING: Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).},
}

@article {pmid38995133,
year = {2024},
author = {Bacigalupo, I and Finocchietti, M and Paoletti, O and Bargagli, AM and Brunori, P and Lombardi, N and Sciancalepore, F and Agabiti, N and Kirchmayer, U},
title = {Incidenza e prevalenza della sclerosi laterale amiotrofica in tre Regioni italiane: uno studio basato sugli archivi amministrativi sanitari.},
journal = {Epidemiologia e prevenzione},
volume = {48},
number = {3},
pages = {201-209},
doi = {10.19191/EP24.3.A710.055},
pmid = {38995133},
issn = {1120-9763},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Italy/epidemiology ; Incidence ; Prevalence ; Male ; Aged ; Female ; Retrospective Studies ; Middle Aged ; Adult ; Databases, Factual ; Aged, 80 and over ; Sex Distribution ; Adolescent ; Archives ; Algorithms ; Young Adult ; Age Distribution ; },
abstract = {OBJECTIVES: to estimate Amyotrophic Lateral Sclerosis (ALS) incidence and prevalence in three Italian Regions (Lazio, Tuscany, and Umbria), using health administrative databases.

DESIGN: retrospective population-based study.

SETTING AND PARTICIPANTS: ALS patients residing in Lazio, Umbria, and Tuscany were identified through an algorithm based on three different administrative databases: hospital discharge records, exemptions from health care co-payment, and emergency departments (study period 2014-2019). Crude, age- and gender-specific prevalence were calculated on 31.12.2019 and incidence rates of ALS were standardised by region, year, and gender between 2014-2019. Using a clinical dataset available in the Lazio Region, the proportion of individuals residing in the region correctly identified as ALS cases by the algorithm were calculated.

MAIN OUTCOMES MEASURES: prevalence and incidence rates.

RESULTS: a total of 1,031 ALS patients (>=18 years) were identified: 408 cases in Tuscany, 546 in Lazio, and 77 in Umbria. ALS standardised prevalence (per 100,000) was similar among regions: 12.31 in Tuscany, 11.52 in Lazio, and 9.90 in Umbria. The 5-year crude rates were higher in men, and in people aged 65-79 years. Among 310 patients included in the clinical dataset, 263 (84.8%) were correctly identified by the algorithm based on health administrative databases.

CONCLUSIONS: ALS prevalence and incidence in three Central Italy Regions are rather similar, but slightly higher than those previously reported. This finding is plausible, given that previous results relate to at least ten years ago and evidenced increasing trends. Overall, the results of this paper encourage the use of administrative data to produce occurrence estimates, useful to both epidemiological surveillance and research and healthcare policies.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology
Italy/epidemiology
Incidence
Prevalence
Male
Aged
Female
Retrospective Studies
Middle Aged
Adult
Databases, Factual
Aged, 80 and over
Sex Distribution
Adolescent
Archives
Algorithms
Young Adult
Age Distribution

@article {pmid38992244,
year = {2024},
author = {von Herbing, IH},
title = {Energetic Costs of Stress in Developing Fishes: Quantifying Allostasis and Allostatic Load.},
journal = {Integrative and comparative biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/icb/icae094},
pmid = {38992244},
issn = {1557-7023},
abstract = {Stress exerts negative effects on fish health through stimulation of the hypothalamic-pituitary-interrenal (HPI) axis and autonomic nervous system (ANS), resulting in heightened neural and neuroendocrine responses. Energetic investment and physiological adaptation are then required to re-establish homeostatic stability or reach a new allostatic state. The cost of the energetic investment is referred to as allostatic load (AL). While determining the sources of stress and assessing their consequences have resulted in estimates of AL, most of this work has been conducted in adult mammals and humans; no ALs exist for developing fish. From a series of experiments on a model species, zebrafish (Danio rerio) which yolk-sac larvae were exposed to two chronic stressors (high-temperature and hypoxia) ALs were quantified based on biomarkers of ontogenetic changes in growth, morphometrics, and metabolic activities. Results showed that for zebrafish yolk-sac larvae, chronic stress imposed high AL and, thus, high total allostatic energetic costs, (Rt (AL)), because of prolonged energy demand in the face of limited resources (e.g., yolk). Under severe chronic stress, energetic costs were sufficiently large that energy-limited developing fish may not be able to fully compensate, resulting in maladaptive responses from allostatic overload, leading either to death or to novel allostatic states, possibly more resilient to environmental change.},
}

@article {pmid38991324,
year = {2024},
author = {Reis, J and Spencer, PS},
title = {An introduction to environmental neurotoxicology: Lessons from a clinical perspective.},
journal = {Journal of the neurological sciences},
volume = {463},
number = {},
pages = {123108},
doi = {10.1016/j.jns.2024.123108},
pmid = {38991324},
issn = {1878-5883},
abstract = {In 1992, the Committee on Neurotoxicology and Models for Assessing Risk of the National Academy of Sciences in Washington DC focused with a scientific perspective on the identification of substances with neurotoxic potential, studies of exposed populations, risk assessment, and biologic markers of disease. This Committee recommended: "all physicians should be trained to take a thorough occupational-exposure history and to be aware of other possible sources of toxic exposure". Although convened after several outbreaks of neurotoxic syndromes, clinical neurological considerations were lacking. After defining keys words, namely Environment, Neurotoxicology and Neurotoxicants, we present some demonstrative cases; e.g., the Epidemic Neuropathy in Cuba, Minamata disease, ALS/PDC on Guam, and the ALS hot spot in the French Alps. Always with a clinical and practical approach, we will then review the milieux that contain and convey potential neurotoxicants, the different exposure routes and the clinical presentations. Drawing lessons from clinical cases, we offer some thoughts concerning the future of Environmental Neurotoxicology (ENT). Pointing notably to the diffuse chemical contamination of ecosystems and living beings, including Homo sapiens, we question the real impact of agents with neurotoxic potential on the human brain, considering the effects, for example, of air pollution, endocrine disruptors and nanoparticles. Concern is expressed over the lack of knowledge of the non-monotonic kinetics of many of these chemicals, the major concern being related to mixtures and low-dose exposures, as well as the delayed appearance in clinical expression of prevalent neurodegenerative diseases.},
}

@article {pmid38991167,
year = {2024},
author = {Cave, R},
title = {How People Living With Amyotrophic Lateral Sclerosis Use Personalized Automatic Speech Recognition Technology to Support Communication.},
journal = {Journal of speech, language, and hearing research : JSLHR},
volume = {},
number = {},
pages = {1-17},
doi = {10.1044/2024_JSLHR-24-00097},
pmid = {38991167},
issn = {1558-9102},
abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive, ultimately fatal disease causing progressive muscular weakness. Most people living with ALS (plwALS) experience dysarthria, eventually becoming unable to communicate using natural speech. Many wish to use speech for as long as possible. Personalized automated speech recognition (ASR) model technology, such as Google's Project Relate, is argued to better recognize speech with dysarthria, supporting maintenance of understanding through real-time captioning. The objectives of this study are how plwALS and communication partners use Relate in everyday conversation over a period of up to 12 months and how it may change with any decline in speech over time.

METHOD: This study videoed interactions between three plwALS and communication partners. We assessed ASR caption accuracy and how well they preserved meaning. Conversation analysis was used to identify participants' own organizational practices in the accomplishment of interaction. Thematic analysis was used to understand better the participants' experiences of using ASR captions.

RESULTS: All plwALS reported lower-than-expected ASR accuracy when used in conversation and felt ASR captioning was only useful in certain contexts. All participants liked the concept of live captioning and were hopeful that future improvements to ASR accuracy may support their communication in everyday life.

CONCLUSIONS: Training is needed on best practices for customization and practical use of ASR technology and for the limitations of ASR in conversational settings. Support is needed for those less confident with technology and to reduce misplaced allocation of ownership of captioning errors, risking negative effects on psychological well-being.},
}

@article {pmid38990927,
year = {2024},
author = {Srinivasan, V and Homer, V and Barton, D and Clutterbuck-James, A and Jenkins, S and Potter, C and Brock, K and Logan, A and Smith, D and Bruce, L and Nagy, Z and Bach, SP},
title = {A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial.},
journal = {PloS one},
volume = {19},
number = {7},
pages = {e0291285},
pmid = {38990927},
issn = {1932-6203},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; Treatment Outcome ; Adult ; Neuroprotective Agents/therapeutic use/administration & dosage/adverse effects ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics.

PATIENTS AND METHODS: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28.

FINDINGS: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection.

INTERPRETATION: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Male
Female
Middle Aged
Aged
Prospective Studies
Treatment Outcome
Adult
Neuroprotective Agents/therapeutic use/administration & dosage/adverse effects

@article {pmid38990842,
year = {2024},
author = {Yip, PK and Pizzasegola, C and Gladman, S and Biggio, ML and Marino, M and Jayasinghe, M and Ullah, F and Dyall, SC and Malaspina, A and Bendotti, C and Michael-Titus, A},
title = {Correction: The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis.},
journal = {PloS one},
volume = {19},
number = {7},
pages = {e0307246},
pmid = {38990842},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0061626.].},
}

@article {pmid38989937,
year = {2025},
author = {Locatelli, M and Farina, C},
title = {Role of copper in central nervous system physiology and pathology.},
journal = {Neural regeneration research},
volume = {20},
number = {4},
pages = {1058-1068},
doi = {10.4103/NRR.NRR-D-24-00110},
pmid = {38989937},
issn = {1673-5374},
abstract = {Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.},
}

@article {pmid38989900,
year = {2024},
author = {Marchica, V and Biasetti, L and Barnard, J and Li, S and Nikolaou, N and Frosch, MP and Lucente, DE and Eldaief, M and King, A and Fanto, M and Troakes, C and Houart, C and Smith, BN},
title = {Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissue.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awae226},
pmid = {38989900},
issn = {1460-2156},
abstract = {Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small-alpha helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterised the phenotypes induced by a genetic loss of function (LoF) and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human WT Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterised by Lamin B2 mis-localisation. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS+/-FTD patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.},
}

@article {pmid38989463,
year = {2024},
author = {Pasternack, N and Doucet-O'Hare, T and Johnson, K and , and Paulsen, O and Nath, A},
title = {Endogenous retroviruses are dysregulated in ALS.},
journal = {iScience},
volume = {27},
number = {7},
pages = {110147},
pmid = {38989463},
issn = {2589-0042},
abstract = {Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease with no cure. Human endogenous retroviruses (HERVs) have been implicated in its pathogenesis but their relevance to ALS is not fully understood. We examined bulk RNA-seq data from almost 2,000 ALS and unaffected control samples derived from the cortex and spinal cord. Using different methods of feature selection, including differential expression analysis and machine learning, we discovered that transcription of HERV-K loci 1q22 and 8p23.1 were significantly upregulated in the spinal cord of individuals with ALS. Additionally, we identified a subset of ALS patients with upregulated HERV-K expression in the cortex and spinal cord. We also found the expression of HERV-K loci 19q11 and 8p23.1 was correlated with protein coding genes previously implicated in ALS and dysregulated in ALS patients in this study. These results clarify the association of HERV-K and ALS and highlight specific genes in the pathobiology of late-stage ALS.},
}

@article {pmid38988889,
year = {2024},
author = {Ansari, U and Alam, M and Nadora, D and Muttalib, Z and Chen, V and Taguinod, I and FitzPatrick, M and Wen, J and Ansari, Z and Lui, F},
title = {Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review.},
journal = {AIMS neuroscience},
volume = {11},
number = {2},
pages = {166-177},
pmid = {38988889},
issn = {2373-7972},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and intricate neurodegenerative disease that impacts upper and lower motor neurons within the central nervous system, leading to their progressive destruction. Despite extensive research, the pathogenesis of this multifaceted disease remains elusive. The United States Food and Drug Administration (FDA) has granted approval for seven medications designed to address ALS and mitigate its associated symptoms. These FDA-sanctioned treatments are Qalsody, Relyvrio, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. In this review, the effects of these seven drugs on ALS based on their mechanism of action, dosing, and clinical presentations are comprehensively summarized. Each medication offers a distinct approach to manage ALS, aiming to alleviate the burdensome symptoms and slow the disease's progression, thereby improving the quality of life for individuals affected by this neurological condition. However, despite these advancements in pharmaceutical interventions, finding a definitive cure for ALS remains a significant challenge. Continuous investigation into ALS pathophysiology and therapeutic avenues remains imperative, necessitating further research collaborations and innovative approaches to unravel the complex mechanisms underlying this debilitating condition.},
}

@article {pmid38988205,
year = {2024},
author = {Arnaldi, P and Casarotto, E and Relucenti, M and Bellese, G and Gagliani, MC and Crippa, V and Castagnola, P and Cortese, K},
title = {A NSC-34 cell line-derived spheroid model: Potential and challenges for in vitro evaluation of neurodegeneration.},
journal = {Microscopy research and technique},
volume = {},
number = {},
pages = {},
doi = {10.1002/jemt.24651},
pmid = {38988205},
issn = {1097-0029},
support = {PRIN2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; PRIN2022KSJZF5//Ministero dell'Università e della Ricerca/ ; //University of Genoa/ ; 100008-2022-KC-FRA_ANATOMIA//Fondi Ricerca Ateneo/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; //University of Genoa/ ; },
abstract = {Three-dimensional (3D) spheroid models aim to bridge the gap between traditional two-dimensional (2D) cultures and the complex in vivo tissue environment. These models, created by self-clustering cells to mimic a 3D environment with surrounding extracellular framework, provide a valuable research tool. The NSC-34 cell line, generated by fusing mouse spinal cord motor neurons and neuroblastoma cells, is essential for studying neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), where abnormal protein accumulation, such as TAR-DNA-binding protein 43 (TDP-43), occurs in affected nerve cells. However, NSC-34 behavior in a 3D context remains underexplored, and this study represents the first attempt to create a 3D model to determine its suitability for studying pathology. We generated NSC-34 spheroids using a nonadhesive hydrogel-based template and characterized them for 6 days. Light microscopy revealed that NSC-34 cells in 3D maintained high viability, a distinct round shape, and forming stable membrane connections. Scanning electron microscopy identified multiple tunnel-like structures, while ultrastructural analysis highlighted nuclear bending and mitochondria alterations. Using inducible GFP-TDP-43-expressing NSC-34 spheroids, we explored whether 3D structure affected TDP-43 expression, localization, and aggregation. Spheroids displayed nuclear GFP-TDP-43 expression, albeit at a reduced level compared with 2D cultures and generated both TDP-35 fragments and TDP-43 aggregates. This study sheds light on the distinctive behavior of NSC-34 in 3D culture, suggesting caution in the use of the 3D model for ALS or TDP-43 pathologies. Yet, it underscores the spheroids' potential for investigating fundamental cellular mechanisms, cell adaptation in a 3D context, future bioreactor applications, and drug penetration studies. RESEARCH HIGHLIGHTS: 3D spheroid generation: NSC-34 spheroids, developed using a hydrogel-based template, showed high viability and distinct shapes for 6 days. Structural features: advanced microscopy identified tunnel-like structures and nuclear and mitochondrial changes in the spheroids. Protein dynamics: the study observed how 3D structures impact TDP-43 behavior, with altered expression but similar aggregation patterns to 2D cultures. Research implications: this study reveals the unique behavior of NSC-34 in 3D culture, suggests a careful approach to use this model for ALS or TDP-43 pathologies, and highlights its potential in cellular mechanism research and drug testing applications.},
}

@article {pmid38988008,
year = {2024},
author = {Murakami, A and Koga, S and Fujioka, S and White, AE and Bieniek, KF and Sekiya, H and DeJesus-Hernandez, M and Finch, NA and van Blitterswijk, M and Nakamura, M and Tsuboi, Y and Murray, ME and Wszolek, ZK and Dickson, DW},
title = {Upper motor neuron-predominant motor neuron disease presenting as atypical parkinsonism: A clinicopathological study.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e13286},
doi = {10.1111/bpa.13286},
pmid = {38988008},
issn = {1750-3639},
support = {P30-AG062677/GF/NIH HHS/United States ; U54-NS100693/GF/NIH HHS/United States ; P01-AG03949/GF/NIH HHS/United States ; R01-AG062348/GF/NIH HHS/United States ; 1U19AG063911/GF/NIH HHS/United States ; RF1-NS123052/GF/NIH HHS/United States ; R01-NS121125/GF/NIH HHS/United States ; FAIN: U19AG063911/GF/NIH HHS/United States ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by upper and lower motor neuron signs. There are, however, cases where upper motor neurons (UMNs) are predominantly affected, leading to clinical presentations of UMN-dominant ALS or primary lateral sclerosis. Furthermore, cases exhibiting an UMN-predominant pattern of motor neuron disease (MND) presenting with corticobasal syndrome (CBS) have been sparsely reported. This study aims to clarify the clinicopathological features of patients with UMN-predominant MND. We reviewed 24 patients with UMN-predominant MND with TDP-43 pathology in the presence or absence of frontotemporal lobar degeneration. Additionally, we reviewed the medical records of patients with pathologically-confirmed corticobasal degeneration (CBD) who received a final clinical diagnosis of CBS (n = 10) and patients with pathologically-confirmed progressive supranuclear palsy (PSP) who received a final clinical diagnosis of PSP syndrome (n = 10). Of 24 UMN-predominant MND patients, 20 had a clinical diagnosis of an atypical parkinsonian disorder, including CBS (n = 11) and PSP syndrome (n = 8). Only two patients had antemortem diagnoses of motor neuron disease. UMN-predominant MND patients with CBS less frequently exhibited apraxia than those with CBD, and they were less likely to meet clinical criteria for possible or probable CBS. Similarly, UMN-predominant MND patients with PSP syndrome less often met clinical criteria for probable PSP than PSP patients with PSP syndrome. Our findings suggest that UMN-predominant MND can mimic atypical parkinsonism, and should be considered in the differential diagnosis of CBS and PSP syndrome, in particular when criteria are not met.},
}

@article {pmid38987905,
year = {2024},
author = {Bergem, AK and Aamotsmo, T},
title = {Navigating parenthood in the face of amyotrophic lateral sclerosis: A qualitative exploration of partner experiences.},
journal = {Scandinavian journal of caring sciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/scs.13282},
pmid = {38987905},
issn = {1471-6712},
abstract = {INTRODUCTION: Among people diagnosed with Amyotrophic Lateral Sclerosis (ALS), there are parents with children living at home. Children in families experiencing severe illness are exposed to stress and health risks. Since 2010, healthcare personnel in Norway must assess whether patients have children under 18 years of age and make sure the children's needs for support are met. A child's ability to cope with family life affected by a serious illness depends on how the parent without the disease manages the situation. Little is known about how the partner of someone affected by ALS manages being next of kin and a parent simultaneously, and what kind of support they need.

METHODS: During 2021-2022, six semi-structured interviews were conducted with partners to persons with ALS, whom had children living at home. The interviews were transcribed verbatim and analysed through qualitative content analysis.

RESULTS: Three themes with subthemes emerged: (1) Together, yet alone; (a) restricted home life, (b) missing the sharing of responsibilities and tasks as equal parents, and (c) caught between children's and partner's needs; (2) Experience of coping while waiting for death; (a) cherishing the moments, (b) sense of coping and concern, and (c) ensuring to get recharged; and (3) Support in times of need; (a) difficult to ask the network for help and (b) the healthcare system does not see the whole family.

CONCLUSIONS: Our respondents felt alone, caught between the needs of their children and partner, without necessary support from the services, and were left to handle everyday life with all new challenges on their own. Future healthcare services need to consider the challenges faced by families dealing with life-limiting illnesses. A family-focused perspective is needed, so is peer support and interventions that address both emotional and practical aspects of life with an ill partner.},
}

@article {pmid38987226,
year = {2024},
author = {Luo, X and Heydari, A and Renfrey, D and Gardner, Z and He, S and Tang, Y and Weiss, G and Rogers, ML and Raston, C},
title = {Sustainability-Driven Accelerated Shear-Mediated Immunoassay for Amyotrophic Lateral Sclerosis Detection.},
journal = {ChemSusChem},
volume = {},
number = {},
pages = {e202401008},
doi = {10.1002/cssc.202401008},
pmid = {38987226},
issn = {1864-564X},
abstract = {Healthcare facilities produce millions of tons of waste annually, with a significant portion consisting of diagnostic plasticware. Here, we introduce a new detection platform that completely replaces traditional assay plates with a piece of membrane, offering a much greener and more sustainable alternative. The membrane, integrated within the portable vortex fluidic device (P-VFD), enables rapid detection of a clinically relevant protein biomarker, urinary p75ECD. This biomarker is utilized to evaluate the prognosis, disease severity, and progression of amyotrophic lateral sclerosis (ALS). This assay has a limit-of-detection (LOD) of 4.03 pg, which is comparable to the plate-based assay (2.24 pg) and has been optimized through a full factorial design of experiments (DOE). P-VFD has great potential in quantifying p75ECD in human biofluids and can significantly reduce the assay time to 5 min compared to the current plate-based p75ECD ELISA assay (3 days), with at least a 4.4-fold reduction in the usage of the detection antibody.},
}

@article {pmid38986433,
year = {2024},
author = {Rifai, OM and Waldron, FM and Sleibi, D and O'Shaughnessy, J and Leighton, DJ and Gregory, JM},
title = {Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e13287},
doi = {10.1111/bpa.13287},
pmid = {38986433},
issn = {1750-3639},
support = {1R01NS127186/NS/NINDS NIH HHS/United States ; BB-2022-C4-L2//Target ALS/ ; 108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)-related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole-exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss-of-function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP-43 (pTDP-43) aggregates, in the motor cortex compared to age- and sex-matched control tissue. We show pathological, cytoplasmic TDP-43 aggregates in all three NEK1-ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1-ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1-positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co-occurring TDP-43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP-43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1-ALS.},
}

@article {pmid38984697,
year = {2024},
author = {Hasan, M and Alam, SM and Rahman, HZ and Khan, MAS and Huq, MR},
title = {Autonomic Dysfunction in Amyotrophic Lateral Sclerosis - A Case-Control Study.},
journal = {Acta medica academica},
volume = {53},
number = {1},
pages = {24-34},
pmid = {38984697},
issn = {1840-2879},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Case-Control Studies ; Female ; Male ; Middle Aged ; Adult ; Bangladesh/epidemiology ; *Autonomic Nervous System Diseases/physiopathology/etiology ; Galvanic Skin Response/physiology ; Autonomic Nervous System/physiopathology ; },
abstract = {INTRODUCTION: This study aimed to explore autonomic nervous system involvement in amyotrophic lateral sclerosis (ALS) patients by evaluating sympathetic skin response (SSR).

MATERIALS AND METHODS: The study included 35 sporadic (ALS) patients (cases), and 35 healthy age and sex-matched participants (controls) aged <60 years. SSR was recorded in the electrophysiology lab of the Neurology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Patients with diseases associated with peripheral or autonomic neuropathy were excluded. Prolonged latency (delayed SSR) or an absent response was considered abnormal SSR.

RESULTS: SSR was found to be abnormal in 17 (48.6 %) ALS cases, with an absent response in the upper limbs of six cases (17.1%). Abnormal SSR was more prevalent in the lower limbs, with 33 (94.3%) and 20 (57.1%) cases having a delayed or absent response, respectively. In comparison, SSR was normal in all control participants (P-value <0.05). Abnormal SSR was significantly more common in the lower limbs of ALS cases with bulbar palsy than those without bulbar palsy (P-value=0.04). There was no association of SSR with disease severity and duration.

CONCLUSION: ALS is significantly associated with abnormal SSR, indicating autonomic nervous system involvement. There could also be an association between bulbar palsy and abnormal SSR among ALS patients. Further studies should be carried out to determine the association of abnormal SSR with disease severity, duration, and type.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology
Case-Control Studies
Female
Male
Middle Aged
Adult
Bangladesh/epidemiology
*Autonomic Nervous System Diseases/physiopathology/etiology
Galvanic Skin Response/physiology
Autonomic Nervous System/physiopathology

@article {pmid38984619,
year = {2024},
author = {Olney, N and Weiss, MD},
title = {Real world experience with sodium phenylbutyrate-taurursodiol for ALS: Lessons learned from a failed drug.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28203},
pmid = {38984619},
issn = {1097-4598},
}

@article {pmid38984582,
year = {2024},
author = {Jiang, S and Nie, H and Hua, S and Xie, M and Xu, R},
title = {Preliminary Analysis of Potentially Overlapping Differentially Expressed Proteins in Both the Spinal Cord and Brain of SOD1 G93A Mice.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037293525240621120033},
pmid = {38984582},
issn = {1875-5550},
abstract = {OBJECTIVE: Proteomic elucidation is an essential step in improving our understanding of the biological properties of proteins in amyotrophic lateral sclerosis (ALS).

METHODS: Preliminary proteomic analysis was performed on the spinal cord and brain of SOD1 G93A (TG) and wild-type (WT) mice using isobaric tags for relative and absolute quantitation.

RESULTS: Partial up- and downregulated proteins showing significant differences between TG and WT mice were identified, of which 105 proteins overlapped with differentially expressed proteins in both the spinal cord and brain of progression mice. Bioinformatic analyses using Gene Ontology, a cluster of orthologous groups, and Kyoto Encyclopedia of Genes and Genomes pathway revealed that the significantly up- and downregulated proteins represented multiple biological functions closely related to ALS, with 105 overlapping differentially expressed proteins in the spinal cord and brain at the progression stage of TG mice closely related to 122 pathways. Differentially expressed proteins involved in a set of molecular functions play essential roles in maintaining neural cell survival.

CONCLUSION: This study provides additional proteomic profiles of TG mice, including potential overlapping proteins in both the spinal cord and brain that participate in pathogenesis, as well as novel insights into the up- and downregulation of proteins involved in the pathogenesis of ALS.},
}

@article {pmid38982381,
year = {2024},
author = {Mioshi, E and Heal, S and Katangwe-Chigamba, T},
title = {'A lightbulb moment': carers' experiences of behavioural symptoms in motor neurone disease before and after MiNDToolkit.},
journal = {BMC neurology},
volume = {24},
number = {1},
pages = {238},
pmid = {38982381},
issn = {1471-2377},
support = {934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; 934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; },
mesh = {Humans ; *Caregivers/psychology ; Male ; *Motor Neuron Disease/psychology/therapy ; Female ; Middle Aged ; *Behavioral Symptoms/therapy/etiology ; Aged ; Adult ; Qualitative Research ; },
abstract = {BACKGROUND: To explore carers' experiences of behavioural symptoms in Motor Neurone Disease (MND), before and after using the MiNDToolkit, a novel internet-based psychoeducational intervention to support management of behavioural symptoms (BehSymp) in MND. The study also investigated carers' views and acceptability of MiNDToolkit.

METHODS: A qualitative process evaluation of carers engagement with, and acceptability of, the MiNDToolkit conducted using semi-structured interviews with carers (n = 11). All interviews were audio-recorded, professionally transcribed verbatim and analysed thematically.

RESULTS: Five themes were identified: (1) In the dark: carers' experiences and reactions to BehSymp; (2) Others can see: the role of HCPs in identifying symptoms - and perceived opportunities for carers to receive support; (3) Shedding light: carers implementation and perceived impact of the MiNDToolkit content; (4) Acceptability and carers' engagement with MiNDToolkit; (5) Future implementation. Carers' experience of BehSymp was particularly distressing when symptoms were apparently out of context. MiNDToolkit appeared to support learning that BehSymp were part of MND. Content resonated with carers, who reported learning about the full picture of MND, which led to acceptance and use of newly learned strategies. Engagement with the platform was good, with varied input from HCPs. Greater and nuanced involvement from HCPs seem important to support management of BehSymp. Recommendations for a full-scale trial emerged, including adding a paper booklet to accompany the intervention and creation of new modules on emotional lability, changes in relationships, and transitioning to a care home.

CONCLUSIONS: MiNDToolkit was acceptable to carers overall. Recommended improvements should be actioned in a full-scale trial.},
}

Humans
*Caregivers/psychology
Male
*Motor Neuron Disease/psychology/therapy
Female
Middle Aged
*Behavioral Symptoms/therapy/etiology
Aged
Adult
Qualitative Research

@article {pmid38981325,
year = {2024},
author = {Asghar, H and Tariq, A and Rasool, G and Hayat, A},
title = {Fabrication of a salivary amylase electrochemical sensor based on surface confined MWCNTs/β-cyclodextrin/starch architect for dental caries in clinical samples.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {160},
number = {},
pages = {108774},
doi = {10.1016/j.bioelechem.2024.108774},
pmid = {38981325},
issn = {1878-562X},
abstract = {Salivary α-amylase (α-ALS) has drawn attention as a possible bioindicator for dental caries. Herein, combining the synergistic properties of multi-walled carbon nanotubes (MWCNTs), β-cyclodextrin (β-CD) and starch, an electrochemical sensor is constructed employing ferrocene (FCN) as an electrochemical indicator to oversee the progression of the enzymatic catalysis of α-ALS. The method involves a two-step chemical reaction sequence on a screen-printed carbon electrode (SPCE). X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Field emission scanning electron microscope (FE-SEM), and Dynamic light scattering (DLS) were used to characterize the synthesized material, while Static water Contact angle measurements, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) were performed to monitor each step of sensor fabrication. The electrochemical sensor permitted to detect α-ALS within the linear range of 0.5-280 U mL[-1], revealing detection (LOD), and quantification (LOQ) values of 0.041 U mL[-1], and 0.159 U mL[-1], respectively. Remarkably, the sensor demonstrated exceptional specificity and selectivity, effectively discriminating against other interfering substances in saliva. Validation of the method involved analyzing α-ALS levels in artificial saliva with an accuracy range of 97 % to 103 %, as well as in real clinical saliva samples across various age groups.},
}

@article {pmid38979291,
year = {2024},
author = {Weiss, A and Gilbert, JW and Flores, IVR and Belgrad, J and Ferguson, C and Dogan, EO and Wightman, N and Mocarski, K and Echeverria, D and Summers, A and Bramato, B and McHugh, N and Furgal, R and Yamada, N and Cooper, D and Monopoli, K and Godinho, BMDC and Hassler, MR and Yamada, K and Greer, PL and Henninger, N and Brown, RH and Khvorova, A},
title = {RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38979291},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA [SOD1] extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.},
}

@article {pmid38979278,
year = {2024},
author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B},
title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.06.25.600403},
pmid = {38979278},
issn = {2692-8205},
abstract = {Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system [1] . Human genetic studies established a causal role for protein assembly in neurodegeneration [2] . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains [1] . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B [3,4] . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.},
}

@article {pmid38979270,
year = {2024},
author = {Baghel, MS and Burns, GD and Tsapatsis, M and Peethambaran Mallika, A and Cruz, ALF and Cao, T and Chen, XK and Rosa, I and Marx, SR and Ye, Y and Sun, S and Li, T and Wong, PC},
title = {Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38979270},
issn = {2692-8205},
abstract = {UNLABELLED: TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp [f/f] mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp [f/f] mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.

HIGHLIGHTS: Loss of TDP-43 repression of cryptic exons is necessary for caspase 3-dependent endoproteolysis of tau at D421 in the mouse brain and human iPSC-derived cortical neurons.The level of caspase 3-dependent cleavage of tau is a major determinant of the vulnerability of mouse brain neurons lacking TDP-43.In a novel mouse model of multiple etiology dementia, TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau to drive tauopathy.In human tauopathies with co-pathology of TDP-43, dysfunction of TDP-43 may promote caspase 3-dependent cleavage of endogenous tau in vulnerable neurons and exacerbate tauopathy-dependent neurodegeneration.

SUMMARY: The pathogenic mechanism by which TDP-43 loss of repression function exacerbates tauopathy-dependent neurodegeneration in multiple etiology dementia (MED) with co-pathology of TDP-43 is unknown. In a novel mouse model of MED, loss of TDP-43 function exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to drive tauopathy. This mechanistic insight informs novel targets and therapeutic strategies for MEDs harboring the co-pathologies of tau and TDP-43, which can be validated using this mouse model of MED.},
}

@article {pmid38979232,
year = {2024},
author = {Keuss, MJ and Harley, P and Ryadnov, E and Jackson, RE and Zanovello, M and Wilkins, OG and Barattucci, S and Mehta, PR and Oliveira, MG and Parkes, JE and Sinha, A and Correa-Sánchez, AF and Oliver, PL and Fisher, EMC and Schiavo, G and Shah, M and Burrone, J and Fratta, P},
title = {Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38979232},
issn = {2692-8205},
support = {/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; },
abstract = {TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.},
}

@article {pmid38979013,
year = {2024},
author = {Shi, W and Ding, R and Chen, Y and Ji, F and Ji, J and Ma, W and Jin, J},
title = {The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress.},
journal = {iScience},
volume = {27},
number = {7},
pages = {110196},
pmid = {38979013},
issn = {2589-0042},
abstract = {Stress granules (SGs) are membrane-less cellular compartments which are dynamically assembled via biomolecular condensation mechanism when eukaryotic cells encounter environmental stresses. SGs are important for gene expression and cell fate regulation. Dysregulation of SG homeostasis has been linked to human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we report that the HRD1-SEL1L ubiquitin ligase complex specifically regulates the homeostasis of heat shock-induced SGs through the ubiquitin-proteasome system (UPS) and the UPS-associated ATPase p97. Mechanistically, the HRD1-SEL1L complex mediates SG homeostasis through the BiP-coupled PERK-eIF2α signaling axis of endoplasmic reticulum (ER) stress, thereby coordinating the unfolded protein response (UPR) with SG dynamics. Furthermore, we show that the distinctive branches of ER stress play differential roles in SG homeostasis. Our study indicates that the UPS and the UPR together via the HRD1-SEL1L ubiquitin ligase to maintain SG homeostasis in a stressor-dependent manner.},
}

@article {pmid38978682,
year = {2024},
author = {Neumann, M and Kothare, H and Ramanarayanan, V},
title = {Multimodal Speech Biomarkers for Remote Monitoring of ALS Disease Progression.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {38978682},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.},
}

@article {pmid38978196,
year = {2024},
author = {Huang, X and Wu, J and Zhang, N and Teng, J and Yang, Q and Zhang, Y and Yin, T and Zhou, W and Fan, D and Ye, S},
title = {Smell loss is associated with cognitive impairment in amyotrophic lateral sclerosis patients.},
journal = {CNS neuroscience & therapeutics},
volume = {30},
number = {7},
pages = {e14851},
pmid = {38978196},
issn = {1755-5949},
support = {82001350//National Natural Science Foundation of China/ ; 2021ZD0204200//STI2030-Major Projects/ ; JCTD-2021-06//The Chinese Academy of Sciences Grants/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; DL2019002//PUTH Cohort Construction Project/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/epidemiology ; Male ; Female ; Middle Aged ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; *Olfaction Disorders/etiology/epidemiology ; Adult ; },
abstract = {BACKGROUND: Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients.

METHODS: The study included 216 ALS patients. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and smell identification test specifically for the Chinese population (CSIT) were administered to evaluate participants' cognitive and olfactory function, respectively.

RESULTS: After covarying for age, sex, BMI, education level, degree of hunger, dietary bias, eagerness for food, stress, smoking status, alcohol consumption, and upper respiratory tract infection (URTI) or rhinitis, CSIT scores were significantly correlated with ECAS scores (r = 0.162, p = 0.028), especially the ALS-specific scores (r = 0.158, p = 0.031). Even after excluding patients with URTI or rhinitis, the results were similar. CSIT scores were significantly correlated with ECAS scores (r = 0.224, p = 0.011), especially the ALS-specific scores (r = 0.205, p = 0.019).

CONCLUSION: In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/psychology/epidemiology
Male
Female
Middle Aged
*Cognitive Dysfunction/epidemiology/etiology
Aged
*Olfaction Disorders/etiology/epidemiology
Adult

@article {pmid38977678,
year = {2024},
author = {M Amaral, D and Soares, DF and Gromicho, M and de Carvalho, M and Madeira, SC and Tomás, P and Aidos, H},
title = {Temporal stratification of amyotrophic lateral sclerosis patients using disease progression patterns.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {5717},
pmid = {38977678},
issn = {2041-1723},
support = {101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Humans ; *Disease Progression ; Male ; Cluster Analysis ; Female ; Middle Aged ; Aged ; },
abstract = {Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups.},
}

*Amyotrophic Lateral Sclerosis/pathology/physiopathology
Humans
*Disease Progression
Male
Cluster Analysis
Female
Middle Aged
Aged

@article {pmid38977656,
year = {2024},
author = {Han, M and Raymond, J and Larson, TC and Mehta, P and Horton, DK},
title = {Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.},
journal = {Journal of racial and ethnic health disparities},
volume = {},
number = {},
pages = {},
pmid = {38977656},
issn = {2196-8837},
abstract = {OBJECTIVE: To characterize the participant demographics in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database compared with the web-portal National Amyotrophic Lateral Sclerosis (ALS) Registry (the Registry).

METHODS: Demographics and ALS symptom information were compared between the self-reported registrant data in the Registry web portal (2010-2021) and the latest available PRO-ACT data (updated August 2022), which is a collection of clinical trials data.

RESULTS: Greater percentages of younger (≤ 59 years old) but smaller percentages of older (60 + years old) participants were represented in PRO-ACT compared to Registry. Enrollment for minority race groups was greater in the Registry portal data, but race information was largely missing/unknown in PRO-ACT database. Median age at the time of diagnosis and age at the time of symptom onset were significantly higher for Registry enrollees compared to the participants of PRO-ACT. Symptom onset sites were similarly reported, but duration between self-noted symptom onset and diagnosis was slight, but significantly longer for the Registry enrollees (11 vs. 9 months). Hispanic were as likely as non-Hispanic to participate in research studies, based on the Registry data.

CONCLUSION: There was a notable difference in the age distribution and minority representation of enrollees between the PRO-ACT and Registry study populations. Age distribution in the PRO-ACT database skewed to a younger and less diverse cohort. Despite the clinical heterogeneity and complex disease mechanism of ALS, identifying the underrepresented demographic niche in the PRO-ACT and Registry study populations can help improve patient participation and criteria for patient selection to enhance generalizability.},
}

@article {pmid38976599,
year = {2024},
author = {Xu, Z and Xu, R},
title = {Current potential diagnostic biomarkers of amyotrophic lateral sclerosis.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {38976599},
issn = {2191-0200},
abstract = {Amyotrophic lateral sclerosis (ALS) currently lacks the useful diagnostic biomarkers. The current diagnosis of ALS is mainly depended on the clinical manifestations, which contributes to the diagnostic delay and be difficult to make the accurate diagnosis at the early stage of ALS, and hinders the clinical early therapeutics. The more and more pathogenesis of ALS are found at the last 30 years, including excitotoxicity, the oxidative stress, the mitochondrial dysfunction, neuroinflammation, the altered energy metabolism, the RNA misprocessing and the most recent neuroimaging findings. The findings of these pathogenesis bring the new clues for searching the diagnostic biomarkers of ALS. At present, a large number of relevant studies about the diagnostic biomarkers are underway. The ALS pathogenesis related to the diagnostic biomarkers might lessen the diagnostic reliance on the clinical manifestations. Among them, the cortical altered signatures of ALS patients derived from both structural and functional magnetic resonance imaging and the emerging proteomic biomarkers of neuronal loss and glial activation in the cerebrospinal fluid as well as the potential biomarkers in blood, serum, urine, and saliva are leading a new phase of biomarkers. Here, we reviewed these current potential diagnostic biomarkers of ALS.},
}

@article {pmid38975625,
year = {2024},
author = {Berkman, O and Raveh, E and Harpaz, E and Kreitman, R and Ben-Ami, E and Nechushtan, E and Birman, N and Drory, VE},
title = {Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2024.2376732},
pmid = {38975625},
issn = {2167-9223},
abstract = {Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs' change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, -0.41, -0.39 and -0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.},
}

@article {pmid38975145,
year = {2024},
author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C},
title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.},
journal = {Heliyon},
volume = {10},
number = {12},
pages = {e32688},
pmid = {38975145},
issn = {2405-8440},
abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.},
}

@article {pmid38974930,
year = {2024},
author = {Aziz, S and Barratt, J and Wilson-Baig, N and Lachowycz, K and Major, R and Barnard, EBG and Rees, P},
title = {A protocol for the ERICA-ARREST feasibility study of Emergency Resuscitative Endovascular Balloon occlusion of the Aorta in Out-of-Hospital Cardiac Arrest.},
journal = {Resuscitation plus},
volume = {19},
number = {},
pages = {100688},
pmid = {38974930},
issn = {2666-5204},
abstract = {BACKGROUND: Fewer than one in ten out-of-hospital cardiac arrest (OHCA) patients survive to hospital discharge in the UK. For prehospital teams to improve outcomes in patients who remain in refractory OHCA despite advanced life support (ALS); novel strategies that increase the likelihood of return of spontaneous circulation, whilst preserving cerebral circulation, should be investigated. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) has been shown to improve coronary and cerebral perfusion during cardiopulmonary resuscitation. Early, prehospital initiation of REBOA may improve outcomes in patients who do not respond to standard ALS. However, there are significant clinical, technical, and logistical challenges with rapidly delivering prehospital REBOA in OHCA; and the feasibility of delivering this intervention in the UK urban-rural setting has not been evaluated.

METHODS: The Emergency Resuscitative Endovascular Balloon Occlusion of the Aorta in Out-of-Hospital Cardiac Arrest (ERICA-ARREST) study is a prospective, single-arm, interventional feasibility study. The trial will enrol 20 adult patients with non-traumatic OHCA. The primary objective is to assess the feasibility of performing Zone I (supra-coeliac) aortic occlusion in patients who remain in OHCA despite standard ALS in the UK prehospital setting. The trial's secondary objectives are to describe the hemodynamic and physiological responses to aortic occlusion; to report key time intervals; and to document adverse events when performing REBOA in this context.

DISCUSSION: Using compressed geography, and targeted dispatch, alongside a well-established femoral arterial access programme, the ERICA-ARREST study will assess the feasibility of deploying REBOA in OHCA in a mixed UK urban and rural setting.Trial registration.ClinicalTrials.gov (NCT06071910), registration date October 10, 2023, https://classic.clinicaltrials.gov/ct2/show/NCT06071910.},
}

@article {pmid38973130,
year = {2024},
author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P},
title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2024.2375330},
pmid = {38973130},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.},
}

@article {pmid38972779,
year = {2024},
author = {Pelaez, MC and Fiore, F and Larochelle, N and Dabbaghizadeh, A and Comaduran, MF and Arbour, D and Minotti, S and Marcadet, L and Semaan, M and Robitaille, R and Nalbantoglu, JN and Sephton, CF and Durham, HD},
title = {Reversal of cognitive deficits in FUS[R521G] amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00388},
doi = {10.1016/j.neurot.2024.e00388},
pmid = {38972779},
issn = {1878-7479},
abstract = {Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS[R521G] or SOD1[G93A] to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS[R521G] mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1[G93A] mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.},
}

@article {pmid38972199,
year = {2024},
author = {Rosén, C and Mitre, B and Nellgård, B and Axelsson, M and Constantinescu, R and Andersen, PM and Dalla, K and Blennow, K and Nilsson, G and Zetterberg, H and Rosén, H},
title = {High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.},
journal = {Journal of the neurological sciences},
volume = {463},
number = {},
pages = {123112},
doi = {10.1016/j.jns.2024.123112},
pmid = {38972199},
issn = {1878-5883},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.},
}

@article {pmid38971939,
year = {2024},
author = {Gomez, D and Selvaraj, MG and Casas, J and Mathiyazhagan, K and Rodriguez, M and Assefa, T and Mlaki, A and Nyakunga, G and Kato, F and Mukankusi, C and Girma, E and Mosquera, G and Arredondo, V and Espitia, E},
title = {Advancing common bean (Phaseolus vulgaris L.) disease detection with YOLO driven deep learning to enhance agricultural AI.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {15596},
pmid = {38971939},
issn = {2045-2322},
mesh = {*Phaseolus/virology/microbiology ; *Deep Learning ; *Plant Diseases/virology/microbiology ; Agriculture/methods ; Plant Leaves/virology/microbiology ; Africa ; Colombia ; },
abstract = {Common beans (CB), a vital source for high protein content, plays a crucial role in ensuring both nutrition and economic stability in diverse communities, particularly in Africa and Latin America. However, CB cultivation poses a significant threat to diseases that can drastically reduce yield and quality. Detecting these diseases solely based on visual symptoms is challenging, due to the variability across different pathogens and similar symptoms caused by distinct pathogens, further complicating the detection process. Traditional methods relying solely on farmers' ability to detect diseases is inadequate, and while engaging expert pathologists and advanced laboratories is necessary, it can also be resource intensive. To address this challenge, we present a AI-driven system for rapid and cost-effective CB disease detection, leveraging state-of-the-art deep learning and object detection technologies. We utilized an extensive image dataset collected from disease hotspots in Africa and Colombia, focusing on five major diseases: Angular Leaf Spot (ALS), Common Bacterial Blight (CBB), Common Bean Mosaic Virus (CBMV), Bean Rust, and Anthracnose, covering both leaf and pod samples in real-field settings. However, pod images are only available for Angular Leaf Spot disease. The study employed data augmentation techniques and annotation at both whole and micro levels for comprehensive analysis. To train the model, we utilized three advanced YOLO architectures: YOLOv7, YOLOv8, and YOLO-NAS. Particularly for whole leaf annotations, the YOLO-NAS model achieves the highest mAP value of up to 97.9% and a recall of 98.8%, indicating superior detection accuracy. In contrast, for whole pod disease detection, YOLOv7 and YOLOv8 outperformed YOLO-NAS, with mAP values exceeding 95% and 93% recall. However, micro annotation consistently yields lower performance than whole annotation across all disease classes and plant parts, as examined by all YOLO models, highlighting an unexpected discrepancy in detection accuracy. Furthermore, we successfully deployed YOLO-NAS annotation models into an Android app, validating their effectiveness on unseen data from disease hotspots with high classification accuracy (90%). This accomplishment showcases the integration of deep learning into our production pipeline, a process known as DLOps. This innovative approach significantly reduces diagnosis time, enabling farmers to take prompt management interventions. The potential benefits extend beyond rapid diagnosis serving as an early warning system to enhance common bean productivity and quality.},
}

*Phaseolus/virology/microbiology
*Deep Learning
*Plant Diseases/virology/microbiology
Agriculture/methods
Plant Leaves/virology/microbiology
Africa
Colombia

@article {pmid38971043,
year = {2024},
author = {Malmström, N and Öhlén, J and Jakobsson Larsson, B and Nilsson, S and Nygren, I and M Andersen, P and Ozanne, A},
title = {Adolescents' challenging and grief-filled transitions when living with a parent with ALS: A qualitative interpretive study.},
journal = {Social science & medicine (1982)},
volume = {354},
number = {},
pages = {117063},
doi = {10.1016/j.socscimed.2024.117063},
pmid = {38971043},
issn = {1873-5347},
abstract = {OBJECTIVE: The study aimed to explore the meaning for adolescents of living with a parent with amyotrophic lateral sclerosis (ALS).

METHODS: The design is qualitative. Interviews were conducted between December 2020 and April 2022 with 11 adolescents (8-25 y), living in households with a parent with ALS in Sweden. The analysis was phenomenologically hermeneutical.

RESULTS: The adolescents were in a difficult and exposed situation, especially if the parent had a severe disability and assistant care providers were in the home. Witnessing the gradual loss of the parent in an indefinite battle against time, while still needing them, elicited grief-filled and hard-to-manage emotions. Everyday life was turned upside down, resulting in greater responsibility for the adolescents, not only in helping with household chores and assisting the ill parent, but also in emotionally protecting both parents. It forced the adolescents to mature faster and put their own life on hold, triggering experiences of being limited. This, together with changing family roles yet being more attached to home, reinforced the imbalance in the adolescents' lives. The interpreted whole of the adolescents' narratives revealed that living with a parent with ALS meant a challenging and grieving transition during an already transition-filled adolescence, which left the adolescents struggling to keep a foothold on a life torn apart.

CONCLUSION: The unbalanced life situation may hinder the adolescents' identity formation and emancipation, which are developmentally important for managing a healthy and independent adulthood. The results emphasize the importance of early targeted support to reach this vulnerable group in order to secure their health.},
}

@article {pmid38970668,
year = {2024},
author = {Ludolph, AC and Dietrich, J and Dreyhaupt, J and Kassubek, J and Del Tredici, K and Rosenbohm, A},
title = {Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): a study in 910 patients.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {38970668},
issn = {1432-1459},
support = {LU 336/15-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally.

METHODS: We conducted an observational study to define the initial sites of disease onset and the clinical progression ('spreading patterns') of motor deficits in a cohort of 910 ALS patients in Germany.

RESULTS: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region.

DISCUSSION: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.},
}

@article {pmid38970158,
year = {2024},
author = {Li, Z and Wen, J and Wu, W and Dai, Z and Liang, X and Zhang, N and Cheng, Q and Zhang, H},
title = {Causal relationship and shared genes between air pollutants and amyotrophic lateral sclerosis: A large-scale genetic analysis.},
journal = {CNS neuroscience & therapeutics},
volume = {30},
number = {7},
pages = {e14812},
pmid = {38970158},
issn = {1755-5949},
support = {2023CQBSHTB3095//Chongqing Postdoctoral Research Special Funding Project/ ; CSTB2023NSCQBHX0002//Chongqing Postdoctoral Science Foundation/ ; 2023MD734131//China Postdoctoral Science Foundation/ ; 2023RC3074//Hunan Youth Science and Technology Talent Project/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Polymorphism, Single Nucleotide/genetics ; *Genome-Wide Association Study ; *Air Pollutants/adverse effects/toxicity ; *Mendelian Randomization Analysis ; Genetic Predisposition to Disease/genetics ; Particulate Matter/adverse effects ; },
abstract = {OBJECTIVE: Air pollutants have been reported to have a potential relationship with amyotrophic lateral sclerosis (ALS). The causality and underlying mechanism remained unknown despite several existing observational studies. We aimed to investigate the potential causality between air pollutants (PM2.5, NOX, and NO2) and the risk of ALS and elucidate the underlying mechanisms associated with this relationship.

METHODS: The data utilized in our study were obtained from publicly available genome-wide association study data sets, in which single nucleotide polymorphisms (SNPs) were employed as the instrumental variantswith three principles. Two-sample Mendelian randomization and transcriptome-wide association (TWAS) analyses were conducted to evaluate the effects of air pollutants on ALS and identify genes associated with both pollutants and ALS, followed by regulatory network prediction.

RESULTS: We observed that exposure to a high level of PM2.5 (OR: 2.40 [95% CI: 1.26-4.57], p = 7.46E-3) and NOx (OR: 2.35 [95% CI: 1.32-4.17], p = 3.65E-3) genetically increased the incidence of ALS in MR analysis, while the effects of NO2 showed a similar trend but without sufficient significance. In the TWAS analysis, TMEM175 and USP35 turned out to be the genes shared between PM2.5 and ALS in the same direction.

CONCLUSION: Higher exposure to PM2.5 and NOX might causally increase the risk of ALS. Avoiding exposure to air pollutants and air cleaning might be necessary for ALS prevention.},
}

*Amyotrophic Lateral Sclerosis/genetics/epidemiology
Humans
*Polymorphism, Single Nucleotide/genetics
*Genome-Wide Association Study
*Air Pollutants/adverse effects/toxicity
*Mendelian Randomization Analysis
Genetic Predisposition to Disease/genetics
Particulate Matter/adverse effects

@article {pmid38969143,
year = {2024},
author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM},
title = {Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102386},
doi = {10.1016/j.arr.2024.102386},
pmid = {38969143},
issn = {1872-9649},
abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.},
}

@article {pmid38968328,
year = {2024},
author = {Gowrishankar, S and Smith, ME and Creber, N and Muzaffar, J and Borsetto, D},
title = {Immunosuppression in stem cell clinical trials of neural and retinal cell types: A systematic review.},
journal = {PloS one},
volume = {19},
number = {7},
pages = {e0304073},
pmid = {38968328},
issn = {1932-6203},
mesh = {Humans ; *Stem Cell Transplantation/methods ; *Immunosuppression Therapy/methods ; Retina/immunology ; Immunosuppressive Agents/therapeutic use ; Clinical Trials as Topic ; },
abstract = {BACKGROUND: Pharmacologic immunosuppression regimes are commonly employed in stem cell clinical trials to mitigate host immune rejection and promote survival and viability of transplanted cells. Immunosuppression and cell survival has been extensively studied in retinal and spinal tissues. The applicability of stem cell therapy is rapidly expanding to other sensory organs such as the ear and hearing. As regenerative therapy is directed to new areas, a greater understanding of immunosuppression strategies and their efficacy is required to facilitate translation to organ-specific biologic microenvironments.

OBJECTIVE: This systematic review appraises the current literature regarding immunosuppression strategies employed in stem cell trials of retinal and neural cells.

METHODS: This systematic review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria included studies presenting data on neural or retinal cells as part of an in-human clinical trial that detailed the immunosuppression regime used. Exclusion criteria included non-English language studies, animal studies, review articles, case reports, editorials, and letters. The databases Medline, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to February 2024. Risk of bias was evaluated using the ROBINS-I tool.

RESULTS: Eighteen articles fit the inclusion criteria. Nine articles concerned retinal cells, 5 concerned spinal cord injury, and 4 concerned amyotrophic lateral sclerosis. A multi-drug and short-term immunosuppression regime were commonly employed in the identified studies. Detected immune responses in treated patients were rare. Common immunosuppression paradigms included tacrolimus, mycophenolate mofetil and tapering doses of steroids. Local immunosuppression with steroids was employed in some studies concerning retinal diseases.

DISCUSSION: A short-term course of systemic immunosuppression seemed efficacious for most included studies, with some showing grafted cells viable months to years after immunosuppression had stopped. Longer-term follow-up is required to see if this remains the case. Side effects related to immunosuppression were uncommon.},
}

Humans
*Stem Cell Transplantation/methods
*Immunosuppression Therapy/methods
Retina/immunology
Immunosuppressive Agents/therapeutic use
Clinical Trials as Topic

@article {pmid38967881,
year = {2024},
author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X},
title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {38967881},
issn = {1590-3478},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.},
}

@article {pmid38967655,
year = {2024},
author = {Müller, P and Draguhn, A and Egorov, AV},
title = {Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {},
number = {},
pages = {},
pmid = {38967655},
issn = {1432-2013},
support = {HE8155/1-2//Deutsche Forschungsgemeinschaft/ ; EG134/2-1//Deutsche Forschungsgemeinschaft/ ; Treat-ION01GM1907A//Bundesministerium für Bildung und Forschung/ ; College for Clinician Scientists//Else Kröner-Fresenius-Stiftung/ ; },
abstract = {Persistent sodium current (INaP) is an important activity-dependent regulator of neuronal excitability. It is involved in a variety of physiological and pathological processes, including pacemaking, prolongation of sensory potentials, neuronal injury, chronic pain and diseases such as epilepsy and amyotrophic lateral sclerosis. Despite its importance, neither the molecular basis nor the regulation of INaP are sufficiently understood. Of particular significance is a solid knowledge and widely accepted consensus about pharmacological tools for analysing the function of INaP and for developing new therapeutic strategies. However, the literature on INaP is heterogeneous, with varying definitions and methodologies used across studies. To address these issues, we provide a systematic review of the current state of knowledge on INaP, with focus on mechanisms and effects of this current in the central nervous system. We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents.},
}

@article {pmid38967638,
year = {2024},
author = {Garau, J and Garofalo, M and Dragoni, F and Scarian, E and Di Gerlando, R and Diamanti, L and Zucca, S and Bordoni, M and Pansarasa, O and Gagliardi, S},
title = {RNA expression profiling in lymphoblastoid cell lines from mutated and non-mutated amyotrophic lateral sclerosis patients.},
journal = {The journal of gene medicine},
volume = {26},
number = {7},
pages = {e3711},
doi = {10.1002/jgm.3711},
pmid = {38967638},
issn = {1521-2254},
support = {//Ministero della Salute/ ; //Italian Agency for Research on ALS-ARiSLA/ ; //Italian Ministry of Health/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Gene Expression Profiling ; *Mutation ; *Transcriptome ; Female ; Male ; Middle Aged ; C9orf72 Protein/genetics/metabolism ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase-1/genetics ; Cell Line ; Aged ; Gene Expression Regulation ; DNA-Binding Proteins ; RNA-Binding Protein FUS ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of upper and lower motor neurons with an unknown etiology. The difficulty of recovering biological material from patients led to employ lymphoblastoid cell lines (LCLs) as a model for ALS because many pathways, typically located in neurons, are also activated in these cells.

METHODS: To investigate the expression of coding and long non-coding RNAs in LCLs, a transcriptomic profiling of sporadic ALS (SALS) and mutated patients (FUS, TARDBP, C9ORF72 and SOD1) and matched controls was realized. Thus, differentially expressed genes (DEGs) were investigated among the different subgroups of patients. Peripheral blood mononuclear cells (PBMCs) were isolated and immortalized into LCLs via Epstein-Barr virus infection; RNA was extracted, and RNA-sequencing analysis was performed.

RESULTS: Gene expression profiles of LCLs were genetic-background-specific; indeed, only 12 genes were commonly deregulated in all groups. Nonetheless, pathways enriched by DEGs in each group were also compared, and a total of 89 Kyoto Encyclopedia of Genes and Genomes (KEGG) terms were shared among all patients. Eventually, the similarity of affected pathways was also assessed when our data were matched with a transcriptomic profile realized in the PBMCs of the same patients.

CONCLUSIONS: We conclude that LCLs are a good model for the study of RNA deregulation in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Gene Expression Profiling
*Mutation
*Transcriptome
Female
Male
Middle Aged
C9orf72 Protein/genetics/metabolism
Leukocytes, Mononuclear/metabolism
Superoxide Dismutase-1/genetics
Cell Line
Aged
Gene Expression Regulation
DNA-Binding Proteins
RNA-Binding Protein FUS

@article {pmid38967302,
year = {2024},
author = {Sîrbulescu, RF and Nicholson, K and Kawai, K and Hilton, OM and Sobell, D and Jin, G and Verrill, DE and Dwyer, LJ and Xiong, Y and Bachanová, P and Kim, SE and Gallup, S and Gelevski, D and Daley, H and Hernandez Rodriguez, DE and Negre, H and Sturtevant, O and Nikiforow, S and Ritz, J and Chen, YB and Reeves, PM and Sluder, AE and Berry, JD and Sadri-Vakili, G and Cudkowicz, M and Poznansky, MC},
title = {Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {38},
number = {13},
pages = {e23796},
doi = {10.1096/fj.202302659R},
pmid = {38967302},
issn = {1530-6860},
support = {//Ward Family Foundation/ ; //Vaccine and Immunotherapy Center Innovation Fund/ ; //Vaccine and Immunotherapy Center Education Fund/ ; //Sean M. Healey and AMG Center for ALS/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology ; Animals ; Mice ; Humans ; *B-Lymphocytes/immunology ; Disease Models, Animal ; Mice, Transgenic ; Male ; Female ; Mice, Inbred C57BL ; Immunomodulation ; Middle Aged ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1[G93A] mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1[G93A] mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19[+] B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1[G93A] mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1[G93A] mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.},
}

*Amyotrophic Lateral Sclerosis/therapy/immunology
Animals
Mice
Humans
*B-Lymphocytes/immunology
Disease Models, Animal
Mice, Transgenic
Male
Female
Mice, Inbred C57BL
Immunomodulation
Middle Aged

@article {pmid38967083,
year = {2024},
author = {Nijs, M and Van Damme, P},
title = {The genetics of amyotrophic lateral sclerosis.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
pmid = {38967083},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS.

RECENT FINDINGS: Large-scale genetic studies have uncovered more than 40 genes contributing to ALS susceptibility. Both rare variants with variable effect size and more common variants with small effect size have been identified. The most common ALS genes are C9orf72, SOD1, TARDBP and FUS. Some of the causative genes of ALS are shared with frontotemporal dementia, confirming the molecular link between both diseases. Access to diagnostic gene testing for ALS has to improve, as effective gene silencing therapies for some genetic subtypes of ALS are emerging, but there is no consensus about which genes to test for.

SUMMARY: Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.},
}

@article {pmid38966756,
year = {2024},
author = {Garg, V and Geurten, BRH},
title = {Diving deep: zebrafish models in motor neuron degeneration research.},
journal = {Frontiers in neuroscience},
volume = {18},
number = {},
pages = {1424025},
pmid = {38966756},
issn = {1662-4548},
abstract = {In the dynamic landscape of biomedical science, the pursuit of effective treatments for motor neuron disorders like hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) remains a key priority. Central to this endeavor is the development of robust animal models, with the zebrafish emerging as a prime candidate. Exhibiting embryonic transparency, a swift life cycle, and significant genetic and neuroanatomical congruencies with humans, zebrafish offer substantial potential for research. Despite the difference in locomotion-zebrafish undulate while humans use limbs, the zebrafish presents relevant phenotypic parallels to human motor control disorders, providing valuable insights into neurodegenerative diseases. This review explores the zebrafish's inherent traits and how they facilitate profound insights into the complex behavioral and cellular phenotypes associated with these disorders. Furthermore, we examine recent advancements in high-throughput drug screening using the zebrafish model, a promising avenue for identifying therapeutically potent compounds.},
}

@article {pmid38966655,
year = {2024},
author = {Saito, S and Ikeguchi, R and Kitagawa, K},
title = {Chronic cerebrospinal fluid leak can cause amyotrophic lateral sclerosis mimic.},
journal = {Journal of general and family medicine},
volume = {25},
number = {4},
pages = {237-238},
pmid = {38966655},
issn = {2189-7948},
abstract = {Chronic cerebrospinal fluid leak with spinal cord compression can mimic the symptoms of ALS, with a snake-eyes appearance on MRI.},
}

@article {pmid38966427,
year = {2024},
author = {Couturier, N and Hörner, SJ and Nürnberg, E and Joazeiro, C and Hafner, M and Rudolf, R},
title = {Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model.},
journal = {Frontiers in cell and developmental biology},
volume = {12},
number = {},
pages = {1429759},
pmid = {38966427},
issn = {2296-634X},
abstract = {Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca[2+] response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.},
}

@article {pmid38965709,
year = {2024},
author = {Arends, S and Drenthen, J and de Koning, L and van den Bergh, P and Hadden, RDM and Kuwabara, S and Reisin, RC and Shahrizaila, N and Ajroud-Driss, S and Antonini, G and Attarian, S and Balducci, C and Bertorini, T and Brannagan, TH and Cavaletti, G and Chao, CC and Chavada, G and Dillmann, KU and Dimachkie, MM and Galassi, G and Gutiérrez-Gutiérrez, G and Harbo, T and Islam, B and Islam, Z and Katzberg, H and Kusunoki, S and Manganelli, F and Miller, JAL and Pardo, J and Pereon, Y and Rajabally, YA and Sindrup, S and Stettner, M and Uncini, A and Verhamme, C and Vytopil, M and Waheed, W and Jacobs, BC and Cornblath, DR and , },
title = {Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.},
journal = {European journal of neurology},
volume = {},
number = {},
pages = {e16335},
doi = {10.1111/ene.16335},
pmid = {38965709},
issn = {1468-1331},
abstract = {BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria.

METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally.

RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%.

CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.},
}

@article {pmid38965379,
year = {2024},
author = {Jacob, SM and Lee, S and Kim, SH and Sharkey, KA and Pfeffer, G and Nguyen, MD},
title = {Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {38965379},
issn = {1759-4766},
abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3-5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.},
}

@article {pmid38964584,
year = {2024},
author = {Peters, S and Bouma, F and Hoek, G and Janssen, N and Vermeulen, R},
title = {Air pollution exposure and mortality from neurodegenerative diseases in the Netherlands: A population-based cohort study.},
journal = {Environmental research},
volume = {259},
number = {},
pages = {119552},
doi = {10.1016/j.envres.2024.119552},
pmid = {38964584},
issn = {1096-0953},
abstract = {BACKGROUND: Long-term exposure to ambient air pollution has been linked with all-cause mortality and cardiovascular and respiratory diseases. Suggestive associations between ambient air pollutants and neurodegeneration have also been reported, but due to the small effect and relatively rare outcomes evidence is yet inconclusive. Our aim was to investigate the associations between long-term air pollution exposure and mortality from neurodegenerative diseases.

METHODS: A Dutch national cohort of 10.8 million adults aged ≥30 years was followed from 2013 until 2019. Annual average concentrations of air pollutants (ultra-fine particles (UFP), nitrogen dioxide (NO2), fine particles (PM2.5 and PM10) and elemental carbon (EC)) were estimated at the home address at baseline, using land-use regression models. The outcome variables were mortality due to amyotrophic lateral sclerosis (ALS), Parkinson's disease, non-vascular dementia, Alzheimer's disease, and multiple sclerosis (MS). Hazard ratios (HR) were estimated using Cox models, adjusting for individual and area-level socio-economic status covariates.

RESULTS: We had a follow-up of 71 million person-years. The adjusted HRs for non-vascular dementia were significantly increased for NO2 (1.03; 95% confidence interval (CI) 1.02-1.05) and PM2.5 (1.02; 95%CI 1.01-1.03) per interquartile range (IQR; 6.52 and 1.47 μg/m[3], respectively). The association with PM2.5 was also positive for ALS (1.02; 95%CI 0.97-1.07). These associations remained positive in sensitivity analyses and two-pollutant models. UFP was not associated with any outcome. No association with air pollution was found for Parkinson's disease and MS. Inverse associations were found for Alzheimer's disease.

CONCLUSION: Our findings, using a cohort of more than 10 million people, provide further support for associations between long-term exposure to air pollutants (PM2.5 and particularly NO2) and mortality of non-vascular dementia. No associations were found for Parkinson and MS and an inverse association was observed for Alzheimer's disease.},
}

@article {pmid38963716,
year = {2024},
author = {Lima, PLGSB and Couto, EM and Nóbrega, PR},
title = {Response letter to: a homozygous p.Val120Leu (c.358G > C) SOD1 mutation led to slowly progressive amyotrophic lateral sclerosis in a Brazilian family.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-2},
doi = {10.1080/21678421.2024.2374372},
pmid = {38963716},
issn = {2167-9223},
}

@article {pmid38963497,
year = {2024},
author = {Yu, G and Bai, Y and Zhang, ZY},
title = {Valosin-Containing Protein (VCP)/p97 Oligomerization.},
journal = {Sub-cellular biochemistry},
volume = {104},
number = {},
pages = {485-501},
pmid = {38963497},
issn = {0306-0225},
mesh = {*Valosin Containing Protein/metabolism/genetics/chemistry ; Humans ; Protein Multimerization ; Animals ; Mutation ; Frontotemporal Dementia/genetics/metabolism ; Adenosine Triphosphatases/metabolism/genetics/chemistry ; Osteitis Deformans/genetics/metabolism ; Cell Cycle Proteins/metabolism/genetics/chemistry ; Myositis, Inclusion Body/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle ; },
abstract = {Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.},
}

*Valosin Containing Protein/metabolism/genetics/chemistry
Humans
Protein Multimerization
Animals
Mutation
Frontotemporal Dementia/genetics/metabolism
Adenosine Triphosphatases/metabolism/genetics/chemistry
Osteitis Deformans/genetics/metabolism
Cell Cycle Proteins/metabolism/genetics/chemistry
Myositis, Inclusion Body/genetics/metabolism
Muscular Dystrophies, Limb-Girdle

@article {pmid38963135,
year = {2024},
author = {Turano, E and Virla, F and Scambi, I and Dabrowska, S and Bankole, O and Mariotti, R},
title = {Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally.},
journal = {European journal of histochemistry : EJH},
volume = {68},
number = {3},
pages = {},
doi = {10.4081/ejh.2024.4040},
pmid = {38963135},
issn = {2038-8306},
mesh = {Animals ; *Extracellular Vesicles/metabolism ; *Mesenchymal Stem Cells/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Adipose Tissue/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving motor neuron (MN) loss in the motor cortex, brainstem and spinal cord leading to progressive paralysis and death. Due to the pathogenetic complexity, there are no effective therapies available. In this context the use of mesenchymal stem cells and their vesicular counterpart is an emerging therapeutic strategy to counteract neurodegeneration. The extracellular vesicles derived from adipose stem cells (ASC-EVs) recapitulate and ameliorate the neuroprotective effect of stem cells and, thanks to their small dimensions, makes their use suitable to develop novel therapeutic approaches for neurodegenerative diseases as ALS. Here we investigate a therapeutic regimen of ASC-EVs injection in SOD1(G93A) mice, the most widely used murine model of ALS. Repeated intranasal administrations of high doses of ASC-EVs were able to ameliorate motor performance of injected SOD1(G93A) mice at the early stage of the disease and produce a significant improvement at the end-stage in the lumbar MNs rescue. Moreover, ASC-EVs preserve the structure of neuromuscular junction without counteracting the muscle atrophy. The results indicate that the intranasal ASC-EVs administration acts in central nervous system sites rather than at peripheral level in SOD1(G93A) mice. These considerations allow us to identify future applications of ASC-EVs that involve different targets simultaneously to maximize the clinical and neuropathological outcomes in ALS in vivo models.},
}

Animals
*Extracellular Vesicles/metabolism
*Mesenchymal Stem Cells/metabolism
Mice
*Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology
*Superoxide Dismutase-1/genetics/metabolism
Mice, Transgenic
Disease Models, Animal
Adipose Tissue/metabolism
Motor Neurons/metabolism
Neuromuscular Junction/metabolism

@article {pmid38963090,
year = {2024},
author = {Pearson, K and Dobak, S},
title = {Current practices in the nutrition management of people with amyotrophic lateral sclerosis (ALS): a survey of U.S. ALS care teams.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2024.2374382},
pmid = {38963090},
issn = {2167-9223},
abstract = {OBJECTIVE: To assess current practices of U.S. professionals providing outpatient ALS nutrition care.

METHODS: A cross-sectional survey assessing nutrition care practices was distributed in February/March 2023 through electronic mailing lists of relevant professional organizations.

RESULTS: Of the 87 professionals completing the survey, 85.1% were registered dietitians and 50.6% had five or fewer years of experience in ALS care. Many (44.2%) professionals reported receiving no training on the nutrition care of people with ALS (PALS), and 40.2% reported having no other ALS dietitians in their close network. Methods utilized to estimate calorie and protein requirements in PALS varied widely. Although 95.4% of respondents reported that their clinic's dietitian participates in feeding tube discussions, many practitioners may be waiting until ALS symptoms negatively impact PALS' breathing, eating, swallowing, or weight to begin discussing feeding tubes. Additionally, few professionals reported institutional practices conducive for refeeding syndrome prevention or monitoring.

CONCLUSIONS: Many professionals providing outpatient nutrition care to PALS possess limited experience, received insufficient training, and are not connected to other ALS dietitians. Specific nutrition care practices, including nutrient need estimation, vary widely among health professionals. Practices surrounding feeding tube discussions and refeeding syndrome may be suboptimal at many institutions. These findings highlight the need for initiatives that educate and connect practitioners providing nutrition care to PALS.},
}

@article {pmid38963079,
year = {2024},
author = {Naruse, H and Iseki, C and Mitsui, J and Miki, J and Nagasawa, H and Kurokawa, K and Kobayashi, R and Sato, H and Goto, J and Satake, W and Ishiura, H and Tsuji, S and Ohta, Y and Toda, T},
title = {A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2024.2374374},
pmid = {38963079},
issn = {2167-9223},
abstract = {Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.},
}

@article {pmid38961496,
year = {2024},
author = {Linse, K and Weber, C and Reilich, P and Schöberl, F and Boentert, M and Petri, S and Rödiger, A and Posa, A and Otto, M and Wolf, J and Zeller, D and Brunkhorst, R and Koch, J and Hermann, A and Großkreutz, J and Schröter, C and Groß, M and Lingor, P and Machetanz, G and Semmler, L and Dorst, J and Lulé, D and Ludolph, A and Meyer, T and Maier, A and Metelmann, M and Regensburger, M and Winkler, J and Schrank, B and Kohl, Z and Hagenacker, T and Brakemeier, S and Weyen, U and Weiler, M and Lorenzl, S and Bublitz, S and Weydt, P and Grehl, T and Kotterba, S and Lapp, HS and Freigang, M and Vidovic, M and Aust, E and Günther, R},
title = {Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.},
journal = {Neurological research and practice},
volume = {6},
number = {1},
pages = {34},
pmid = {38961496},
issn = {2524-3489},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them.

METHODS: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment.

PERSPECTIVE: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed.

TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.},
}