@article {pmid38750212,
year = {2024},
author = {Leventoux, N and Morimoto, S and Ishikawa, M and Nakamura, S and Ozawa, F and Kobayashi, R and Watanabe, H and Supakul, S and Okamoto, S and Zhou, Z and Kobayashi, H and Kato, C and Hirokawa, Y and Aiba, I and Takahashi, S and Shibata, S and Takao, M and Yoshida, M and Endo, F and Yamanaka, K and Kokubo, Y and Okano, H},
title = {Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.},
journal = {Acta neuropathologica},
volume = {147},
number = {1},
pages = {84},
pmid = {38750212},
issn = {1432-0533},
support = {JP15J03921//Japan Society for the Promotion of Science/ ; JP18K07368//Japan Society for the Promotion of Science/ ; JP18KK0239//Japan Society for the Promotion of Science/ ; JP19K17002//Japan Society for the Promotion of Science/ ; JP19K08002//Japan Society for the Promotion of Science/ ; JP21H05278//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP17K10083//Japan Society for the Promotion of Science/ ; JP20H03567//Japan Society for the Promotion of Science/ ; JP22K18388//Japan Society for the Promotion of Science/ ; JP23H02882//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP21K06417//Japan Society for the Promotion of Science/ ; JP18K06506//Japan Society for the Promotion of Science/ ; JP22H04923//Japan Society for the Promotion of Science/ ; JP25305030//Japan Society for the Promotion of Science/ ; JP15K09364//Japan Society for the Promotion of Science/ ; JP17H01689//Japan Society for the Promotion of Science/ ; JP18K07514//Japan Society for the Promotion of Science/ ; JP18K07368//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP21F21410//Japan Society for the Promotion of Science/ ; JP21H05273//Japan Society for the Promotion of Science/ ; JP22KF0333//Japan Society for the Promotion of Science/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP22bm0804023//Japan Agency for Medical Research and Development/ ; JP22gm6510006//Japan Agency for Medical Research and Development/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP17ek0109139//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; JP20ek0109329//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; H29-Nanchi-Ippan-085//Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases/ ; JP18KK0239//Japanese Foundation for Research and Promotion of Endoscopy/ ; JP16H06277//MEXT/ ; },
mesh = {*Astrocytes/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Transcription Factors/genetics/metabolism ; *Mitochondrial Proteins/genetics/metabolism ; Mitochondria/pathology/metabolism ; Male ; Female ; Middle Aged ; Aged ; },
abstract = {Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.},
}

*Astrocytes/pathology/metabolism
*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
Humans
*DNA-Binding Proteins/metabolism/genetics
*Transcription Factors/genetics/metabolism
*Mitochondrial Proteins/genetics/metabolism
Mitochondria/pathology/metabolism
Male
Female
Middle Aged
Aged

@article {pmid38749729,
year = {2024},
author = {Kunieda, K and Hayashi, Y and Fujishima, I and Shimohata, T},
title = {Weight and Muscle Mass Loss Associated with Acute Disease Can be Reversed with Appropriate Nutrition Therapy and Exercise in a Patient with Amyotrophic Lateral Sclerosisa: A Case Report.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.3622-24},
pmid = {38749729},
issn = {1349-7235},
abstract = {Introduction Nutritional interventions targeting weight loss are useful for the treatment of amyotrophic lateral sclerosis (ALS). However, the changes in body composition after nutritional intervention remain unclear. We herein present a patient with ALS who experienced an increased weight and muscle mass owing to nutritional therapy and physical exercise. Case Presentation An 86-year-old man presented with dysphagia and dysarthria. The patient was diagnosed with bulbar-type ALS. As weight loss progressed, a gastrostomy was performed. After 21 months of disease onset, gastrointestinal bleeding due to a bumper ulcer led to further weight loss (from 40.2 kg to 36.8 kg). The patient experienced difficulty walking and ingesting food orally. Although the total daily energy expenditure (TDEE) was estimated to be 1,122 kcal/day, an intake of 1,500 kcal/day beyond the calculated TDEE was administered. The patient continued to perform daily voluntary exercises in addition to his usual rehabilitation. After 5 months, his weight increased from 36.8 kg to 40.4 kg. Muscle mass increased from 25.1 kg to 30.1 kg, as measured using a multifrequency bioelectrical impedance device. Muscle strength improved from 8.5/10.0 kg to 15.0/18.0 kg in grip strength and from 15.2 kPa to 20.4 kPa in tongue pressure. The patient's physical and swallowing functions also improved. Conclusion In patients with ALS, a decreased body weight and muscle mass due to acute disease may be improved by appropriate nutritional therapy and physical exercise.},
}

@article {pmid38749539,
year = {2024},
author = {Schwartze, JT and Das, S and Suggitt, D and Baxter, J and Tunstall, S and Ronan, N and Stannard, H and Rezgui, A and Jafar, W and Baxter, DN},
title = {Ward-based in situ simulation: lessons learnt from a UK District General Hospital.},
journal = {BMJ open quality},
volume = {13},
number = {2},
pages = {},
pmid = {38749539},
issn = {2399-6641},
mesh = {Humans ; United Kingdom ; Male ; Female ; *Patient Care Team/standards/statistics & numerical data ; Hospitals, General/statistics & numerical data ; Clinical Competence/statistics & numerical data/standards ; Simulation Training/methods/statistics & numerical data/standards ; Hospitals, District/statistics & numerical data ; Adult ; Patient Safety/standards/statistics & numerical data ; },
abstract = {INTRODUCTION: In situ simulation (ISS) enables multiprofessional healthcare teams to train for real emergencies in their own working environment and identify latent patient safety threats. This study aimed to determine ISS impact on teamwork, technical skill performance, healthcare staff perception and latent error identification during simulated medical emergencies.

MATERIALS AND METHODS: Unannounced ISS sessions (n=14, n=75 staff members) using a high-fidelity mannequin were conducted in medical, paediatric and rehabilitation wards at Stepping Hill Hospital (Stockport National Health Service Foundation Trust, UK). Each session encompassed a 15 min simulation followed by a 15 min faculty-led debrief.

RESULTS: The clinical team score revealed low overall teamwork performances during simulated medical emergencies (mean±SEM: 4.3±0.5). Linear regression analysis revealed that overall communication (r=0.9, p<0.001), decision-making (r=0.77, p<0.001) and overall situational awareness (r=0.73, p=0.003) were the strongest statistically significant predictors of overall teamwork performance. Neither the number of attending healthcare professionals, their professional background, age, gender, degree of clinical experience, level of resuscitation training or previous simulation experience statistically significantly impacted on overall teamwork performance. ISS positively impacted on healthcare staff confidence and clinical training. Identified safety threats included unknown location of intraosseous kits, poor/absent airway management, incomplete A-E assessments, inability to activate the major haemorrhage protocol, unknown location/dose of epinephrine for anaphylaxis management, delayed administration of epinephrine and delayed/absence of attachment of pads to the defibrillator as well as absence of accessing ALS algorithms, poor chest compressions and passive behaviour during simulated cardiac arrests.

CONCLUSION: Poor demonstration of technical/non-technical skills mandate regular ISS interventions for healthcare professionals of all levels. ISS positively impacts on staff confidence and training and drives identification of latent errors enabling improvements in workplace systems and resources.},
}

Humans
United Kingdom
Male
Female
*Patient Care Team/standards/statistics & numerical data
Hospitals, General/statistics & numerical data
Clinical Competence/statistics & numerical data/standards
Simulation Training/methods/statistics & numerical data/standards
Hospitals, District/statistics & numerical data
Adult
Patient Safety/standards/statistics & numerical data

@article {pmid38748878,
year = {2024},
author = {Koopman, M and Güngördü, L and Janssen, L and Seinstra, RI and Richmond, JE and Okerlund, N and Wardenaar, R and Islam, P and Hogewerf, W and Brown, AEX and Jorgensen, EM and Nollen, EAA},
title = {Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity.},
journal = {Cell reports},
volume = {43},
number = {5},
pages = {114204},
doi = {10.1016/j.celrep.2024.114204},
pmid = {38748878},
issn = {2211-1247},
abstract = {Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping and subsequent dissection of the neuromuscular circuit, we show that TDP-43 worms have profound defects in GABA neurons. Moreover, acetylcholine neurons appear functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of, among others, G-protein-coupled receptors restores neurotransmission, but inefficiently rescues locomotion. Rebalancing the excitatory-to-inhibitory ratio in the neuromuscular system by simultaneous stimulation of the affected GABA- and acetylcholine neurons, however, not only synergizes the effects of boosting individual neurotransmitter systems, but instantaneously improves movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.},
}

@article {pmid38748695,
year = {2024},
author = {Kim, HS and Woo, H and Choi, SJ and Baek, JG and Ryu, JS and Shin, HI and Park, KS and Beom, J},
title = {Factors associated with adherence to noninvasive positive pressure ventilation in amyotrophic lateral sclerosis.},
journal = {PloS one},
volume = {19},
number = {5},
pages = {e0302515},
pmid = {38748695},
issn = {1932-6203},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Female ; Male ; Middle Aged ; *Positive-Pressure Respiration/methods ; *Noninvasive Ventilation ; Aged ; Retrospective Studies ; Blood Gas Analysis ; Length of Stay ; Patient Compliance ; Respiratory Function Tests ; Adult ; },
abstract = {INTRODUCTION: This cohort study aimed to investigate the factors associated with noninvasive positive pressure ventilation adherence and assess the long-term effects of noninvasive positive pressure ventilation adherence in patients with amyotrophic lateral sclerosis (ALS).

METHODS: The medical records of patients with ALS admitted to a tertiary hospital for noninvasive positive pressure ventilation initiation were retrospectively reviewed. Pulmonary function parameters, variables of blood gas analysis, the site of symptom onset, the time from onset and diagnosis to noninvasive positive pressure ventilation application, ALS Functional Rating Scale-Revised, neurophysiological index, and the length of hospital stay were evaluated. The adherence to noninvasive positive pressure ventilation was defined as the use of noninvasive positive pressure ventilation for ≥ 2 h/day or ≥ 4 h/day. The correlations between noninvasive positive pressure ventilation adherence or length of hospital stay and other clinical parameters were analyzed.

RESULTS: Fifty-one patients with ALS were included in the study. The time from onset and diagnosis to NIPPV application was reduced by 16 months in the adherent group than that in the non-adherent group; however, the parameters of blood gas analysis and pulmonary function tests did not differ significantly between the groups. Furthermore, the neurophysiological index of the abductor digiti minimi muscle was higher by 4.05 in the adherent group than that in the non-adherent group. The adherence to noninvasive positive pressure ventilation prolonged tracheostomy-free survival compared to that of non-adherence. Desaturation events, lower forced vital capacity, last pCO2, bicarbonate, and base excess, and higher differences in pCO2, were associated with an increase in the length of hospital stay.

CONCLUSIONS: Noninvasive positive pressure ventilation application shortly after symptom onset and ALS diagnosis in patients with CO2 retention and reduced forced vital capacity can be considered for successful adherence. Adherence to noninvasive positive pressure ventilation may result in reduced tracheostomy conversion rates and prolonged tracheostomy-free survival.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/physiopathology
Female
Male
Middle Aged
*Positive-Pressure Respiration/methods
*Noninvasive Ventilation
Aged
Retrospective Studies
Blood Gas Analysis
Length of Stay
Patient Compliance
Respiratory Function Tests
Adult

@article {pmid38748065,
year = {2024},
author = {Lu, T and Luo, L and Yang, J and Cheng, X and Sun, J},
title = {Circulating Levels of T-Cell Traits and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {38748065},
issn = {1559-1182},
support = {WZ21M01 and WX20C35//the Wuhan Municipal Health Commission/ ; WZ21M01 and WX20C35//the Wuhan Municipal Health Commission/ ; 2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; 2017B030314176, 2018-75, and 2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) represents a rare and potentially fatal neurodegenerative disease. Diverse T-cell subsets could potentially exert diametrically opposite impacts upon ALS development. A two-sample Mendelian randomization (MR) analysis was performed to investigate the correlation between 244 T-cell subsets and ALS risk. Genetic instrumental variables were procured from a standard genome-wide association study (GWAS) that encompassed 244 T-cell subsets in 3757 individuals of European lineage. ALS-related data were collected from a GWAS comprising 20,806 ALS instances and 59,804 European control participants. Multiple sensitivity analyses were performed to verify the robustness of the significant results. Reverse MR analysis was used for delineating the effects of ALS on the characteristics of T-cells. After multiple comparison corrections, 24 out of the 244 subtypes demonstrated a potential association with ALS risk. Significantly, 75% of these associations encompassed the expression of the CD3 on diverse T-cell subtypes, revealing a highly consistent inverse relation to ALS risk. The proportion of T regulatory cells (Tregs) in CD4+ T cells and secreting Tregs in CD4+ T cells demonstrated negative associations with the risk of ALS. CCR7 expression on naive CD4+ T cells and CCR7 expression on naive CD8+ T cells showed positive associations with ALS risk. Certain T-cell subsets, particularly those identified by CD3 expression on terminally differentiated CD8+ T cells, proportions of Tregs, and CCR7 expression, indicated an association with ALS risk. These findings harmonize with and extend previous observational studies investigating the involvement of T lymphocyte subset-induced immunological processes in ALS.},
}

@article {pmid38747354,
year = {2024},
author = {Borghero, G and Pierri, V and Pili, F and Muroni, A and Ercoli, T and Pateri, MI and Pilotto, S and Maccabeo, A and Chiò, A and Defazio, G},
title = {Percutaneous gastrostomy, mechanical ventilation and survival in amyotrophic lateral sclerosis : an observational study in an incident cohort.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2024.2351185},
pmid = {38747354},
issn = {2167-9223},
abstract = {OBJECTIVE: To analyze disease-modifying effects of percutaneous endoscopic gastrostomy (PEG) insertion for supporting nutrition, noninvasive ventilation (NIV), and tracheostomy-assisted ('invasive') ventilation (TIV) in amyotrophic lateral sclerosis (ALS).

METHODS: We retrospectively analyzed survival in a large population-based incident cohort that was prospectively followed up in our center. Analysis considered several known ALS-related prognostic variables.

RESULTS: In this population, PEG and NIV in multivariable analysis significantly correlated to survival as computed by disease onset to death/tracheostomy. NIV was associated with better survival while PEG was associated with reduced survival. Other independent prognostic factors were age at ALS onset, diagnostic delay, and flail arm/leg and pure upper motor neuron (PUMN) phenotypes. The length of survival after TIV was significantly associated with age at ALS onset (inverse correlation) whereas other variables did not. The length of survival after TIV correlated to age at ALS onset in such a way that each additional year of age at ALS onset decreased survival by about 0.7 months. Patients who underwent both TIV and NIV did not experience a better survival than those who underwent TIV alone.

CONCLUSION: The lack of effect of enteral nutrition on ALS survival probably reflected the timing of PEG insertion in patients with more severe disease. By contrast, patients who used mechanical ventilation had an increased overall survival compared with non-ventilated ones. The study also provided new information showing that the combined use of NIV and TIV did not may prolong ALS survival as compared to TIV alone.},
}

@article {pmid38747014,
year = {2024},
author = {Gale, J and Aizenman, E},
title = {The physiological and pathophysiological roles of copper in the nervous system.},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.16370},
pmid = {38747014},
issn = {1460-9568},
support = {5T32AG021885/NH/NIH HHS/United States ; NS043277/NH/NIH HHS/United States ; },
abstract = {Copper is a critical trace element in biological systems due the vast number of essential enzymes that require the metal as a cofactor, including cytochrome c oxidase, superoxide dismutase and dopamine-β-hydroxylase. Due its key role in oxidative metabolism, antioxidant defence and neurotransmitter synthesis, copper is particularly important for neuronal development and proper neuronal function. Moreover, increasing evidence suggests that copper also serves important functions in synaptic and network activity, the regulation of circadian rhythms, and arousal. However, it is important to note that because of copper's ability to redox cycle and generate reactive species, cellular levels of the metal must be tightly regulated to meet cellular needs while avoiding copper-induced oxidative stress. Therefore, it is essential that the intricate system of copper transporters, exporters, copper chaperones and copper trafficking proteins function properly and in coordinate fashion. Indeed, disorders of copper metabolism such as Menkes disease and Wilson disease, as well as diseases linked to dysfunction of copper-requiring enzymes, such as SOD1-linked amyotrophic lateral sclerosis, demonstrate the dramatic neurological consequences of altered copper homeostasis. In this review, we explore the physiological importance of copper in the nervous system as well as pathologies related to improper copper handling.},
}

@article {pmid38746326,
year = {2024},
author = {Spencer, BE and Xie, SX and Elman, LB and Quinn, CC and Amado, D and Baer, M and Lee, EB and Van Deerlin, V and Dratch, L and Massimo, L and Irwin, DJ and McMillan, CT},
title = {C9orf72 repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.30.24306638},
pmid = {38746326},
abstract = {In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), the presence of secondary motor or cognitive-behavioral symptoms, respectively, is associated with shorter survival. However, factors influencing the risk and hazard of secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with amyotrophic lateral sclerosis (n=172) and behavioral-variant frontotemporal degeneration (n=69). Only individuals who had neuropathological confirmation of a TDP-43 proteinopathy at autopsy or had a C9orf72 repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether they were modified by the presence of a C9orf72 repeat expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [1.97-9.14]; p<0.001) and an increased hazard (HR= 4.77 [2.33-9.79], p<0.001) for developing secondary symptoms in C9orf72 expansion carriers compared to noncarriers. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary motor or cognitive-behavioral symptoms. These findings highlight the need for clinician vigilance to detect the onset of secondary motor symptoms and cognitive-behavioral in patients carrying a C9orf72 repeat expansion, regardless of initial clinical syndrome, and may warrant dual referrals between cognitive and neuromuscular clinics in these cases.},
}

@article {pmid38745522,
year = {2024},
author = {Mioshi, E and Grant, K and Flanagan, E and Heal, S and Copsey, H and Gould, RL and Hammond, M and Shepstone, L and Ashford, PA},
title = {An online intervention for carers to manage behavioral symptoms in motor neuron disease (MiNDToolkit): a randomized parallel multi-center feasibility trial.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2024.2350658},
pmid = {38745522},
issn = {2167-9223},
abstract = {BACKGROUND: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design: Randomized, parallel, multi-center, feasibility trial.

SETTING: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23.

PARTICIPANTS: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control.

INTERVENTION: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables.

MAIN OUTCOMES: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period.

CONCLUSION: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.},
}

@article {pmid38745521,
year = {2024},
author = {Fernandez, A and Guenegou, L and Corcia, P and Bailly, N},
title = {The effect of social support on the emotional well-being of people with amyotrophic lateral sclerosis: Exploring the mediating role of spirituality.},
journal = {Palliative & supportive care},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/S1478951524000610},
pmid = {38745521},
issn = {1478-9523},
abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that, so far, is considered always fatal. Treatments mainly consist in increasing survival and aim to improve the quality of life of people with ALS (pwALS). Social support and spirituality have been shown to play a key role in pwALS' quality of life. Our study explored it in depth by investigating the underlying mechanisms linking social support, spirituality, and emotional well-being.

METHODS: Thirty-six pwALS underwent a battery of tests evaluating emotional well-being (emotional well-being scale of the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire), social support (6-item Social Support Questionnaire), and spiritual well-being (12-item Functional Assessment of Chronic Illness Therapy - Spiritual well-being). Our recruitment was web-based through the FILSLAN and the ARSLA websites as well as through Facebook® advertisements (ALS groups). Data were analyzed by Pearson correlation analysis and Process macro was used in an SPSS program to analyze the mediator variable effect.

RESULTS: Availability of social support, spiritual well-being, and 2 of its dimensions, i.e., meaning and peace, were positively correlated with emotional well-being. The mediational analyses showed that spiritual well-being, meaning, and peace act as mediators in the association between availability of social support and good emotional well-being.

SIGNIFICANCE OF RESULTS: Availability of social support and spirituality are essential for the emotional well-being of pwALS. Spirituality as a mediator between availability of social support and emotional well-being appears as real novel finding which could be explored further. Spiritual well-being, meaning, and peace appear as coping resources for pwALS. We provide practical guidance for professionals working with pwALS.},
}

@article {pmid38745475,
year = {2024},
author = {Katangwe-Chigamba, T and Flanagan, E and Mioshi, E},
title = {Implementation of the MiNDToolkit intervention for the management of behavioral symptoms in MND by healthcare professionals: a mixed-methods process evaluation.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2024.2349924},
pmid = {38745475},
issn = {2167-9223},
abstract = {OBJECTIVE: MiNDToolkit is a novel psychoeducational intervention for carers to support management of behavioral symptoms in people living with motor neuron disease (PlwMND). Implementation of MiNDToolkit involves delivery of an online intervention to carers, which is reinforced by trained healthcare professionals (HCPs).

METHODS: A mixed-methods process evaluation of the MiNDToolkit feasibility trial was conducted, focusing on reinforcement of the intervention by HCPs. Quantitative data, descriptively analyzed, were included from platform analytics, questionnaire, and 10 semi-structured interviews with HCPs. Interviews were transcribed verbatim; data were inductively analyzed using Reflective Thematic Analysis.

RESULTS: The MiNDToolkit training and platform is a beneficial and acceptable resource for HCPs with potential to increase knowledge and confidence in identifying and managing behavioral symptoms in MND. Implementation barriers included HCPs' perceptions that highlighting behavior changes would be burdensome to carers and assumptions that carers would take the initiative to ask for support from clinicians. Degree of intervention reinforcement varied, with most HCPs delegating intervention delivery solely to the online platform.

CONCLUSIONS: Implementation of the MiNDToolkit was viewed to be feasible and the platform thought to increase accessibility of support to carers. The flexible approach to delivery (online platform and optional HCP reinforcement) is acceptable as an intervention for supporting carers of PlwMND with behavioral symptoms. However, MiNDToolkit should not negate HCP involvement in providing medical and practical information to PlwMND and families. Future research should explore ways to incorporate support for carers in the management of PlwMND alongside standard care, alongside tools such as the MiNDToolkit.},
}

@article {pmid38745425,
year = {2024},
author = {Nona, RJ and Henderson, RD and McCombe, PA},
title = {Neutrophil-to-lymphocyte ratio at diagnosis as a biomarker for survival of amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/21678421.2024.2351187},
pmid = {38745425},
issn = {2167-9223},
abstract = {Introduction: The neutrophil-to-lymphocyte ratio (NLR) has previously been reported to be associated with survival in ALS. To provide further information about the role of NLR as a biomarker in ALS, we performed a systematic review, analyzed data from our local cohort of ALS subjects and performed a meta-analysis. Methods: (1) The systematic review used established methods. (2) Using data from our cohort of subjects, we analyzed the association of NLR with survival. (3) Meta-analysis was performed using previous studies and our local data. Results: (1) In the systematic review, higher NLR was associated with shorter survival in all studies. (2) In our subjects, survival was significantly shorter in patients in the highest NLR groups. (3) Meta-analysis showed subjects with highest NLR tertile or with NLR >3 had significantly shorter survival than other subjects. Discussion: This study supports NLR as a biomarker in ALS; high NLR is associated with poor survival.},
}

@article {pmid38744216,
year = {2024},
author = {Trivedi, RR and Archambault, AS and Pavlak, C and Gastaldi, M and Cantoni, C and Ghezzi, L and Cross, AH and Miller, TM and Wu, GF},
title = {Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.},
journal = {Journal of the neurological sciences},
volume = {461},
number = {},
pages = {123041},
doi = {10.1016/j.jns.2024.123041},
pmid = {38744216},
issn = {1878-5883},
abstract = {Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.},
}

@article {pmid38743595,
year = {2024},
author = {Klose, V and Jesse, S and Lewerenz, J and Kassubek, J and Dorst, J and Rosenbohm, A and Nagel, G and Wernecke, D and Roselli, F and Tumani, H and Ludolph, AC},
title = {Blood-CSF barrier integrity in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awae144},
pmid = {38743595},
issn = {1460-2156},
abstract = {The integrity of the blood-CSF barrier plays a major role in inflammation, but also in shielding the central nervous system from external and systemic - potentially toxic - factors. Here we report results of measurements of the albumin quotient - which is thought to mirror the integrity of the blood/CSF barrier - in 1059 amyotrophic lateral sclerosis patients. The results were compared with groups of patients suffering from Alzheimer´s disease, facial palsy and tension headache. The albumin quotient, an accepted measure of the blood/CSF barrier integrity, was not significantly different from control populations. In addition, we found that the albumin quotient correlated with survival of the patients; this effect was mainly driven by male patients and influenced by age, BMI and diabetes mellitus. We conclude that the blood/CSF barrier is intact in this large cohort of ALS patients and that the albumin quotient correlates with survival. Whether this is important for the pathogenesis of the disease, requires mechanistic studies.},
}

@article {pmid38743390,
year = {2024},
author = {Vignolo, M and Zuccarino, R and Truffelli, R and Gemelli, C and Giove, E and Ferraro, PM and Manunza, D and Trinchero, C and Cipollina, I and Lungu, M and Lizio, A and Gragnano, G and Cabona, C and Pardini, M and Caponnetto, C and Rao, F},
title = {Dog-assisted physiotherapy in amyotrophic lateral sclerosis: a randomized controlled pilot study.},
journal = {European journal of physical and rehabilitation medicine},
volume = {},
number = {},
pages = {},
doi = {10.23736/S1973-9087.24.08343-6},
pmid = {38743390},
issn = {1973-9095},
abstract = {BACKGROUND: Animal-assisted therapy (AAT) is an intervention in which the animal acts as a co-therapist. It has been mainly used in the context of patients with dementia, showing positive effects on psychological symptoms, but its potential as a physiotherapy treatment for patients with neuromuscular disorders, amyotrophic lateral sclerosis (ALS) in particular, has not yet been investigated.

AIM: The aim of the study was to evaluate the impact of AAT, specifically of dog-assisted therapy, on motor functions and psychological status in patients with ALS.

DESIGN: This study was a randomized controlled pilot study.

SETTING: The study was carried out at the Rehabilitation Unit NEuroMuscular Omnicenter (NEMO) of Arenzano, Genoa.

POPULATION: Sixty hospitalized ALS patients were enrolled.

METHODS: All patients ran a regular two-weeks neurorehabilitation program twice a day. For three days a week, in place of the morning traditional treatment, the AAT group performed a rehabilitation session with a simultaneous interaction with the therapy-dog, while the control group performed a traditional rehabilitation session. The outcome measures were the Timed Up and Go Test, the Short Physical Performance Battery (SPPB), the Six Minutes Walk Test, the Ten Meters walking Test and the Hospital Anxiety and Depression Scale.

RESULTS: Both groups showed an amelioration in motor scales. However, SPPB subscales as well as HADS scores showed a statistically significant improvement only in the AAT group (P values from <0.0001 to 0.0004). Additionally, across almost all motor and psychological measures, post-treatments values were significantly better for the AAT group (P values from <0.0001 to 0.01).

CONCLUSIONS: The obtained results not only suggest that AAT is comparable to traditional physiotherapy treatments, but also evidence that this type of treatment has greater beneficial effects on motor and psychological symptoms in patients with ALS.

This study provides first evidence that AAT is a powerful rehabilitation strategy in patients with ALS, improving both motor and psychological symptoms, and therefore possibly ameliorating quality of life.},
}

@article {pmid38743164,
year = {2024},
author = {Zoccolella, S and Milella, G and Giugno, A and Filardi, M and D'Errico, E and Tamburrino, L and Devitofrancesco, V and Damato, R and Piomboni, F and Misceo, S and Logroscino, G},
title = {Nerve conduction study on the split-hand plus index in Amyotrophic lateral sclerosis: correlations with lower motor neuron impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {38743164},
issn = {1590-3478},
abstract = {INTRODUCTION: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL).

AIMS: In this case-control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features.

METHODS: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP.

RESULTS: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r.

CONCLUSION: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment.},
}

@article {pmid38742757,
year = {2024},
author = {Shephard, VK and Brown, ML and Thompson, BA and Harpur, A and McAlary, L},
title = {Rapid classification of a novel ALS-causing I149S variant in superoxide dismutase-1.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2024.2351177},
pmid = {38742757},
issn = {2167-9223},
abstract = {Variants of the oxygen free radical scavenging enzyme superoxide dismutase-1 (SOD1) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These variants occur in roughly 20% of familial ALS cases, and 1% of sporadic ALS cases. Here, we identified a novel SOD1 variant in a patient in their 50s who presented with movement deficiencies and neuropsychiatric features. The variant was heterozygous and resulted in the isoleucine at position 149 being substituted with a serine (I149S). In silico analysis predicted the variant to be destabilizing to the SOD1 protein structure. Expression of the SOD1[I149S] variant with a C-terminal EGFP tag in neuronal-like NSC-34 cells resulted in extensive inclusion formation and reduced cell viability. Immunoblotting revealed that the intramolecular disulphide between Cys57 and Cys146 was fully reduced for SOD1[I149S]. Furthermore, SOD1[I149S] was highly susceptible to proteolytic digestion, suggesting a large degree of instability to the protein fold. Finally, fluorescence correlation spectroscopy and native-PAGE of cell lysates showed that SOD1[I149S] was monomeric in solution in comparison to the dimeric SOD1[WT]. This experimental data was obtained within 3 months and resulted in the rapid re-classification of the variant from a variant of unknown significance (VUS) to a clinically actionable likely pathogenic variant.},
}

@article {pmid38742544,
year = {2024},
author = {Donohue, C and Vasilopoulos, T and Wymer, JP and Plowman, EK},
title = {Relationship between pulmonary, cough, and swallowing functions in individuals with amyotrophic lateral sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28113},
pmid = {38742544},
issn = {1097-4598},
support = {1R01NS100859/NS/NINDS NIH HHS/United States ; },
abstract = {INTRODUCTION/AIMS: Evaluations of pulmonary, cough, and swallow function are frequently performed to assess disease progression in amyotrophic lateral sclerosis (ALS), yet the relationship between these functions remains unknown. We therefore aimed to determine relationships between these measures in individuals with ALS.

METHODS: One hundred individuals with ALS underwent standardized tests: forced vital capacity (FVC), maximum expiratory/inspiratory pressure (MEP, MIP), voluntary cough peak expiratory flow (PEF), and videofluoroscopic swallow evaluation (VF). Duplicate raters completed independent, blinded ratings using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Descriptives, Spearman's Rho correlations, Kruskal-Wallis analyses, and Pearson's chi-squared tests were completed.

RESULTS: Mean and standard deviation across pulmonary and cough measures were FVC: 74.2% predicted (± 22.6), MEP: 91.6 cmH2O (± 46.4), MIP cmH2O: 61.1 (± 28.9), voluntary PEF: 352.7 L/min (± 141.6). DIGEST grades included: 0 (normal swallowing): 31%, 1 (mild dysphagia): 48%, 2 (moderate dysphagia): 10%, 3 (severe dysphagia): 10%, and 4 (life-threatening dysphagia): 1%. Positive correlations were observed: MEP-MIP: r = .76, MIP-PEF: r = .68, MEP-PEF: r = .61, MIP-FVC: r = .60, PEF-FVC: r = .49, and MEP-FVC: r = .46, p < .0001. MEP (p = .009) and PEF (p = .04) differed across DIGEST safety grades. Post hoc analyses revealed significant between group differences in MEP and PEF across DIGEST safety grades 0 versus 1 and grades 0 versus 3, (p < .05).

DISCUSSION: In this cohort of individuals with ALS, pulmonary function, and voluntary cough were associated. Expiratory metrics (MEP, PEF) were diminished in individuals with unsafe swallowing, increasing their risk for effectively defending the airway.},
}

@article {pmid38742276,
year = {2024},
author = {Cheung, SW and Bhavnani, E and Simmons, DG and Bellingham, MC and Noakes, PG},
title = {Perineuronal nets are phagocytosed by MMP-9 expressing microglia and astrocytes in the SOD1[G93A] ALS mouse model.},
journal = {Neuropathology and applied neurobiology},
volume = {50},
number = {3},
pages = {e12982},
doi = {10.1111/nan.12982},
pmid = {38742276},
issn = {1365-2990},
support = {GIC1842//Motor Neuron Disease Research Australia/ ; I2326//Motor Neuron Disease Research Australia/ ; GIV1842//Motor Neuron Disease Research Australia/ ; IG2326//Motor Neuron Disease Research Australia/ ; 1188169//National Health & Medical Research Council Australia/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Disease Models, Animal ; *Microglia/metabolism/pathology ; *Mice, Transgenic ; Mice ; *Matrix Metalloproteinase 9/metabolism ; *Astrocytes/metabolism/pathology ; Motor Neurons/pathology/metabolism ; Phagocytosis/physiology ; Superoxide Dismutase-1/genetics/metabolism ; Extracellular Matrix/metabolism/pathology ; },
abstract = {AIMS: Perineuronal nets (PNNs) are an extracellular matrix structure that encases excitable neurons. PNNs play a role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can trigger neuronal death, which has been implicated in amyotrophic lateral sclerosis (ALS). We investigated the spatio-temporal timeline of PNN breakdown and the contributing cellular factors in the SOD1[G93A] strain, a fast-onset ALS mouse model.

METHODS: This was conducted at the presymptomatic (P30), onset (P70), mid-stage (P130), and end-stage disease (P150) using immunofluorescent microscopy, as this characterisation has not been conducted in the SOD1[G93A] strain.

RESULTS: We observed a significant breakdown of PNNs around α-motor neurons in the ventral horn of onset and mid-stage disease SOD1[G93A] mice compared with wild-type controls. This was observed with increased numbers of microglia expressing matrix metallopeptidase-9 (MMP-9), an endopeptidase that degrades PNNs. Microglia also engulfed PNN components in the SOD1[G93A] mouse. Further increases in microglia and astrocyte number, MMP-9 expression, and engulfment of PNN components by glia were observed in mid-stage SOD1[G93A] mice. This was observed with increased expression of fractalkine, a signal for microglia engulfment, within α-motor neurons of SOD1[G93A] mice. Following PNN breakdown, α-motor neurons of onset and mid-stage SOD1[G93A] mice showed increased expression of 3-nitrotyrosine, a marker for protein oxidation, which could render them vulnerable to death.

CONCLUSIONS: Our observations suggest that increased numbers of MMP-9 expressing glia and their subsequent engulfment of PNNs around α-motor neurons render these neurons sensitive to oxidative damage and eventual death in the SOD1[G93A] ALS model mouse.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics
*Disease Models, Animal
*Microglia/metabolism/pathology
*Mice, Transgenic
Mice
*Matrix Metalloproteinase 9/metabolism
*Astrocytes/metabolism/pathology
Motor Neurons/pathology/metabolism
Phagocytosis/physiology
Superoxide Dismutase-1/genetics/metabolism
Extracellular Matrix/metabolism/pathology

@article {pmid38741492,
year = {2024},
author = {Kanda, S and Kanda, T},
title = {[Multifocal Motor Neuropathy].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {76},
number = {5},
pages = {526-533},
doi = {10.11477/mf.1416202639},
pmid = {38741492},
issn = {1881-6096},
mesh = {Humans ; *Polyneuropathies/physiopathology/diagnosis ; Immunoglobulins, Intravenous/therapeutic use/administration & dosage ; },
abstract = {Multifocal motor neuropathy (MMN), an acquired chronic progressive immune-mediated motor neuropathy, is characterized by asymmetrical distal upper limb muscle weakness and muscle atrophy without sensory impairment. Differentiation from amyotrophic lateral sclerosis is usually challenging, and electrophysiological studies show multifocal conduction blocks. Immunoglobulin (Ig)M GM1 antibodies are detected in approximately 50% of patients. In contrast to chronic inflammatory demyelinating polyneuropathy, corticosteroids are ineffective for management of MMN, and IVIg is the sole established treatment.},
}

Humans
*Polyneuropathies/physiopathology/diagnosis
Immunoglobulins, Intravenous/therapeutic use/administration & dosage

@article {pmid38741111,
year = {2024},
author = {Maresova, P and Rezny, L and Bauer, P and Valko, M and Kuca, K},
title = {Nonpharmacological intervention therapies for dementia: potential break-even intervention price and savings for selected risk factors in the European healthcare system.},
journal = {BMC public health},
volume = {24},
number = {1},
pages = {1293},
pmid = {38741111},
issn = {1471-2458},
support = {ERDF No. CZ.02.1.01/0.0/0.0/18_069/0010054-IT4Neuro(degeneration)//Ministry of Education Youth and Sports/ ; Excellence 2022//UHK FIM/ ; },
mesh = {Humans ; *Dementia/economics/epidemiology/prevention & control ; Risk Factors ; Europe/epidemiology ; Cost Savings ; Aged ; Health Care Costs/statistics & numerical data ; Models, Theoretical ; Male ; Female ; Prevalence ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: New effective treatments for dementia are lacking, and early prevention focusing on risk factors of dementia is important. Non-pharmacological intervention therapies aimed at these factors may provide a valuable tool for reducing the incidence of dementia. This study focused on the development of a mathematical model to predict the number of individuals with neurodegenerative diseases, specifically Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. Scenarios for non-pharmacological intervention therapies based on risk factor reduction were also assessed. The estimated total costs and potential cost savings from societal were included.

METHODS: Based on demographic and financial data from the EU, a mathematical model was developed to predict the prevalence and resulting care costs of neurodegenerative diseases in the population. Each disease (Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis) used parameters that included prevalence, incidence, and death risk ratio, and the simulation is related to the age of the cohort and the disease stage.

RESULTS: A replicable simulation for predicting the prevalence and resulting cost of care for neurodegenerative diseases in the population exhibited an increase in treatment costs from 267 billion EUR in 2021 to 528 billion EUR by 2050 in the EU alone. Scenarios related to the reduction of the prevalence of dementia by up to 20% per decade led to total discounted treatment cost savings of up to 558 billion EUR.

CONCLUSION: The model indicates the magnitude of the financial burden placed on EU healthcare systems due to the growth in the population prevalence of neurodegenerative diseases in the coming decades. Lifestyle interventions based on reducing the most common risk factors could serve as a prevention strategy to reduce the incidence of dementia with substantial cost-savings potential. These findings could support the implementation of public health approaches throughout life to ultimately prevent premature mortality and promote a healthier and more active lifestyle in older individuals.},
}

Humans
*Dementia/economics/epidemiology/prevention & control
Risk Factors
Europe/epidemiology
Cost Savings
Aged
Health Care Costs/statistics & numerical data
Models, Theoretical
Male
Female
Prevalence
Aged, 80 and over
Middle Aged

@article {pmid38739991,
year = {2024},
author = {Li, X and Liu, N and Wu, D and Li, SC and Wang, Q and Zhang, DW and Song, LL and Huang, M and Chen, X and Li, W},
title = {Hippocampal transcriptomic analyses reveal the potential antiapoptotic mechanism of a novel anticonvulsant agent Q808 on pentylenetetrazol-induced epilepsy in rats.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {175},
number = {},
pages = {116746},
doi = {10.1016/j.biopha.2024.116746},
pmid = {38739991},
issn = {1950-6007},
abstract = {Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.},
}

@article {pmid38739934,
year = {2024},
author = {Xin, J and Huang, S and Wen, J and Li, Y and Li, A and Satyanarayanan, SK and Yao, X and Su, H},
title = {Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.0440},
pmid = {38739934},
issn = {2152-5250},
abstract = {Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.},
}

@article {pmid38739752,
year = {2024},
author = {Droppelmann, CA and Campos-Melo, D and Noches, V and McLellan, C and Szabla, R and Lyons, TA and Amzil, H and Withers, B and Kaplanis, B and Sonkar, KS and Simon, A and Buratti, E and Junop, M and Kramer, JM and Strong, MJ},
title = {Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awae078},
pmid = {38739752},
issn = {1460-2156},
support = {/CAPMC/CIHR/Canada ; },
abstract = {Aggregation of the RNA-binding protein TAR DNA binding protein (TDP-43) is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein GEF (guanine exchange factor) and RNA-binding protein rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that an N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs of TDP-43 competing with RNA and that the IPT/TIG domain of NF242 is essential for this interaction. Genetic expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with a strong affinity for TDP-43 aggregates and a mechanism that includes competition with RNA sequestration, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.},
}

@article {pmid38738747,
year = {2024},
author = {de Araújo, CM and de Alcântara, C and Alencar, MA and da Gama, NAS and Cruzeiro, MM and França, MC and Jaeger, A and Camargos, ST and Machado, TH and de Souza, LC},
title = {Language impairment in sporadic and familial (type 8) amyotrophic lateral sclerosis: A comparative study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28109},
pmid = {38738747},
issn = {1097-4598},
support = {//Brazilian National Council for Scientific and Technological Development (CNPq)/ ; 001//CAPES/ ; },
abstract = {INTRODUCTION/AIMS: Language is frequently affected in patients with sporadic amyotrophic lateral sclerosis (sALS), with reduced performance in naming, syntactic comprehension, grammatical expression, and orthographic processing. However, the language profile of patients with familial type 8 ALS (ALS8), linked to p.P56S VAPB mutation, remains unclear. We investigated language in patients with ALS8 by examining their auditory comprehension and verbal production.

METHODS: We included three groups of participants: (1) patients with sALS (n = 20), (2) patients with familial ALS8 (n = 22), and (3) healthy controls (n = 21). The groups were matched for age, sex, and education level. All participants underwent a comprehensive language battery, including the Boston Diagnostic Aphasia Examination, the reduced Token test, letter fluency, categorical fluency (animals), word definition from the Cambridge Semantic Memory Research Battery, and a narrative discourse analysis. Participants also were evaluated using Addenbrooke's Cognitive Exam-Revised Version, the Hospital Anxiety and Depression Scale, and the ALS Functional Rating Scale-Revised.

RESULTS: Compared to controls, sALS and ALS8 patients had impaired performance on oral (syntactic and phonological processing) comprehension and inappropriate discourse cohesion. sALS and ALS8 did not differ in any language measure. There was no correlation between language scores and functional and psychiatric scales.

DISCUSSION: ALS8 patients exhibit language deficits that are independent of motor features. These findings are consistent with the current evidence suggesting that ALS8 has prominent non-motor features.},
}

@article {pmid38738727,
year = {2024},
author = {Bhushan, B and Singh, K and Kumar, S and Bhardwaj, A},
title = {Advancements in CRISPR-Based Therapies for Genetic Modulation in Neurodegenerative Disorders.},
journal = {Current gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665232292246240426125504},
pmid = {38738727},
issn = {1875-5631},
abstract = {: Neurodegenerative disorders pose significant challenges in the realm of healthcare, as these conditions manifest in complex, multifaceted ways, often attributed to genetic anomalies. With the emergence of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, a new frontier has been unveiled in the quest for targeted, precise genetic manipulation. This abstract explores the recent advancements and potential applications of CRISPR-based therapies in addressing genetic components contributing to various neurodegenerative disorders. The review delves into the foundational principles of CRISPR technology, highlighting its unparalleled ability to edit genetic sequences with unprecedented precision. In addition, it talks about the latest progress in using CRISPR to target specific genetic mutations linked to neurodegenerative diseases like Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. It talks about the most important studies and trials that show how well and safely CRISPR-based therapies work. This shows how this technology can change genetic variants that cause diseases. Notably, the discussion emphasizes the challenges and ethical considerations associated with the implementation of CRISPR in clinical settings, including off-target effects, delivery methods, and long-term implications. Furthermore, the article explores the prospects and potential hurdles in the widespread application of CRISPR technology for treating neurodegenerative disorders. It touches upon the need for continued research, improved delivery mechanisms, and ethical frameworks to ensure responsible and equitable access to these groundbreaking therapies.},
}

@article {pmid38738637,
year = {2024},
author = {Błaszczyk, L and Ryczek, M and Das, B and Mateja-Pluta, M and Bejger, M and Śliwiak, J and Nakatani, K and Kiliszek, A},
title = {Antisense RNA C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms a triplex-like structure and binds small synthetic ligand.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae376},
pmid = {38738637},
issn = {1362-4962},
support = {UMO-2022/45/B/NZ7/03543//National Science Centre/ ; 22H00351//Japan Society for the Promotion of Science/ ; },
abstract = {The abnormal expansion of GGGGCC/GGCCCC hexanucleotide repeats (HR) in C9orf72 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Structural polymorphisms of HR result in the multifactorial pathomechanism of ALS/FTD. Consequently, many ongoing studies are focused at developing therapies targeting pathogenic HR RNA. One of them involves small molecules blocking sequestration of important proteins, preventing formation of toxic nuclear foci. However, rational design of potential therapeutics is hindered by limited number of structural studies of RNA-ligand complexes. We determined the crystal structure of antisense HR RNA in complex with ANP77 ligand (1.1 Å resolution) and in the free form (0.92 and 1.5 Å resolution). HR RNA folds into a triplex structure composed of four RNA chains. ANP77 interacted with two neighboring single-stranded cytosines to form pseudo-canonical base pairs by adopting sandwich-like conformation and adjusting the position of its naphthyridine units to the helical twist of the RNA. In the unliganded structure, the cytosines formed a peculiar triplex i-motif, assembled by trans C•C+ pair and a third cytosine located at the Hoogsteen edge of the C•C+ pair. These results extend our knowledge of the structural polymorphisms of HR and can be used for rational design of small molecules targeting disease-related RNAs.},
}

@article {pmid38738213,
year = {2023},
author = {Fan, C and Hahn, N and Kamdar, F and Avansino, D and Wilson, GH and Hochberg, L and Shenoy, KV and Henderson, JM and Willett, FR},
title = {Plug-and-Play Stability for Intracortical Brain-Computer Interfaces: A One-Year Demonstration of Seamless Brain-to-Text Communication.},
journal = {Advances in neural information processing systems},
volume = {36},
number = {},
pages = {42258-42270},
pmid = {38738213},
issn = {1049-5258},
support = {R01 DC014034/DC/NIDCD NIH HHS/United States ; R01 EB028171/EB/NIBIB NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; },
abstract = {Intracortical brain-computer interfaces (iBCIs) have shown promise for restoring rapid communication to people with neurological disorders such as amyotrophic lateral sclerosis (ALS). However, to maintain high performance over time, iBCIs typically need frequent recalibration to combat changes in the neural recordings that accrue over days. This requires iBCI users to stop using the iBCI and engage in supervised data collection, making the iBCI system hard to use. In this paper, we propose a method that enables self-recalibration of communication iBCIs without interrupting the user. Our method leverages large language models (LMs) to automatically correct errors in iBCI outputs. The self-recalibration process uses these corrected outputs ("pseudo-labels") to continually update the iBCI decoder online. Over a period of more than one year (403 days), we evaluated our Continual Online Recalibration with Pseudo-labels (CORP) framework with one clinical trial participant. CORP achieved a stable decoding accuracy of 93.84% in an online handwriting iBCI task, significantly outperforming other baseline methods. Notably, this is the longest-running iBCI stability demonstration involving a human participant. Our results provide the first evidence for long-term stabilization of a plug-and-play, high-performance communication iBCI, addressing a major barrier for the clinical translation of iBCIs.},
}

@article {pmid38738022,
year = {2024},
author = {De Jesus-Morales, K and De Jesús-Rojas, W and Ramos-Benitez, MJ},
title = {Neutrophil-to-Lymphocyte Ratio Dynamics From Pre-diagnosis to End-Stage Amyotrophic Lateral Sclerosis (ALS): A Case Study on Association With Progression and Clinical Events.},
journal = {Cureus},
volume = {16},
number = {4},
pages = {e58109},
pmid = {38738022},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons, resulting in muscle weakness and paralysis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential marker for monitoring disease severity and progression in ALS, yet longitudinal analyses of NLR are limited. Our study conducts an in-depth examination of NLR dynamics from before diagnosis through the disease's progression to its end stage. We analyze the case of a 56-year-old Puerto Rican male with ALS, tracking his NLR over 13 years - six years before and seven years after his diagnosis - alongside assessments of clinical symptoms and lung function. Our findings indicate that NLR values were initially normal but significantly increased with the onset of symptoms. NLR remained elevated above the normal range, with a notable exception during a period of edaravone therapy when levels normalized. The study demonstrates a clear elevation in NLR associated with ALS progression and critical clinical events, such as symptom onset, diagnosis, and the initiation of respiratory support. This research is, to our knowledge, the first to provide a detailed characterization of NLR changes from the pre-diagnostic phase to end-stage ALS, showing its correlation with clinical deterioration, decreased pulmonary function, and key clinical events. Our results contribute to the body of evidence on NLR's role in ALS while enhancing our understanding of ALS's natural progression.},
}

@article {pmid38735361,
year = {2024},
author = {D'Agostino, F and Eugenio Agrò, F and Petrosino, P and Ferri, C and Ristagno, G},
title = {Are Instructors Correctly Gauging Ventilation Competence Acquired by Course Attendees?.},
journal = {Resuscitation},
volume = {},
number = {},
pages = {110240},
doi = {10.1016/j.resuscitation.2024.110240},
pmid = {38735361},
issn = {1873-1570},
abstract = {Achievement of adequate ventilation skills during training courses is mainly based on instructors' perception of attendees' capability to ventilate with correct rate and chest compression:ventilation ratio, while leading to chest raising, as evidence of adequate tidal volume. Accuracy in evaluating ventilation competence was assessed in 20 ACLS provider course attendees, by comparing course instructors' evaluation with measures from a ventilation feedback device. According to course instructors, all candidates acquired adequate ventilation competence. However, data from the feedback device indicated a ventilation not aligned with current guidelines, with higher tidal volume and lower rate (p<0.01). Deploying quality ventilation during CPR is a skill whose acquisition starts with effective training. Therefore, course instructors' capability to accurately evaluate attendees' ventilation maneuvers is crucial.},
}

@article {pmid38735299,
year = {2024},
author = {Gould, RL and McDermott, CJ and Thompson, BJ and Rawlinson, CV and Bursnall, M and Bradburn, M and Kumar, P and Turton, EJ and White, DA and Serfaty, MA and Graham, CD and McCracken, LM and Goldstein, LH and Al-Chalabi, A and Orrell, RW and Williams, T and Noad, R and Baker, I and Faull, C and Lambert, T and Chhetri, SK and Ealing, J and Hanratty, A and Radunovic, A and Gunawardana, N and Meadows, G and Gorrie, GH and Young, T and Lawrence, V and Cooper, C and Shaw, PJ and Howard, RJ and , },
title = {Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(24)00533-6},
pmid = {38735299},
issn = {1474-547X},
abstract = {BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease.

METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391).

FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention.

INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services.

FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.},
}

@article {pmid38735139,
year = {2024},
author = {Im, G and Choi, D},
title = {Molecular and physiological characterization of AIP1, encoding the acetolactate synthase regulatory subunit in rice.},
journal = {Biochemical and biophysical research communications},
volume = {718},
number = {},
pages = {150087},
doi = {10.1016/j.bbrc.2024.150087},
pmid = {38735139},
issn = {1090-2104},
abstract = {Flooding deprives plants of oxygen and thereby causes severe stress by interfering with energy production, leading to growth retardation. Enzymes and metabolites may help protect plants from waterlogging and hypoxic environmental conditions. Acetolactate synthase (ALS) is a key enzyme in the biosynthesis of branched-chain amino acids (BCAAs), providing the building blocks for proteins and various secondary metabolites. Additionally, under energy-poor conditions, free BCAAs can be used as an alternative energy source by mitochondria through a catabolic enzyme chain reaction. In this study, we characterized ALS-INTERACTING PROTEIN 1 (OsAIP1), which encodes the regulatory subunit of ALS in rice (Oryza sativa). This gene was expressed in all parts of the rice plant, and its expression level was significantly higher in submerged and low-oxygen environments. Rice transformants overexpressing OsAIP1 showed a higher survival rate under hypoxic stress than did non-transgenic control plants under the same conditions. The OsAIP1-overexpressing plants accumulated increased levels of BCAAs, demonstrating that OsAIP1 is an important factor in the hypoxia resistance mechanism. These results suggest that ALS proteins are part of a defense mechanism that improves the tolerance of plants to low-oxygen environments.},
}

@article {pmid38734896,
year = {2024},
author = {Sun, S and Shen, Y and Zhang, X and Ding, N and Xu, Z and Zhang, Q and Li, L},
title = {The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2024.05.016},
pmid = {38734896},
issn = {1525-0024},
abstract = {The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PR[F/F] mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.},
}

@article {pmid38734122,
year = {2024},
author = {Panchalingam, S and Kasivelu, G},
title = {Exploring the impact of circular RNA on ALS progression: A systematic review.},
journal = {Brain research},
volume = {1838},
number = {},
pages = {148990},
doi = {10.1016/j.brainres.2024.148990},
pmid = {38734122},
issn = {1872-6240},
abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disease that damages motor neurons and causes gradual muscular weakening and paralysis. Although studies have linked a number of genetic and environmental factors to ALS, the specific causes and mechanisms of the disease are still unclear. The pivotal role of circular RNA in the pathogenesis of ALS is a newly emerging area of research. The term "circular RNA" describes a particular class of RNA molecule that, in contrast to most RNA molecules, has a closed-loop structure. According to recent research, circular RNA might be essential for the development and progression of ALS. It has been discovered that these circular RNAs support important cellular functions related to ALS, including protein turnover, mitochondrial function, RNA processing, and cellular transport. Gaining knowledge about the precise roles and processes of circular RNA in the development of ALS could assist in understanding the pathophysiology of the disease and possibly pave the way for the development of targeted therapies. However, the understanding of circular RNA in ALS is still limited, and more research is needed to fully elucidate its role. In order to gain a comprehensive understanding of the role of circRNAs in ALS, it is imperative to delve into the various mechanisms through which circRNAs may contribute to the development and progression of the disease. Examining the current status of circRNA research in ALS and offering insights into their potential as therapeutic targets and diagnostic markers are the primary objectives of this review.},
}

@article {pmid38733435,
year = {2024},
author = {Liu, S and Hong, Y and Wang, BR and Wei, ZQ and Zhao, HD and Jiang, T and Zhang, YD and Shi, JQ},
title = {The presence and clinical significance of autoantibodies in amyotrophic lateral sclerosis: a narrative review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {38733435},
issn = {1590-3478},
abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.},
}

@article {pmid38732386,
year = {2024},
author = {Zhang, Y and Zhao, A and Mu, L and Teng, X and Ma, Y and Li, R and Lei, K and Ji, L and Wang, X and Li, P},
title = {First Clarification of the Involvement of Glycosyltransferase MdUGT73CG22 in the Detoxification Metabolism of Nicosulfuron in Apple.},
journal = {Plants (Basel, Switzerland)},
volume = {13},
number = {9},
pages = {},
pmid = {38732386},
issn = {2223-7747},
support = {No. ZR202102180037//Shandong Provincial Natural Science Foundation of China/ ; No. LCUGYTD2022-04//Guangyue Young Scholar Innovation Team of Liaocheng University/ ; },
abstract = {Nicosulfuron, an acetolactate synthase (ALS) inhibitor herbicide, is a broad-spectrum and highly effective post-emergence herbicide. Glycosyltransferases (GTs) are widely found in organisms and transfer sugar molecules from donors to acceptors to form glycosides or sugar esters, thereby altering the physicochemical properties of the acceptor molecule, such as participating in detoxification. In this study, nine glycosyltransferases in group D of the apple glycosyltransferase family I were predicted to possibly be involved in the detoxification metabolism of ALS-inhibiting herbicides based on gene chip data published online. In order to confirm this, we analysed whether the expression of the nine glycosyltransferase genes in group D was induced by the previously reported ALS-inhibiting herbicides by real-time PCR (polymerase chain reaction). It was found that the ALS-inhibiting herbicide nicosulfuron significantly increased the expression of the MdUGT73CG22 gene in group D. Further investigation of the mechanism of action revealed that the apple glycosyltransferase MdUGT73CG22 glycosylated and modified nicosulfuron both in vivo and ex vivo to form nicosulfuron glycosides, which were involved in detoxification metabolism. In conclusion, a new glycosyltransferase, MdUGT73CG22, was identified for the first time in this study, which can glycosylate modifications of the ALS-inhibiting herbicide nicosulfuron and may be involved in the detoxification process in plants, which can help to further improve the knowledge of the non-targeted mechanism of herbicides.},
}

@article {pmid38732027,
year = {2024},
author = {Cantara, S and Simoncelli, G and Ricci, C},
title = {Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.},
journal = {International journal of molecular sciences},
volume = {25},
number = {9},
pages = {},
pmid = {38732027},
issn = {1422-0067},
mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use ; *Motor Neuron Disease/genetics/therapy ; Animals ; Muscular Atrophy, Spinal/therapy/genetics ; Amyotrophic Lateral Sclerosis/genetics/therapy ; },
abstract = {Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.},
}

Humans
*Oligonucleotides, Antisense/therapeutic use
*Motor Neuron Disease/genetics/therapy
Animals
Muscular Atrophy, Spinal/therapy/genetics
Amyotrophic Lateral Sclerosis/genetics/therapy

@article {pmid38731036,
year = {2024},
author = {Ueha, R and Miura, C and Matsumoto, N and Sato, T and Goto, T and Kondo, K},
title = {Vocal Fold Motion Impairment in Neurodegenerative Diseases.},
journal = {Journal of clinical medicine},
volume = {13},
number = {9},
pages = {},
pmid = {38731036},
issn = {2077-0383},
abstract = {Vocal fold motion impairment (VFMI) is the inappropriate movement of the vocal folds during respiration, leading to vocal fold adduction and/or abduction problems and causing respiratory and vocal impairments. Neurodegenerative diseases (NDDs) are a wide range of disorders characterized by progressive loss of neurons and deposition of altered proteins in the brain and peripheral organs. VFMI may be unrecognized in patients with NDDs. VFMI in NDDs is caused by the following: laryngeal muscle weakness due to muscular atrophy, caused by brainstem and motor neuron degeneration in amyotrophic lateral sclerosis; hyperactivity of laryngeal adductors in Parkinson's disease; and varying degrees of laryngeal adductor hypertonia and abductor paralysis in multiple system atrophy. Management of VFMI depends on whether there is a presence of glottic insufficiency or insufficient glottic opening with/without severe dysphagia. VFMI treatment options for glottic insufficiency range from surgical interventions, including injection laryngoplasty and medialization thyroplasty, to behavioral therapies; for insufficient glottic opening, various options are available based on the severity and underlying cause of the condition, including continuous positive airway pressure therapy, botulinum toxin injection, tracheostomy, vocal fold surgery, or a combination of interventions. In this review, we outline the mechanisms, clinical features, and management of VFMI in NDDs and provide a guide for physicians who may encounter these clinical features in their patients. NDDs are always progressive; hence, timely evaluation, proper diagnosis, and appropriate management of the patient will greatly affect their vocal, respiratory, and swallowing functions as well as their quality of life.},
}

@article {pmid38729175,
year = {2024},
author = {Bayraktar, B and Golbasi, H and Omeroglu, I and Golbasi, C and Tunver Can, S and Ince, O and Bayraktar, MG and Ozer, M and Ekin, A},
title = {Evaluation of placenta and fetal lung using shear wave elastography in gestational diabetes mellitus: An innovative approach.},
journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2323-0941},
pmid = {38729175},
issn = {1438-8782},
abstract = {PURPOSE: This study aims to investigate placental and fetal lung stiffness in pregnant women with and without gestational diabetes, considering the well-established delay in fetal lung maturation associated with gestational diabetes.

MATERIALS AND METHODS: This prospective cohort study was conducted at a tertiary center and included pregnant women who underwent a 75-gram oral glucose tolerance test between 24-28 weeks of gestation. Elastography measurements were performed using point shear wave elastography (pSWE).

RESULTS: The study included 60 pregnant women diagnosed with gestational diabetes and 60 pregnant women in the control group. SWE velocity of peripheral placenta, central placenta, and lung were higher in the gestational diabetes group compared to the control group. Furthermore, SWE velocity of peripheral placenta, central placenta, and lung were higher in newborns with neonatal respiratory morbidity. Based on the ROC analysis of gestational diabetes patients the AUC for lung SWE velocity was 0.88 (cut-off 12.4 kPa, 95% CI: 0.77-0.99, p<0.001) with a sensitivity of 71.4% and specificity of 95.6% in predicting neonatal respiratory morbidity.

CONCLUSION: Fetal placental and lung stiffness increase in fetuses of pregnant women with diabetes. Moreover, higher fetal lung stiffness during the fetal period is associated with increased neonatal respiratory morbidity. Zweck: Diese Studie zielt darauf ab, die Lungensteifheit der Plazenta und des Fötus bei schwangeren Frauen mit und ohne Schwangerschaftsdiabetes zu untersuchen, wobei die bekannte Verzögerung der fetalen Lungenreifung im Zusammenhang mit Schwangerschaftsdiabetes berücksichtigt wird. Materialien und Methoden: Diese prospektive Kohortenstudie wurde an einem tertiären Zentrum durchgeführt und umfasste schwangere Frauen, die sich zwischen der 24. und 28. Schwangerschaftswoche einem oralen 75-Gramm-Glukosetoleranztest unterzogen. Elastographiemessungen wurden mittels Punktscherwellenelastographie (pSWE) durchgeführt. Ergebnisse: Die Studie umfasste 60 schwangere Frauen mit diagnostiziertem Schwangerschaftsdiabetes und 60 schwangere Frauen in der Kontrollgruppe. Die SWE-Geschwindigkeit der peripheren Plazenta, der zentralen Plazenta und der Lunge war in der Gruppe mit Schwangerschaftsdiabetes höher als in der Kontrollgruppe. Darüber hinaus war die SWE-Geschwindigkeit der peripheren Plazenta, der zentralen Plazenta und der Lunge bei Neugeborenen mit neonataler respiratorischer Morbidität höher. Basierend auf der ROC-Analyse von Patienten mit Schwangerschaftsdiabetes betrug die AUC für die Lungen-SWE-Geschwindigkeit 0,88 (Grenzwert 12,4 kPa, 95 %-KI: 0,77-0,99, p < 0,001) mit einer Sensitivität von 71,4 % und einer Spezifität von 95,6 % bei der Vorhersage neonataler Erkrankungen Atemwegsmorbidität. Schlussfolgerung: Die Steifheit der fetalen Plazenta und der Lunge nimmt bei Feten schwangerer Frauen mit Diabetes zu. Darüber hinaus ist eine höhere fetale Lungensteifheit während der Fetalperiode mit einer erhöhten Atemwegsmorbidität bei Neugeborenen verbunden.},
}

@article {pmid38728654,
year = {2024},
author = {McFarlane, R and Heverin, M and Walsh, C and Hardiman, O},
title = {Irish Amyotrophic Lateral Sclerosis Incidence: Age, Period, and Cohort Effects Using a Partial Least Squares Regression Model.},
journal = {Neurology},
volume = {102},
number = {11},
pages = {e209391},
doi = {10.1212/WNL.0000000000209391},
pmid = {38728654},
issn = {1526-632X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Ireland/epidemiology ; Incidence ; Aged ; Middle Aged ; Male ; Female ; Adult ; Least-Squares Analysis ; Aged, 80 and over ; Registries ; Age Factors ; Cohort Effect ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: To investigate the underlying reasons for variability in the incidence rate of amyotrophic lateral sclerosis (ALS) within the Irish population between the years 1996 and 2021.

METHODS: The Irish ALS register was used to calculate the incidence and to subsequently extract age at diagnosis (age), year of diagnosis (period), and date of birth (cohort) for all incident patients within the study period (n = 2,771). An age-period-cohort (APC) model using partial least squares regression was constructed to examine each component separately and their respective contribution to the incidence while minimizing the well-known identifiability problem of APC effects. A dummy regression model consisting of 5 periods, 19 cohorts, and 16 age groups was used to examine nonlinear relationships within the data over time. The CIs for each of these were estimated using the jackknife method.

RESULTS: The nonlinear model achieved R[2] of 99.43% with 2-component extraction. Age variation was evident with those in the ages 65-79 years contributing significantly to the incidence (βmax = 0.0746, SE = 0.000410, CI 0.00665-0.00826). However, those aged 25-60 years contributed significantly less (βmin = -0.00393, SE = 0.000291, CI -0.00454 to -0.00340). Each successive period showed an increase in the regression model coefficient suggesting an increasing incidence over time, independent of the other factors examined-an increase of β from -0.00489 (SE = 0.000264, CI -0.00541 to -0.00437) to 0.00973 (SE = 0.000418, CI 0.0105-0.00891). A cohort effect was demonstrated showing that the contribution of those born between 1927 and 1951 contributed to a significantly greater degree than the other birth cohorts (βmax = 0.00577, SE = 0.000432, CI 0.00493-0.00662).

DISCUSSION: Using the Irish population-based ALS Register, robust age, period, and cohort effects can be identified. The age effect may be accounted for by demographic shifts within the population. Changes in disease categorization, competing risks of death, and improved surveillance may account for period effects. The cohort effect may reflect lifestyle and environmental factors associated with the challenging economic circumstances in Ireland between 1927 and 1951. Age-period-cohort studies can help to account for changes in disease incidence and prevalence, providing additional insights into likely demographic and environmental factors that influence population-based disease risk.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology
Ireland/epidemiology
Incidence
Aged
Middle Aged
Male
Female
Adult
Least-Squares Analysis
Aged, 80 and over
Registries
Age Factors
Cohort Effect
Cohort Studies

@article {pmid38727285,
year = {2024},
author = {Gao, Y and Lu, Y and Liang, X and Zhao, M and Yu, X and Fu, H and Yang, W},
title = {CD4[+] T-Cell Senescence in Neurodegenerative Disease: Pathogenesis and Potential Therapeutic Targets.},
journal = {Cells},
volume = {13},
number = {9},
pages = {},
pmid = {38727285},
issn = {2073-4409},
support = {20230505039ZP//Jilin Province Science and Technology Department/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/immunology/pathology/therapy ; *CD4-Positive T-Lymphocytes/immunology ; *Cellular Senescence/immunology ; Animals ; Aging/immunology/pathology ; T-Cell Senescence ; },
abstract = {With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence. T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4[+] T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4[+] T-cells in NDs. In this review, we summarize the classification and function of CD4[+] T-cell subpopulations, the characteristics of CD4[+] T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4[+] T-cell senescence.},
}

Humans
*Neurodegenerative Diseases/immunology/pathology/therapy
*CD4-Positive T-Lymphocytes/immunology
*Cellular Senescence/immunology
Animals
Aging/immunology/pathology
T-Cell Senescence

@article {pmid38726613,
year = {2024},
author = {LaForge, JR},
title = {A Poem About ALS.},
journal = {The American journal of nursing},
volume = {124},
number = {5},
pages = {10},
doi = {10.1097/01.NAJ.0001016304.08449.3a},
pmid = {38726613},
issn = {1538-7488},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing ; Poetry as Topic ; },
}

Humans
*Amyotrophic Lateral Sclerosis/nursing
Poetry as Topic

@article {pmid38726604,
year = {2024},
author = {López Gómez, JJ and Díaz Marín, C and Castillo-García, T and Larrad-Sainz, A and Gastaldo-Simeón, R and Juarros-Martínez, S and Leunda-Eizmendi, L and Civera Andrés, M and Matía Martín, P},
title = {[Medical nutrition therapy in amyotrophic lateral sclerosis - Do we act or react? A case report and multidisciplinary review].},
journal = {Nutricion hospitalaria},
volume = {},
number = {},
pages = {},
doi = {10.20960/nh.05189},
pmid = {38726604},
issn = {1699-5198},
abstract = {BACKGROUND: amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a progressive course. The current prevalence is between 3 and 6 cases/100,000. Malnutrition is closely related to patient prognosis in ALS. The implications of this conditions have been that we should recommend patient care in a multidisciplinary unit.

CASE REPORT: the case presented shows the evolution of a patient with ALS. The patient was referred to different clinical departments after neurological evaluation and her nutritional, functional and respiratory status were assessed. There was no nutritional deterioration at diagnosis; however, intake was below energy-protein requirements. The clinical evolution of the patient showed a decrease in muscle mass with preservation of weight and fat mass. "Aggressive" measures to control nutritional status such as gastrostomy were rejected in the initial stages of the disease, but had to be carried out after development of dysphagia and associated malnutrition. This situation of progressive morphofunctional deterioration and the development of disease-related complications made essential the participation of different health services and professionals in its control.

DICUSSION: the management of ALS in a multidisciplinary manner allows to improve the course of the disease and the quality of life of both the patients and their families. Patient follow-up is based on the adjustment and management of complications. The basis of the relationship with these patients includes maintaining an adequate communication with them and their families, and ensuring joint decision-making about their condition.},
}

@article {pmid38726482,
year = {2024},
author = {Henden, L and Fearnley, LG and Southwood, D and Smith, A and Rowe, DB and Kiernan, MC and Pamphlett, R and Bahlo, M and Blair, IP and Williams, KL},
title = {Short tandem repeat expansions in LRP12 are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2024.2348636},
pmid = {38726482},
issn = {2167-9223},
abstract = {In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in LRP12 is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether LRP12 CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for LRP12 CGG expansions using ExpansionHunter v4. All individuals had LRP12 CGG repeat lengths within the normal range of 3-25 units. To date, LRP12 CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.},
}

@article {pmid38725125,
year = {2024},
author = {Kim, D and Kim, S and Seok, JM and Shin, KJ and Oh, E and Jeon, MY and Park, J and Chang, HJ and Youn, J and Oh, J and Sohn, E and Park, J and Cho, JW and Kim, BJ},
title = {Establishment of a registry of clinical data and bioresources for rare nervous system diseases.},
journal = {Osong public health and research perspectives},
volume = {15},
number = {2},
pages = {174-181},
pmid = {38725125},
issn = {2210-9099},
support = {2023ER050600//National Institute of Health research/ ; },
abstract = {Rare diseases are predominantly genetic or inherited, and patients with these conditions frequently exhibit neurological symptoms. Diagnosing and treating many rare diseases is a complex challenge, and their low prevalence complicates the performance of research, which in turn hinders the advancement of therapeutic options. One strategy to address this issue is the creation of national or international registries for rare diseases, which can help researchers monitor and investigate their natural progression. In the Republic of Korea, we established a registry across 5 centers that focuses on 3 rare diseases, all of which are characterized by gait disturbances resulting from motor system dysfunction. The registry will collect clinical information and human bioresources from patients with amyotrophic lateral sclerosis, spinocerebellar ataxia, and hereditary spastic paraplegia. These resources will be stored at ICreaT and the National Biobank of Korea. Once the registry is complete, the data will be made publicly available for further research. Through this registry, our research team is dedicated to identifying genetic variants that are specific to Korean patients, uncovering biomarkers that show a strong correlation with clinical symptoms, and leveraging this information for early diagnosis and the development of treatments.},
}

@article {pmid38724513,
year = {2024},
author = {Zhou, T and Solis, NV and Marshall, M and Yao, Q and Garleb, R and Yang, M and Pearlman, E and Filler, SG and Liu, H},
title = {Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3926},
pmid = {38724513},
issn = {2041-1723},
support = {R01 GM117111/GM/NIGMS NIH HHS/United States ; R01 EY018612/EY/NEI NIH HHS/United States ; },
mesh = {Animals ; Mice ; beta-Glucans/metabolism/immunology ; Candida albicans/immunology ; *Candidiasis/immunology/microbiology ; CD11b Antigen/metabolism/immunology ; *CD18 Antigens/metabolism ; Dendritic Cells/immunology/metabolism ; *Fungal Proteins/metabolism/immunology ; *Lectins, C-Type/metabolism/immunology ; *Macrophages/immunology/metabolism ; Signal Transduction ; },
abstract = {Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMβ2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the "outside-in signaling" for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.},
}

Animals
Mice
beta-Glucans/metabolism/immunology
Candida albicans/immunology
*Candidiasis/immunology/microbiology
CD11b Antigen/metabolism/immunology
*CD18 Antigens/metabolism
Dendritic Cells/immunology/metabolism
*Fungal Proteins/metabolism/immunology
*Lectins, C-Type/metabolism/immunology
*Macrophages/immunology/metabolism
Signal Transduction

@article {pmid38723941,
year = {2024},
author = {Doeleman, LC and Boomars, R and Radstok, A and Schober, P and Dellaert, Q and Hollmann, MW and Koster, RW and van Schuppen, H},
title = {Ventilation during cardiopulmonary resuscitation with mechanical chest compressions: how often are two insufflations being given during the 3-second ventilation pauses?.},
journal = {Resuscitation},
volume = {},
number = {},
pages = {110234},
doi = {10.1016/j.resuscitation.2024.110234},
pmid = {38723941},
issn = {1873-1570},
abstract = {BACKGROUND: Mechanical chest compression devices in 30:2 mode provide 3-second pauses to allow for two insufflations. We aimed to determine how often two insufflations are provided in these ventilation pauses, in order to assess if prehospital providers are able to ventilate out-of-hospital cardiac arrest (OHCA) patients successfully during mechanical chest compressions.

METHODS: Data from OHCA cases of the regional ambulance service of Utrecht, The Netherlands, were prospectively collected in the UTrecht studygroup for OPtimal registry of cardIAc arrest database (UTOPIA). Compression pauses and insufflations were visualized on thoracic impedance and waveform capnography signals recorded by manual defibrillators. Ventilation pauses were analyzed for number of insufflations, duration of the subintervals of the ventilation cycles, and ratio of successfully providing two insufflations over the course of the resuscitation. Generalized linear mixed effects models were used to accurately estimate proportions and means.

RESULTS: In 250 cases, 8473 ventilation pauses were identified, of which 4305 (51%) included two insufflations. When corrected for non-independence of the data across repeated measures within the same subjects with a mixed effects analysis, two insufflations were successfully provided in 45% of ventilation pauses (95% CI: 40-50%). In 19% (95% CI: 16-22%) none were given.

CONCLUSION: Providing two insufflations during pauses in mechanical chest compressions is mostly unsuccessful. We recommend developing strategies to improve giving insufflations when using mechanical chest compression devices. Increasing the pause duration might help to improve insufflation success.},
}

@article {pmid38723906,
year = {2024},
author = {Koike, Y},
title = {Molecular mechanisms linking loss of TDP-43 function to amyotrophic lateral sclerosis/frontotemporal dementia-related genes.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neures.2024.05.001},
pmid = {38723906},
issn = {1872-8111},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion and cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43). TDP-43 plays a key role in regulating the splicing of numerous genes, including TARDBP. This review aims to delineate two aspects of ALS/FTD pathogenesis associated with TDP-43 function. First, we provide novel mechanistic insights into the splicing of UNC13A, a TDP-43 target gene. Single nucleotide polymorphisms (SNPs) in UNC13A are the most common risk factors for ALS/FTD. We found that TDP-43 represses "cryptic exon" inclusion during UNC13A RNA splicing. A risk-associated SNP in this exon results in increased RNA levels of UNC13A retaining the cryptic exon. Second, we described the perturbation of the TDP-43 autoregulatory mechanism caused by age-related DNA demethylation. Aging is a major risk factor for sporadic ALS/FTD. Typically, TDP-43 levels are regulated via alternative splicing of TARDBP mRNA. We hypothesized that TARDBP methylation is altered by aging, thereby disrupting TDP-43 autoregulation. We found that demethylation reduces the efficiency of alternative splicing and increases TARDBP mRNA levels. Moreover, we demonstrated that, with aging, this region is demethylated in the human motor cortex and is associated with the early onset of ALS.},
}

@article {pmid38723752,
year = {2024},
author = {Singh, K and Sethi, P and Datta, S and Chaudhary, JS and Kumar, S and Jain, D and Gupta, JK and Kumar, S and Guru, A and Panda, SP},
title = {Advances in Gene Therapy Approaches Targeting Neuro-inflammation in Neurodegenerative Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102321},
doi = {10.1016/j.arr.2024.102321},
pmid = {38723752},
issn = {1872-9649},
abstract = {Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. In AD, the binding of Aβ with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs.},
}

@article {pmid38722513,
year = {2024},
author = {Sultana, J and Ragagnin, AMG and Parakh, S and Saravanabavan, S and Soo, KY and Vidal, M and Jagaraj, CJ and Ding, K and Wu, S and Shadfar, S and Don, EK and Deva, A and Nicholson, G and Rowe, DB and Blair, I and Yang, S and Atkin, JD},
title = {C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {38722513},
issn = {1559-1182},
support = {10305133//National Health and Medical Research Council/ ; 1086887//National Health and Medical Research Council/ ; 1095215//National Health and Medical Research Council/ ; 1176913//National Health and Medical Research Council/ ; },
abstract = {Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are debilitating neurodegenerative conditions affecting either motor neurons (ALS) in the brain and spinal cord or neurons in the frontal and/or temporal cortical lobes (FTD). HREs undergo repeat-associated non-ATG (RAN) translation on both sense and anti-sense strands, generating five distinct dipeptide repeat proteins (DPRs), poly-GA, -GR, -GP, -PA and -PR. Perturbed proteostasis is well-recognised in ALS pathogenesis, including processes affecting the endoplasmic reticulum (ER) and Golgi compartments. However, these mechanisms have not been well characterised for C9orf72-mediated ALS/FTD. In this study we demonstrate that C9orf72 DPRs polyGA, polyGR and polyGP (× 40 repeats) disrupt secretory protein transport from the ER to the Golgi apparatus in neuronal cells. Consistent with this finding, these DPRs also induce fragmentation of the Golgi apparatus, activate ER stress, and inhibit the formation of the omegasome, the precursor of the autophagosome that originates from ER membranes. We also demonstrate Golgi fragmentation in cells undergoing RAN translation that express polyGP. Furthermore, dysregulated ER-Golgi transport was confirmed in C9orf72 patient dermal fibroblasts. Evidence of aberrant ER-derived vesicles in spinal cord motor neurons from C9orf72 ALS patients compared to controls was also obtained. These data thus confirm that ER proteostasis and ER-Golgi transport is perturbed in C9orf72-ALS in the absence of protein over-expression. Hence this study identifies novel molecular mechanisms associated with the ER and Golgi compartments induced by the C9orf72 HRE.},
}

@article {pmid38721655,
year = {2024},
author = {Christoforidou, E and Moody, L and Joilin, G and Simoes, FA and Gordon, D and Talbot, K and Hafezparast, M},
title = {The ALS-associated TDP-43M337V mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner.},
journal = {Disease models & mechanisms},
volume = {},
number = {},
pages = {},
doi = {10.1242/dmm.050638},
pmid = {38721655},
issn = {1754-8411},
support = {Hafezparast/Apr21/880-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; },
abstract = {Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation may originate from microglia. Furthermore, TDP-43, involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia, and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, miR-16-5p, miR-99a-5p, and miR-191-5p by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and identified their predicted targets, which include primarily genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.},
}

@article {pmid38721118,
year = {2024},
author = {Lu, L and Deng, Y and Xu, R},
title = {Current potential therapeutics of amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1402962},
pmid = {38721118},
issn = {1664-2295},
abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neurological disorder for which there is still no cure. The disease seriously jeopardizes the health and lifespan of adult populations. The authors extensively retrieved the current literature about clinical and experimental ALS treatments. Based on them, this review primarily focused on summarizing the current potential clinical usage and trialing therapeutics of ALS. Currently, the clinical ALS treatments have focused primarily on relieving symptoms to improve the quality of life yet. There are a number of therapeutic approaches such as medicine, gene therapy, neuron protectants, combination therapy and stem cells. Among them, Stem cells including embryonic stem cells, mesenchymal stem cells, neural stem cells, and many other types of stem cells have been used in ALS treatment, and although the short-term efficacy is good, it is worth exploring whether this improved efficacy leads to prolonged patient survival. In addition, the supportive treatments also exert an important effect on improving the quality of life and prolong the survival of ALS patients in absence of effectively care for stopping or reversing the progression of ALS.},
}

@article {pmid38720896,
year = {2024},
author = {Zong, J and Yang, Y and Wang, H and Zhang, H and Yang, X and Yang, X},
title = {The two-directional prospective association between inflammatory bowel disease and neurodegenerative disorders: a systematic review and meta-analysis based on longitudinal studies.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1325908},
pmid = {38720896},
issn = {1664-3224},
mesh = {Humans ; *Inflammatory Bowel Diseases/complications ; *Neurodegenerative Diseases/epidemiology/etiology ; Longitudinal Studies ; Risk Factors ; Prospective Studies ; },
abstract = {OBJECTIVE: Previous studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders.

METHODS: We accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model.

RESULTS: The final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer's disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03-1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13-1.36, P<0.001), multiple sclerosis (HR =2.07, 95% CI:1.42-3.02, P<0.001) and Parkinson's disease (HR =1.23, 95% CI:1.10-1.38, P<0.001). Two articles reported an increased incidence of amyotrophic lateral sclerosis or multiple system atrophy in IBD patients. Three studies investigated the prospective association between multiple sclerosis and IBD, revealing an elevated risk of the latter in patients with the former. (HR=1.87, 95% CI:1.66-2.10, P<0.001).

INTERPRETATION: These findings verified the two-directional relationship between the brain-gut axis, specifically demonstrating a heightened risk of various neurodegenerative diseases among IBD patients. It may be profitable to prepare screening strategies for IBD patients to find neurodegenerative diseases during the long-term course of treatment for IBD with a view to potential earlier diagnosis and treatment of neurodegenerative diseases, reducing public health and social burden.

PROSPERO (CRD42023437553).},
}

Humans
*Inflammatory Bowel Diseases/complications
*Neurodegenerative Diseases/epidemiology/etiology
Longitudinal Studies
Risk Factors
Prospective Studies

@article {pmid38720484,
year = {2024},
author = {Fernandes, JMA and Gondim, FAA},
title = {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 = {1-3},
doi = {10.1080/21678421.2024.2346824},
pmid = {38720484},
issn = {2167-9223},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease usually associated with severe weakness and death within 2-5 years. SOD1 mutations cause hereditary ALS in autosomal dominant and rarely in recessive pattern. We describe a new phenotype of slowly progressive fALS due to homozygous SOD1 mutations (c.358G > C, p.Val120Leu) in a Brazilian family. We reviewed the medical chart and interviewed the index patient and other relatives. A 41-year-old man developed weakness in his legs, leading to frequent falls, followed over the next few months with progressive arm fasciculations and muscle atrophy. The SOD1 enzymatic activity in erythrocytes was slightly decreased. A genetic test panel disclosed homozygous SOD1 mutations (c.358G > C, p.Val120Leu). His asymptomatic parents also carried one mutant allele and 2 brothers and a sister had died with ALS. We reported a new family with homozygous SOD1 mutation and slowly progressive ALS course. Further studies are necessary to confirm whether this mutation can also lead to disease in heterozygosis with incomplete penetrance.},
}

@article {pmid38720470,
year = {2024},
author = {Didcote, L and Al-Chalabi, A and Goldstein, LH},
title = {How the coronavirus pandemic affected the lives of people with ALS and their spouses in the UK from spouses' perspectives: a qualitative study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2024.2346501},
pmid = {38720470},
issn = {2167-9223},
abstract = {OBJECTIVE: This study set out to investigate, using qualitative methodology, the experiences of spouses of people with Amyotrophic Lateral Sclerosis (ALS) during the coronavirus pandemic, with particular focus on spouse distress and cognitive and behavioral change in people with ALS (pwALS).

METHODS: Qualitative semi-structured interviews of nine spouses of pwALS living in England were conducted between 11/09/2020 and 20/04/2021, focusing on spouses' perspectives of how their lives and the lives of pwALS were affected by the pandemic and related lockdowns. Interviews were subject to thematic analysis.

RESULTS: Four superordinate themes were identified from the spouses' interviews: (i) pandemic behaviors, which encompassed accounts of cautious behavior, relaxation of cautious behavior, and other people's attitudes to shielding the person with ALS; (ii) changes to daily life caused by the pandemic and progression of ALS; (iii) distress in spouses, which included anxiety, depression, and burden; and (iv) ALS-related behavioral impairment. Spouses also provided mixed accounts of telehealth care, pointing out its convenience but some felt that face-to-face appointments were preferable.

CONCLUSIONS: While many reactions to the pandemic reported by spouses of pwALS may have been similar to those of the general population or other vulnerable groups, interviews indicated the potential for the pandemic to have made more apparent certain aspects of behavioral change in pwALS with which carers may require support. Clinicians need to acknowledge spouses' concerns about the potential limitations of remote clinical consultations, enquire about cognitive and behavioral change, and consider how input should be best provided in such limiting circumstances.},
}

@article {pmid38719860,
year = {2024},
author = {Cusaro, CM and Capelli, E and Picco, AM and Brusoni, M},
title = {Incidence of resistance to ALS and ACCase inhibitors in Echinochloa species and soil microbial composition in Northern Italy.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {10544},
pmid = {38719860},
issn = {2045-2322},
support = {ECS00000036//MUR - M4C2 1.5 of PNRR funded by the European Union - NextGenerationEU/ ; },
mesh = {*Soil Microbiology ; Italy/epidemiology ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Acetolactate Synthase/antagonists & inhibitors/genetics ; *Echinochloa/drug effects ; *Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors ; Plant Weeds/drug effects ; Microbiota/drug effects ; Biodiversity ; Bacteria/drug effects/genetics/isolation & purification/classification ; Soil/chemistry ; Fungi/drug effects/isolation & purification/genetics ; },
abstract = {The increasing amount of weeds surviving herbicide represents a very serious problem for crop management. The interaction between microbial community of soil and herbicide resistance, along with the potential evolutive consequences, are still poorly known and need to be investigated to better understand the impact on agricultural management. In our study, we analyzed the microbial composition of soils in 32 farms, located in the Northern Italy rice-growing area (Lombardy) with the aim to evaluate the relationship between the microbial composition and the incidence of resistance to acetolactate synthase (ALS) and acetyl-CoA carboxylase (ACCase) inhibiting herbicides in Echinochloa species. We observed that the coverage of weeds survived herbicide treatment was higher than 60% in paddy fields with a low microbial biodiversity and less than 5% in those with a high microbial biodiversity. Fungal communities showed a greater reduction in richness than Bacteria. In soils with a reduced microbial diversity, a significant increase of some bacterial and fungal orders (i.e. Lactobacillales, Malasseziales and Diaporthales) was observed. Interestingly, we identified two different microbial profiles linked to the two conditions: high incidence of herbicide resistance (H-HeR) and low incidence of herbicide resistance (L-HeR). Overall, the results we obtained allow us to make hypotheses on the greater or lesser probability of herbicide resistance occurrence based on the composition of the soil microbiome and especially on the degree of biodiversity of the microbial communities.},
}

*Soil Microbiology
Italy/epidemiology
*Herbicide Resistance
*Herbicides/pharmacology
*Acetolactate Synthase/antagonists & inhibitors/genetics
*Echinochloa/drug effects
*Acetyl-CoA Carboxylase/genetics/antagonists & inhibitors
Plant Weeds/drug effects
Microbiota/drug effects
Biodiversity
Bacteria/drug effects/genetics/isolation & purification/classification
Soil/chemistry
Fungi/drug effects/isolation & purification/genetics

@article {pmid38718295,
year = {2024},
author = {Huang, J and Fu, Y and Wang, A and Shi, K and Peng, Y and Yi, Y and Yu, R and Gao, J and Feng, J and Jiang, G and Song, Q and Jiang, J and Chen, H and Gao, X},
title = {Brain Delivery of Protein Therapeutics by Cell Matrix-inspired Biomimetic Nanocarrier.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e2405323},
doi = {10.1002/adma.202405323},
pmid = {38718295},
issn = {1521-4095},
abstract = {Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, we used the cell matrix components hyaluronic acid (HA) and protamine (PRTM) to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated it into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitated the penetration of protein therapeutics across the BBB and enabled their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitated rapid intracellular delivery and release of CAT via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduced the latency of TBI mice and doubled the number of crossing platforms), and enhanced motor function and prolonged survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases. This article is protected by copyright. All rights reserved.},
}

@article {pmid38717990,
year = {2024},
author = {Yu, X and Sun, J and Yang, Y and Zhang, J and Lu, Y and Tang, W},
title = {Enhanced Herbicide Metabolism and Target Site Mutation Enabled the Multiple Resistance to Cyhalofop-butyl, Florpyrauxifen-benzyl, and Penoxsulam in Echinochloa crus-galli.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.4c02450},
pmid = {38717990},
issn = {1520-5118},
abstract = {This study investigated the multiple herbicide resistance (MHR) mechanism of one Echinochloa crus-galli population that was resistant to florpyrauxifen-benzyl (FPB), cyhalofop-butyl (CHB), and penoxsulam (PEX). This population carried an Ala-122-Asn mutation in the acetolactate synthase (ALS) gene but no mutation in acetyl-CoA carboxylase (ACCase) and transport inhibitor response1 (TIR1) genes. The metabolism rate of PEX was 2-fold higher, and the production of florpyrauxifen-acid and cyhalofop-acid was lower in the resistant population. Malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) could reverse the resistance, suggesting that cytochrome P450 (CYP450) and glutathione S-transferase (GST) contribute to the enhanced metabolism. According to RNA-seq and qRT-PCR validation, two CYP450 genes (CYP71C42 and CYP71D55), one GST gene (GSTT2), two glycosyltransferase genes (rhamnosyltransferase 1 and IAAGLU), and two ABC transporter genes (ABCG1 and ABCG25) were induced by CHB, FPB, and PEX in the resistant population. This study revealed that the target mutant and enhanced metabolism were involved in the MHR mechanism in E. crus-galli.},
}

@article {pmid38717875,
year = {2024},
author = {Chen, M and Zhou, P},
title = {2CFastICA: A N ovel Method for H igh D ensity S urface EMG D ecomposition B ased on K ernel C onstrained FastICA and C orrelation C onstrained FastICA.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2024.3398822},
pmid = {38717875},
issn = {1558-0210},
abstract = {This study presents a novel high density surface electromyography (EMG) decomposition method, named as 2CFastICA, because it incorporates two key algorithms: kernel constrained FastICA and correlation constrained FastICA. The former focuses on overcoming the local convergence of FastICA without requiring the peel-off strategy used in the progressive FastICA peel-off (PFP) framework. The latter further refines the output of kernel constrained FastICA by correcting possible erroneous or missed spikes. The two constrained FastICA algorithms supplement each other to warrant the decomposition performance. The 2CFastICA method was validated using simulated surface EMG signals with different motor unit numbers and signal to noise ratios (SNRs). Two source validation was also performed by simultaneous high density surface EMG and intramuscular EMG recordings, showing a matching rate (MR) of (97.2 ± 3.5) % for 170 common motor units. In addition, a different form of two source validation was also conducted taking advantages of the high density surface EMG characteristics of patients with amyotrophic lateral sclerosis, showing a MR of (99.4 ± 0.9) % for 34 common motor units from interference and sparse datasets. Both simulation and experimental results indicate that 2CFastICA can achieve similar decomposition performance to PFP. However, the efficiency of decomposition can be greatly improved by 2CFastICA since the complex signal processing procedures associated with the peel-off strategy are not required any more. Along with this paper, we also provide the MATLAB open source code of 2CFastICA for high density surface EMG decomposition.},
}

@article {pmid38717430,
year = {2024},
author = {Boyce, D and Raymond, J and Larson, TC and Kirkland, E and Horton, DK and Mehta, P},
title = {What do you think caused your ALS? An analysis of the CDC national amyotrophic lateral sclerosis patient registry qualitative risk factor data using artificial intelligence and qualitative methodology.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2024.2349920},
pmid = {38717430},
issn = {2167-9223},
abstract = {Objective: Amyotrophic lateral sclerosis (ALS) is an incurable, progressive neurodegenerative disease with a significant health burden and poorly understood etiology. This analysis assessed the narrative responses from 3,061 participants in the Centers for Disease Control and Prevention's National ALS Registry who answered the question, "What do you think caused your ALS?" Methods: Data analysis used qualitative methods and artificial intelligence (AI) using natural language processing (NLP), specifically, Bidirectional Encoder Representations from Transformers (BERT) to explore responses regarding participants' perceptions of the cause of their disease. Results: Both qualitative and AI analysis methods revealed several, often aligned themes, which pointed to perceived causes including genetic, environmental, and military exposures. However, the qualitative analysis revealed detailed themes and subthemes, providing a more comprehensive understanding of participants' perceptions. Although there were areas of alignment between AI and qualitative analysis, AI's broader categories did not capture the nuances discovered using the more traditional, qualitative approach. The qualitative analysis also revealed that the potential causes of ALS were described within narratives that sometimes indicate self-blame and other maladaptive coping mechanisms. Conclusions: This analysis highlights the diverse range of factors that individuals with ALS consider as perceived causes for their disease. Understanding these perceptions can help clinicians to better support people living with ALS (PLWALS). The analysis highlights the benefits of using traditional qualitative methods to supplement or improve upon AI-based approaches. This rapidly evolving area of data science has the potential to remove barriers to accessing the rich narratives of people with lived experience.},
}

@article {pmid38717009,
year = {2024},
author = {Zhang, X and Sun, Y and Zhang, X and Shen, D and Shu, S and Yang, X and Liu, M and Cui, L and Liu, Q and Zhang, X},
title = {Genotype-phenotype association and functional analysis of hnRNPA1 mutations in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2024.2346502},
pmid = {38717009},
issn = {2167-9223},
abstract = {BACKGROUND: Pathogenic variants in hnRNPA1 have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on hnRNPA1 mutant spectrum and pathogenicity of variants were rare.

METHODS: We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in hnRNPA1 in our ALS patients. The hnRNPA1 mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant hnRNPA1 into 293T cell.

RESULTS: Among 207 ALS patients recruited, 3 rare hnRNPA1 variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 hnRNPA1 mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD ("prion-like" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed.

CONCLUSION: Mutations in hnRNPA1 are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of hnRNPA1 cause stress granule misprocessing.},
}

@article {pmid38716751,
year = {2024},
author = {Schito, P and Manera, U and Russo, T and Cremona, G and Riboldi, E and Tettamanti, A and Agosta, F and Quattrini, A and Chiò, A and Filippi, M and Calvo, A and Riva, N},
title = {Use of the combination of spirometry, arterial blood gas analysis and overnight oximetry to predict the outcomes of patients affected by motor neuron disease: The Milan-Torin respiratory score (Mi-To-RS).},
journal = {European journal of neurology},
volume = {},
number = {},
pages = {e16316},
doi = {10.1111/ene.16316},
pmid = {38716751},
issn = {1468-1331},
support = {//Giovanni Marazzina Foundation/ ; },
abstract = {BACKGROUND AND PURPOSE: The use of multiple tests, including spirometry, arterial blood gas (ABG) analysis and overnight oximetry (OvOx), is highly recommended to monitor the respiratory function of patients with motor neuron disease (MND). In this study, we propose a composite score to simplify the respiratory management of MND patients and better stratify their prognosis.

MATERIALS AND METHODS: We screened the clinical charts of 471 non-ventilated MND patients referred to the Neuro-rehabilitation Unit of the San Raffaele Scientific Institute of Milan (January 2001-December 2019), collecting spirometric, ABG and OvOx parameters. To evaluate the prognostic role of each measurement, univariate Cox regression for death/tracheostomy was performed, and the variables associated with survival were selected to design a scoring system. Univariate and multivariate Cox regression analyses were then carried out to evaluate the prognostic role of the score. Finally, results were replicated in an independent cohort from the Turin ALS Center.

RESULTS: The study population included 450 patients. Six measurements were found to be significantly associated with survival and were selected to design a scoring system (maximum score = 8 points). Kaplan-Meier analysis showed significant stratification of survival and time to non-invasive mechanical ventilation adaptation according to score values, and multivariate analysis confirmed the independent effect of the respiratory score on survival of each cohort.

CONCLUSION: Forced vital capacity, ABG and OvOx parameters provide complementary information for the respiratory management and prognosis of MND patients and the combination of these parameters into a single score might help neurologists predict prognosis and guide decisions on the timing of the implementation of different diagnostic or therapeutic approaches.},
}

@article {pmid38715656,
year = {2024},
author = {Paul, S and Dansithong, W and Gandelman, M and Figueroa, KP and Scoles, DR and Pulst, SM},
title = {Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2.},
journal = {Neurology. Genetics},
volume = {10},
number = {2},
pages = {e200144},
pmid = {38715656},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive neurodegenerative polyglutamine (polyQ) disease, is caused by a CAG repeat expansion in the ataxin-2 (ATXN2) gene. In this study, we determined miRNA transcriptomes in SCA2-BAC-ATXN2[Q72] transgenic mice.

METHODS: We assessed the expression of miRNAs in SCA2 transgenic mouse cerebella using the HiSeq Illumina sequencer. We used the miRNA target filter tool in Qiagen Ingenuity Pathway Analysis (IPA) to identify target genes of differentially expressed miRNAs (DEmiRs) within in the SCA2 mouse transcriptomes and then performed pathway analyses.

RESULTS: Our analysis revealed significant changes in the expression levels of multiple miRNAs in mice with SCA2. We identified 81 DEmiRs in mice with SCA2, with 52 miRNAs upregulated and 29 miRNAs downregulated after onset of rotarod deficit. Subsequent IPA processing enabled us to establish connections between these DEmiRs and specific biological regulatory functions. Furthermore, by using the IPA miRNA target filter, we identified target genes of DEmiRs in the SCA2-BAC-ATXN2[Q72] transcriptome data set and demonstrated their significant impact on several biological functional and disease pathways.

DISCUSSION: Our study establishes the role of both DEmiRs and their targets in SCA2 pathogenesis. By expressing mutant ATXN2 under the control of its endogenous regulatory elements in the SCA2-BAC-ATXN2[Q72] mouse model, we identified a set of DEmiRs that are shared across multiple neurodegenerative diseases including other SCAs, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). There was a significant overlap of both DEmiRs and their targets of BAC-ATXN2[Q72] transcriptomes in dysregulated pathways that characterize SCA2. This observation also extended to dysregulated pathways in ALS, AD, and PD. DEmiRs identified in this study may represent therapeutic targets for neurodegeneration or lead to biomarkers for characterizing various neurodegenerative diseases.},
}

@article {pmid38713169,
year = {2024},
author = {Nikel, LM and Talbot, K and Vahsen, BF},
title = {Recent insights from human induced pluripotent stem cell models into the role of microglia in amyotrophic lateral sclerosis.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e2400054},
doi = {10.1002/bies.202400054},
pmid = {38713169},
issn = {1521-1878},
support = {Talbot/Apr22/889-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, primarily leading to the degeneration of motor neurons. The traditional focus on motor neuron-centric mechanisms has recently shifted towards understanding the contribution of non-neuronal cells, such as microglia, in ALS pathophysiology. Advances in induced pluripotent stem cell (iPSC) technology have enabled the generation of iPSC-derived microglia monocultures and co-cultures to investigate their role in ALS pathogenesis. Here, we briefly review the insights gained from these studies into the role of microglia in ALS. While iPSC-derived microglia monocultures have revealed intrinsic cellular dysfunction due to ALS-associated mutations, microglia-motor neuron co-culture studies have demonstrated neurotoxic effects of mutant microglia on motor neurons. Based on these findings, we briefly discuss currently unresolved questions and how they could be addressed in future studies. iPSC models hold promise for uncovering disease-relevant pathways in ALS and identifying potential therapeutic targets.},
}

@article {pmid38712849,
year = {2024},
author = {Ludolph, AC and Corcia, P and Desnuelle, C and Heiman-Patterson, T and Mora, JS and Mansfield, CD and Couratier, P},
title = {Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28101},
pmid = {38712849},
issn = {1097-4598},
support = {//AB Science/ ; },
abstract = {The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.},
}

@article {pmid38712174,
year = {2024},
author = {Ozkan, A and Padmanabhan, HK and Shipman, SL and Azim, E and Kumar, P and Sadegh, C and Basak, AN and Macklis, JD},
title = {Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.21.590488},
pmid = {38712174},
abstract = {Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo , or for optimally informative disease modeling and/or therapeutic screening in vitro , it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing inappropriate proneural Neurog2 expression by progenitors. We FACS-purify these genetically accessible progenitors from postnatal mouse cortex and establish a pure culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2 , while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo . They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2 -driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from genetically accessible cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.},
}

@article {pmid38715858,
year = {2021},
author = {Gupta, S and Sharma, U},
title = {Metabolomics of neurological disorders in India.},
journal = {Analytical science advances},
volume = {2},
number = {11-12},
pages = {594-610},
pmid = {38715858},
issn = {2628-5452},
abstract = {Metabolomics is the comprehensive study of the metabolome and its alterations within biological fluids and tissues. Over the years, applications of metabolomics have been explored in several areas, including personalised medicine in diseases, metabolome-wide association studies (MWAS), pharmacometabolomics and in combination with other branches of omics such as proteomics, transcriptomics and genomics. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the major analytical techniques widely employed in metabolomics. In addition, MS is coupled with chromatography techniques like gas chromatography (GC) and liquid chromatography (LC) to separate metabolites before analysis. These analytical techniques have made possible identification and quantification of large numbers of metabolites, encompassing characterization of diseases and facilitating a systematic and rational therapeutic strategy based on metabolic patterns. In recent years, the metabolomics approach has been used to obtain a deeper insight into the underlying biochemistry of neurodegenerative disorders and the discovery of biomarkers of clinical implications. The current review mainly focuses on an Indian perspective of metabolomics for the identification of metabolites and metabolic alterations serving as potential diagnostic biomarkers for neurological diseases including acute spinal cord injury, amyotrophic lateral sclerosis, tethered cord syndrome, spina bifida, stroke, Parkinson's disease, glioblastoma and neurological disorders with inborn errors of metabolism.},
}

@article {pmid38712171,
year = {2024},
author = {Islam, Z and Polash, A and Suzawa, M and Chim, B and Kuhn, S and Sultana, S and Cutrona, N and Smith, PT and Kabat, J and Ganesan, S and Foroushani, A and Hafner, M and Muljo, SA},
title = {MATRIN3 deficiency triggers autoinflammation via cGAS-STING activation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.01.587645},
pmid = {38712171},
abstract = {UNLABELLED: Interferon-stimulated genes (ISGs) comprise a program of immune effectors important for host immune defense. When uncontrolled, ISGs play a central role in interferonopathies and other inflammatory diseases. The mechanisms responsible for turning on ISGs are not completely known. By investigating MATRIN3 (MATR3), a nuclear RNA-binding protein mutated in familial ALS, we found that perturbing MATR3 results in elevated expression of ISGs. Using an integrative approach, we elucidate a pathway that leads to activation of cGAS-STING. This outlines a plausible mechanism for pathogenesis in a subset of ALS, and suggests new diagnostic and therapeutic approaches for this fatal disease.

ONE-SENTENCE SUMMARY: Mis-splicing of Tudor Domain Containing 3 (TDRD3) in the absence of MATR3 unleashes R-loops and interferon-stimulated genes.},
}

@article {pmid38711658,
year = {2024},
author = {Otero, G and Bolatto, C and Isasi, E and Cerri, S and Rodríguez, P and Boragno, D and Marco, M and Parada, C and Stancov, M and Cuitinho, MN and Olivera-Bravo, S},
title = {Adult aberrant astrocytes submitted to late passage cultivation lost differentiation markers and decreased their pro-inflammatory profile.},
journal = {Heliyon},
volume = {10},
number = {9},
pages = {e30360},
pmid = {38711658},
issn = {2405-8440},
abstract = {In amyotrophic lateral sclerosis (ALS), astrocytes are considered key players in some non-cell non-neuronal autonomous mechanisms that underlie motor neuron death. However, it is unknown how much of these deleterious features were permanently acquired. To assess this point, we evaluated if the most remarkable features of neurotoxic aberrant glial phenotypes (AbAs) isolated from paralytic rats of the ALS model G93A Cu/Zn superoxide dismutase 1 (SOD1) could remain upon long lasting cultivation. Real time PCR, immunolabelling and zymography analysis showed that upon many passages, AbAs preserved the cell proliferation capacity, mitochondrial function and response to different compounds that inhibit some key astrocyte functions but decreased the expression of parameters associated to cell lineage, homeostasis and inflammation. As these results are contrary to the sustained inflammatory status observed along disease progression in SOD1G93A rats, we propose that the most AbAs remarkable features related to homeostasis and neurotoxicity were not permanently acquired and might depend on the signaling coming from the injuring microenvironment present in the degenerating spinal cord of terminal rats.},
}

@article {pmid38711616,
year = {2024},
author = {Chen, L and Chen, G and Zhang, M and Zhang, X},
title = {Modeling sporadic juvenile ALS in iPSC-derived motor neurons explores the pathogenesis of FUS[R503fs] mutation.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1364164},
pmid = {38711616},
issn = {1662-5102},
abstract = {INTRODUCTION: Fused in sarcoma (FUS) mutations represent the most common genetic etiology of juvenile amyotrophic lateral sclerosis (JALS), for which effective treatments are lacking. In a prior report, we identified a novel FUS mutation, c.1509dupA: p. R503fs (FUSR503fs), in a sporadic JALS patient.

METHODS: The physicochemical properties and structure of FUSR503fs protein were analyzed by software: Multi-electrode array (MEA) assay, calcium activity imaging assay and transcriptome analysis were used to explore the pathophysiological mechanism of iPSC derived motor neurons.

RESULTS: Structural analysis and predictions regarding physical and chemical properties of this mutation suggest that the reduction of phosphorylation and glycosylation sites, along with alterations in the amino acid sequence, may contribute to abnormal FUS accumulation within the cytoplasm and nucleus of induced pluripotent stem cell- derived motor neurons (MNs). Multi-electrode array and calcium activity imaging indicate diminished spontaneous electrical and calcium activity signals in MNs harboring the FUS[R503fs] mutation. Transcriptomic analysis reveals upregulation of genes associated with viral infection and downregulation of genes involved in neural function maintenance, such as the ATP6V1C2 gene. Treatment with ropinirole marginally mitigates the electrophysiological decline in FUS[R503fs] MNs, suggesting the utility of this cell model for mechanistic exploration and drug screening.

DISCUSSION: iPSCs-derived motor neurons from JALS patients are promising tools for drug screening. The pathological changes in motor neurons of FUS[R503fs] may occur earlier than in other known mutation types that have been reported.},
}

@article {pmid38711277,
year = {2024},
author = {Vakilipour, P and Fekrvand, S},
title = {Brain-to-brain interface technology: A brief history, current state, and future goals.},
journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1002/jdn.10334},
pmid = {38711277},
issn = {1873-474X},
abstract = {A brain-to-brain interface (BBI), defined as a combination of neuroimaging and neurostimulation methods to extract and deliver information between brains directly without the need for the peripheral nervous system, is a budding communication technique. A BBI system is made up of two parts known as the brain-computer interface part, which reads a sender's brain activity and digitalizes it, and the computer-brain interface part, which writes the delivered brain activity to a receiving brain. As with other technologies, BBI systems have gone through an evolutionary process since they first appeared. The BBI systems have been employed for numerous purposes, including rehabilitation for post-stroke patients, communicating with patients suffering from amyotrophic lateral sclerosis, locked-in syndrome and speech problems following stroke. Also, it has been proposed that a BBI system could play an important role on future battlefields. This technology was not only employed for communicating between two human brains but also for making a direct communication path among different species through which motor or sensory commands could be sent and received. However, the application of BBI systems has provoked significant challenges to human rights principles due to their ability to access and manipulate human brain information. In this study, we aimed to review the brain-computer interface and computer-brain interface technologies as components of BBI systems, the development of BBI systems, applications of this technology, arising ethical issues and expectations for future use.},
}

@article {pmid38711257,
year = {2024},
author = {Horty, LG and Martin, T},
title = {Synthesis of Radiolabeled [[14]C]Rimsulfuron and Stable Isotope Labeled Rimsulfuron-[M + 3] to Support Crop Metabolism Studies for Reregistration.},
journal = {Journal of labelled compounds & radiopharmaceuticals},
volume = {},
number = {},
pages = {},
doi = {10.1002/jlcr.4096},
pmid = {38711257},
issn = {1099-1344},
abstract = {Rimsulfuron is a sulfonylurea herbicide that controls grass and broadleaf weeds in maize, potatoes, fruits, nuts, and other crops. It can also be used as a burndown herbicide to clear invasive weed species along roadsides and other nonagricultural land. Rimsulfuron acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. As is common practice, rimsulfuron has been subject to periodic reviews by regulatory agencies for reregistration since its introduction into the market in the early 1990s. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this reregistration process for rimsulfuron, a new confined rotational crop study was required to address a data gap requested by the European Food Safety Authority (EFSA). Consequently, the corresponding pyridine and pyrimidine radiolabeled [[14]C]rimsulfuron and [M + 3] stable isotopes of rimsulfuron were synthesized for this study to support the reregistration process.},
}

@article {pmid38709603,
year = {2024},
author = {Demaree, D and Brignone, J and Bromberg, M and Zhang, H},
title = {Preliminary study on effects of neck exoskeleton structural design in patients with amyotrophic lateral sclerosis.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2024.3397584},
pmid = {38709603},
issn = {1558-0210},
abstract = {Neck muscle weakness due to amyotrophic lateral sclerosis (ALS) can result in dropped head syndrome, adversely impacting the quality of life of those affected. Static neck collars are currently prescribed to hold the head in a fixed upright position. However, these braces are uncomfortable and do not allow any voluntary head-neck movements. By contrast, powered neck exoskeletons have the potential to enable head-neck movements. Our group has recently improved the mechanical structure of a state-of-the-art neck exoskeleton through a weighted optimization. To evaluate the effect of the structural changes, we conducted an experiment in which patients with ALS were asked to perform head-neck tracking tasks while using the two versions of the neck exoskeleton. We found that the neck muscle activation was significantly reduced when assisted by the structurally enhanced design compared to no assistance provided. The improved structure also improved kinematics tracking performance, allowing users to better achieve the desired head poses. In comparison, the previous design did not help reduce the muscle effort required to perform these tasks and even slightly worsened the kinematic tracking performance. It was also found that biomechanical benefits gained from using the structurally improved design were consistent across participants with both mild and severe neck weakness. Furthermore, we observed that participants preferred to use the powered neck exoskeletons to voluntarily move their heads and make eye contact during a conversation task rather than remain in a fixed upright position. Each of these findings highlights the importance of the structural design of neck exoskeletons in achieving desired biomechanical benefits and suggests that neck exoskeletons can be a viable method to improve the daily life of patients with ALS.},
}

@article {pmid38709037,
year = {2024},
author = {Ketabforoush, A and Wang, M and Smith, CL and Arnold, WD and Nichols, NL},
title = {Assessing Rat Diaphragm Motor Unit Connectivity Outcome Measures as Quantitative Biomarkers of Phrenic Motor Neuron Degeneration and Compensation.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {206},
pages = {},
doi = {10.3791/66568},
pmid = {38709037},
issn = {1940-087X},
mesh = {Animals ; *Motor Neurons/pathology ; Rats ; *Phrenic Nerve ; *Diaphragm/innervation/physiopathology ; Biomarkers/analysis/metabolism ; Action Potentials/physiology ; Nerve Degeneration/pathology ; Rats, Sprague-Dawley ; },
abstract = {Loss of ventilatory muscle function is a consequence of motor neuron injury and neurodegeneration (e.g., cervical spinal cord injury and amyotrophic lateral sclerosis, respectively). Phrenic motor neurons are the final link between the central nervous system and muscle, and their respective motor units (groups of muscle fibers innervated by a single motor neuron) represent the smallest functional unit of the neuromuscular ventilatory system. Compound muscle action potential (CMAP), single motor unit potential (SMUP), and motor unit number estimation (MUNE) are established electrophysiological approaches that enable the longitudinal assessment of motor unit integrity in animal models over time but have mostly been applied to limb muscles. Therefore, the objectives of this study are to describe an approach in preclinical rodent studies that can be used longitudinally to quantify the phrenic MUNE, motor unit size (represented as SMUP), and CMAP, and then to demonstrate the utility of these approaches in a motor neuron loss model. Sensitive, objective, and translationally relevant biomarkers for neuronal injury, degeneration, and regeneration in motor neuron injury and diseases can significantly aid and accelerate experimental research discoveries to clinical testing.},
}

Animals
*Motor Neurons/pathology
Rats
*Phrenic Nerve
*Diaphragm/innervation/physiopathology
Biomarkers/analysis/metabolism
Action Potentials/physiology
Nerve Degeneration/pathology
Rats, Sprague-Dawley

@article {pmid38708921,
year = {2024},
author = {Monteiro, KLC and Dos Santos Alcântara, MG and de Aquino, TM and da Silva-Júnior, EF},
title = {Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS).},
journal = {Current neuropharmacology},
volume = {22},
number = {7},
pages = {1169-1188},
pmid = {38708921},
issn = {1875-6190},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Biological Products/therapeutic use/pharmacology ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Plants, Medicinal/chemistry ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the death of motor neurons and consequent muscle paralysis. Despite many efforts to address it, current therapy targeting ALS remains limited, increasing the interest in complementary therapies. Over the years, several herbal preparations and medicinal plants have been studied to prevent and treat this disease, which has received remarkable attention due to their blood-brain barrier penetration properties and low toxicity. Thus, this review presents the therapeutic potential of a variety of medicinal herbs and their relationship with ALS and their physiopathological pathways.},
}

*Amyotrophic Lateral Sclerosis/drug therapy
Humans
*Biological Products/therapeutic use/pharmacology
Animals
Neuroprotective Agents/therapeutic use/pharmacology
Plants, Medicinal/chemistry

@article {pmid38708063,
year = {2024},
author = {Maria, B and Massimo, G and Antonio, B and Giuseppe, S and Giovanna, BE},
title = {BerTime: A novel tool for supporting ALS algorithm application in clinical practice.},
journal = {Resuscitation plus},
volume = {18},
number = {},
pages = {100636},
pmid = {38708063},
issn = {2666-5204},
}

@article {pmid38706964,
year = {2024},
author = {Edman, S and Horwath, O and Van der Stede, T and Blackwood, SJ and Moberg, I and Strömlind, H and Nordström, F and Ekblom, M and Katz, A and Apró, W and Moberg, M},
title = {Pro-Brain-Derived Neurotrophic Factor (BDNF), but Not Mature BDNF, Is Expressed in Human Skeletal Muscle: Implications for Exercise-Induced Neuroplasticity.},
journal = {Function (Oxford, England)},
volume = {5},
number = {3},
pages = {zqae005},
pmid = {38706964},
issn = {2633-8823},
mesh = {Humans ; *Brain-Derived Neurotrophic Factor/metabolism/blood ; *Exercise/physiology ; *Muscle, Skeletal/metabolism ; *Neuronal Plasticity/physiology ; Male ; Adult ; Lactic Acid/blood/metabolism ; Protein Precursors/metabolism ; Young Adult ; Female ; },
abstract = {Exercise promotes brain plasticity partly by stimulating increases in mature brain-derived neurotrophic factor (mBDNF), but the role of the pro-BDNF isoform in the regulation of BDNF metabolism in humans is unknown. We quantified the expression of pro-BDNF and mBDNF in human skeletal muscle and plasma at rest, after acute exercise (+/- lactate infusion), and after fasting. Pro-BDNF and mBDNF were analyzed with immunoblotting, enzyme-linked immunosorbent assay, immunohistochemistry, and quantitative polymerase chain reaction. Pro-BDNF was consistently and clearly detected in skeletal muscle (40-250 pg mg[-1] dry muscle), whereas mBDNF was not. All methods showed a 4-fold greater pro-BDNF expression in type I muscle fibers compared to type II fibers. Exercise resulted in elevated plasma levels of mBDNF (55%) and pro-BDNF (20%), as well as muscle levels of pro-BDNF (∼10%, all P < 0.05). Lactate infusion during exercise induced a significantly greater increase in plasma mBDNF (115%, P < 0.05) compared to control (saline infusion), with no effect on pro-BDNF levels in plasma or muscle. A 3-day fast resulted in a small increase in plasma pro-BDNF (∼10%, P < 0.05), with no effect on mBDNF. Pro-BDNF is highly expressed in human skeletal muscle, particularly in type I fibers, and is increased after exercise. While exercising with higher lactate augmented levels of plasma mBDNF, exercise-mediated increases in circulating mBDNF likely derive partly from release and cleavage of pro-BDNF from skeletal muscle, and partly from neural and other tissues. These findings have implications for preclinical and clinical work related to a wide range of neurological disorders such as Alzheimer's, clinical depression, and amyotrophic lateral sclerosis.},
}

Humans
*Brain-Derived Neurotrophic Factor/metabolism/blood
*Exercise/physiology
*Muscle, Skeletal/metabolism
*Neuronal Plasticity/physiology
Male
Adult
Lactic Acid/blood/metabolism
Protein Precursors/metabolism
Young Adult
Female

@article {pmid38705796,
year = {2024},
author = {Grangeon, L and Wallon, D and Bourre, B and Guillaume, M and Guegan-Massardier, E and Guyant-Marechal, L and Liard, A and Sibert, L and Maltete, D},
title = {Development of an Objective Structured Clinical Examination (OSCE) to evaluate the diagnosis announcement of chronic neurological disease by residents in neurology.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2024.02.390},
pmid = {38705796},
issn = {0035-3787},
abstract = {BACKGROUND: There is little consensus on how to make a diagnosis announcement of severe chronic disease in neurology. Other medical specialties, such as oncology, have developed assessment methods similar to the Objective Structured Clinical Examination (OSCE) to address this issue. Here we report the implementation of an OSCE focused on the diagnosis announcement of chronic disease in neurology by residents.

OBJECTIVE: We aimed to evaluate the acceptability, feasibility and validity in routine practice of an OSCE combined with a theoretical course focused on diagnosis announcement in neurology.

METHOD: Eighteen neurology residents were prospectively included between 2019 and 2022. First, they answered a questionnaire on their previous level of training in diagnosis announcement. Second, in a practical session with a simulated patient, they made a 15-min diagnosis announcement and then had 5mins of immediate feedback with an expert observer, present in the room. The OSCE consisted of 4 different stations, with standardized scenarios dedicated to the announcement of multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Third, in a theory session, expert observers covered the essential theoretical points. All residents and expert observers completed an evaluation of the "practical session" and the "theory session".

RESULTS: Residents estimated their previous level of diagnosis announcement training at 3.1/5. The most feared announcements were AD and ALS. The "practical session" was rated at a mean of 4.1/5 by the residents and 4.8/5 by the expert observers, and the "theory session" at a mean of 4.7/5 by the residents and 5/5 by the expert observers. After the OSCEs, 11 residents felt more confident about making an announcement.

CONCLUSION: This study has shown a benefit of using an OSCE to learn how to make a diagnosis announcement of severe chronic disease in neurology. OSCEs could be used in many departments in routine practice and seem adapted to residents.},
}

@article {pmid38705786,
year = {2024},
author = {Ishikawa, A and Takeda, T and Kokubun, S and Saito, Y and Isose, S and Ito, K and Arai, K and Sugiyama, A and Kuwabara, S and Honda, K},
title = {Putaminal hypointensity on T2-weighted MRI mimicking multiple system atrophy in amyotrophic lateral sclerosis: An autopsy case report.},
journal = {Journal of the neurological sciences},
volume = {},
number = {},
pages = {123025},
doi = {10.1016/j.jns.2024.123025},
pmid = {38705786},
issn = {1878-5883},
}

@article {pmid38705318,
year = {2024},
author = {Mororó, MCC and Mahnke, LC and Assis, CRD and da Silva, RA and Cabrera, MP and Bezerra, RP and Carvalho Júnior, LB and Alves, MHME},
title = {Acetylcholinesterase purification from human erythrocytes using magnetic nanoparticles containing procainamide.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {132094},
doi = {10.1016/j.ijbiomac.2024.132094},
pmid = {38705318},
issn = {1879-0003},
abstract = {This work presents a magnetic purification method of human erythrocyte Acetylcholinesterase (EC 3.1.1.7; AChE) based on affinity binding to procainamide (Proca) as ligand. Acetylcholinesterase is an acetylcholine-regulating enzyme found in different areas of the body and associated with various neurological disorders, such as Parkinson, Alzheymer and Amyotrophic Lateral Sclerosis. AChE from human erythrocyte purification has been attempted in recent years with low degree of purity. Here, magnetic nanoparticles (MNP) were synthesized and coated with polyaniline (PANI) and procainamide (PROCA) was covalently linked to the PANI. The extracted human erythrocyte AChE formed a complex with the MNP@PANI-PROCA and an external magnet separated it from the undesired proteins. Finally, the enzyme was collected by increasing the ionic strength. Experimental Box-Behnken design was developed to optimize this process of human erythrocyte AChE purification protocol. The enzyme was purified in all fifteen experiments. However, the best AChE purification result was achieved, about 2000 times purified, when 100 mg of MNP@PANI-PROCA was incubated for one hour with 4 ml hemolysate extract. The SDS-PAGE of this preparation presented a molecular weight of approximately 70 kDa, corroborating with few previous studies of AChE from erythrocyte purification.},
}

@article {pmid38705104,
year = {2024},
author = {Dharmadasa, T and Pavey, N and Tu, S and Menon, P and Huynh, W and Mahoney, CJ and Timmins, HC and Higashihara, M and van den Bos, M and Shibuya, K and Kuwabara, S and Grosskreutz, J and Kiernan, MC and Vucic, S},
title = {Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {163},
number = {},
pages = {68-89},
doi = {10.1016/j.clinph.2024.04.010},
pmid = {38705104},
issn = {1872-8952},
abstract = {Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.},
}

@article {pmid38703766,
year = {2024},
author = {Alfahel, L and Gschwendtberger, T and Kozareva, V and Dumas, L and Gibbs, R and Kertser, A and Baruch, K and Zaccai, S and Kahn, J and Thau-Habermann, N and Eggenschwiler, R and Sterneckert, J and Hermann, A and Sundararaman, N and Vaibhav, V and Van Eyk, JE and Rafuse, VF and Fraenkel, E and Cantz, T and Petri, S and Israelson, A},
title = {Targeting low levels of MIF expression as a potential therapeutic strategy for ALS.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {101546},
doi = {10.1016/j.xcrm.2024.101546},
pmid = {38703766},
issn = {2666-3791},
abstract = {Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1[G37R] mice significantly improves their motor function, delays disease progression, and extends survival. Moreover, MIF treatment reduces neuroinflammation and misfolded SOD1 accumulation, rescues MNs, and corrects dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we reveal low MIF levels in human induced pluripotent stem cell-derived MNs from familial ALS patients with different genetic mutations, as well as in post mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients.},
}

@article {pmid38703699,
year = {2024},
author = {Grapperon, AM and Harlay, V and Boucekine, M and Devos, D and Rolland, AS and Desnuelle, C and Delmont, E and Verschueren, A and Attarian, S},
title = {Could the motor unit number index be an early prognostic biomarker for amyotrophic lateral sclerosis?.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {163},
number = {},
pages = {47-55},
doi = {10.1016/j.clinph.2024.04.013},
pmid = {38703699},
issn = {1872-8952},
abstract = {OBJECTIVE: To evaluate the associations between motor unit number index (MUNIX) and disease progression and prognosis in amyotrophic lateral sclerosis (ALS) in a large-scale longitudinal study.

METHODS: MUNIX was performed at the patient's first visit, at 3, 6, and 12 months in 4 muscles. MUNIX data from the patients were compared with those from 38 age-matched healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), the forced vital capacity (FVC), and the survival of the patients.

RESULTS: Eighty-two patients were included at baseline, 62 were evaluated at three months, 48 at six months, and 33 at twelve months. MUNIX score was lower in ALS patients compared to controls. At baseline, MUNIX was correlated with ALSFRS-R and FVC. Motor unit size index (MUSIX) was correlated with patient survival. Longitudinal analyses showed that MUNIX decline was greater than ALSFRS-R decline at each evaluation. A baseline MUNIX score greater than 378 predicted survival over the 12-month period with a sensitivity of 82% and a specificity of 56%.

CONCLUSIONS: This longitudinal study suggests that MUNIX could be an early quantitative marker of disease progression and prognosis in ALS.

SIGNIFICANCE: MUNIX might be considered as potential indicator for monitoring disease progression.},
}

@article {pmid38703513,
year = {2024},
author = {El Khalfi, R and Maupoint, E and Chiavassa-Gandois, H and Goumarre, C and Filliole, A and Lapègue, F and Fabry, V and Acket, B and Laforet, A and Sans, N and Cintas, P and Faruch-Bilfeld, M},
title = {Assessment of whole-body muscle MRI for the early diagnosis of Amyotrophic Lateral Sclerosis.},
journal = {European journal of radiology},
volume = {176},
number = {},
pages = {111481},
doi = {10.1016/j.ejrad.2024.111481},
pmid = {38703513},
issn = {1872-7727},
abstract = {OBJECTIVES: To evaluate muscle signal abnormalities on whole-body muscle MRI with T2 and diffusion-weighted imaging in early ALS stages.

METHODS: 101 muscles were analyzed in newly diagnosed ALS patients and healthy controls on a whole-body MRI protocol including four-point T2-Dixon imaging and diffusion-weighted imaging (b0 and b800). Sensitivity and inter-observer agreement were assessed.

RESULTS: 15 patients (mean age, 64 +/- 12 [SD], 9 men) who met the Awaji-Shima criteria for definite, probable or possible ALS and 9 healthy controls were assessed (mean age, 53 +/- 13 [SD], 2 men). 61 % of the muscles assessed in ALS patients (62/101) showed signal hyperintensities on T2-weighted imaging, mainly in the upper and lower extremities (legs, hands and feet). ALS patients had a significantly higher number of involved muscles compared to healthy controls (p = 0,006). Diffusion-weighted imaging allowed for the detection of additional involvement in 22 muscles, thus improving the sensitivity of whole-body MRI from 60 % (using T2-weighted imaging only) up to 80 % (with the combination of T2-weighted and diffusion-weighted imaging).

CONCLUSIONS: ALS patients exhibited significant muscle signal abnormalities on T2-weighted and diffusion-weighted imaging in early disease stages. Whole-body MRI could be used for pre-EMG mapping of muscle involvement in order to choose suitable targets, thus improving early diagnosis.},
}

@article {pmid38703371,
year = {2024},
author = {Thumbadoo, KM and Dieriks, BV and Murray, HC and Swanson, MEV and Yoo, JH and Mehrabi, NF and Turner, C and Dragunow, M and Faull, RLM and Curtis, MA and Siddique, T and Shaw, CE and Newell, KL and Henden, L and Williams, KL and Nicholson, GA and Scotter, EL},
title = {Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awae140},
pmid = {38703371},
issn = {1460-2156},
abstract = {Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants (resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases), and p.P497L (three cases)). Using multiplexed (5-label) fluorescent immunohistochemistry, we mapped the co-localisation of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates, and p62, in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5), and UBQLN2-linked (n = 8) cases. We differentiate between i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins, and ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis/and frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.},
}

@article {pmid38702287,
year = {2024},
author = {Tazir, M and Nouioua, S},
title = {Distal hereditary motor neuropathies.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2023.09.005},
pmid = {38702287},
issn = {0035-3787},
abstract = {Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy. Electrophysiology, with normal motor and sensory conduction velocities, can suggest the diagnosis of dHMN and guide the genetic study. More than thirty genes are currently associated with HMNs, but around 60 to 70% of cases of dHMN remain uncharacterized genetically. Recent cohort studies showed that HSPB1, GARS, BICB2 and DNAJB2 are among the most frequent dHMN genes and that the prevalence of the disease was calculated as 2.14 and 2.3 per 100,000. The determination of the different genes involved in dHMNs made it possible to observe a genotypic overlap with some other neurogenetic disorders and other hereditary neuropathies such as CMT2, mainly with the HSPB1, HSPB8, BICD2 and TRPV4 genes of AD-inherited transmission and recently observed with SORD gene of AR transmission which seems relatively frequent and potentially curable. Distal hereditary motor neuropathy that predominates in the upper limbs is linked mainly to three genes: GARS, BSCL2 and REEP1, whereas dHMN with vocal cord palsy is associated with SLC5A7, DCTN1 and TRPV4 genes. Among the rare AR forms of dHMN like IGHMBP2 and DNAJB2, the SIGMAR1 gene mutations as well as VRK1 variants are associated with a motor neuropathy phenotype often associated with upper motoneuron involvement. The differential diagnosis of these latter arises with juvenile forms of amyotrophic lateral sclerosis, that could be caused also by variations of these genes, as well as hereditary spastic paraplegia. A differential diagnosis of dHMN related to Brown Vialetto Van Laere syndrome due to riboflavin transporter deficiency is important to consider because of the therapeutic possibility.},
}

@article {pmid38700207,
year = {2024},
author = {Keeley, O and Coyne, AN},
title = {Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease.},
journal = {Nucleus (Austin, Tex.)},
volume = {15},
number = {1},
pages = {2349085},
pmid = {38700207},
issn = {1949-1042},
mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; Cell Nucleus/metabolism ; Frontotemporal Dementia/metabolism/pathology/genetics ; Endosomes/metabolism ; },
abstract = {The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.},
}

Humans
*Endosomal Sorting Complexes Required for Transport/metabolism
*Neurodegenerative Diseases/metabolism/pathology/genetics
Animals
Cell Nucleus/metabolism
Frontotemporal Dementia/metabolism/pathology/genetics
Endosomes/metabolism

@article {pmid38697975,
year = {2024},
author = {Tsitkov, S and Valentine, K and Kozareva, V and Donde, A and Frank, A and Lei, S and , and E Van Eyk, J and Finkbeiner, S and Rothstein, JD and Thompson, LM and Sareen, D and Svendsen, CN and Fraenkel, E},
title = {Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3606},
pmid = {38697975},
issn = {2041-1723},
support = {RF1 AG057331/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; Male ; Female ; Middle Aged ; Case-Control Studies ; Chromatin/metabolism/genetics ; Aged ; Epigenomics/methods ; Chromatin Immunoprecipitation Sequencing/methods ; Disease Progression ; Epigenesis, Genetic ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*Induced Pluripotent Stem Cells/metabolism
*Motor Neurons/metabolism/pathology
Male
Female
Middle Aged
Case-Control Studies
Chromatin/metabolism/genetics
Aged
Epigenomics/methods
Chromatin Immunoprecipitation Sequencing/methods
Disease Progression
Epigenesis, Genetic

@article {pmid38697285,
year = {2024},
author = {Tuerxun, K and Tang, RH and Abudoumijiti, A and Yusupu, Z and Aikebaier, A and Mijiti, S and Ibrahim, I and Cao, YL and Yasheng, A and Wu, YQ},
title = {Comparative proteomics analysis of samples from hepatic cystic echinococcosis patients using data-independent acquisition approach.},
journal = {Journal of proteomics},
volume = {},
number = {},
pages = {105191},
doi = {10.1016/j.jprot.2024.105191},
pmid = {38697285},
issn = {1876-7737},
abstract = {Cystic echinococcosis is a zoonotic disease resulting from infection caused by the larval stage of Echinococcus granulosus. This study aimed to assess the specific proteins that are potential candidates for the development of a vaccine against E. granulosus. The data-independent acquisition approach was employed to identify differentially expressed proteins (DEPs) in E. granulosus samples. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was employed to identify several noteworthy proteins. Results: The DEPs in E. granulosus samples were identified (245 pericystic wall vs. parasite-free yellowish granuloma (PYG, 1725 PY vs. PYG, 2274 PN vs. PYG). Further examination of these distinct proteins revealed their predominant enrichment in metabolic pathways, amyotrophic lateral sclerosis, and neurodegeneration-associated pathways. Notably, among these DEPs, SH3BGRL, MST1, TAGLN2, FABP5, UBE2V2, and RARRES2 exhibited significantly higher expression levels in the PYG group compared with the PY group (P < 0.05). The findings may contribute to the understanding of the pathological mechanisms underlying echinococcosis, providing valuable insights into the development of more effective diagnostic tools, treatment modalities, and preventive strategies. SIGNIFICANCE: CE is a major public health hazard in the western regions of China, Central Asia, South America, the Mediterranean countries, and eastern Africa. Echinococcus granulosus is responsible for zoonotic disease through infection Our analysis focuses on the proteins in various samples by data-dependent acquisition (DIA) for proteomic analysis. The importance of this research is to develop new strategies and targets to protect against E. granulosus infections in humans.},
}

@article {pmid38697002,
year = {2024},
author = {Su, T and Gan, Y and Ma, S and Wu, H and Lu, S and Zhi, M and Wang, B and Lu, Y and Yao, J},
title = {Graves' disease and the risk of five autoimmune diseases: A Mendelian randomization and colocalization study.},
journal = {Diabetes & metabolic syndrome},
volume = {18},
number = {5},
pages = {103023},
doi = {10.1016/j.dsx.2024.103023},
pmid = {38697002},
issn = {1878-0334},
abstract = {BACKGROUND: Epidemiological studies have consistently demonstrated a high prevalence of concurrent autoimmune diseases in individuals with Graves' disease (GD).

OBJECTIVE: The objective of this study is to establish a causal association between GD and autoimmune diseases.

METHODS: We employed a two-sample Mendelian randomization (MR) to infer a causal association between GD and five autoimmune diseases, namely rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS), in the East Asian and European population. Genetic correlations were explored through linkage disequilibrium score regression analysis (LDSC). Finally, colocalization analyses were performed to investigate possible genetic foundations.

RESULTS: Bidirectional MR analysis indicated that genetically predicted GD increased the risk of RA (Odds Ratio (OR): 1.34, 95 % Confidence Interval (CI): 1.21 to 1.47, P < 0.001) and SLE (OR: 1.21, 95%CI: 1.08 to 1.35, P < 0.001) in the East Asian population. In contrast, we found that genetically predicted RA (OR: 1.14, 95%CI: 1.05 to 1.24, P = 0.002) and SLE (OR: 1.10, 95%CI: 1.03 to 1.17, P = 0.003) were associated with a higher risk of GD. The results have been partially validated in European cohorts. Colocalization analysis suggested the potential existence of shared causal variants between GD and other autoimmune diseases. In particular, gene ARID5B may play an important role in the incidence of autoimmune diseases.

CONCLUSION: This study has confirmed that GD was associated with RA and SLE and found a possible key gene ARID5B. It may be necessary to strengthen detection to prevent the occurrence of comorbidities in clinical practice.},
}

@article {pmid38696744,
year = {2024},
author = {},
title = {Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.},
journal = {Neurology},
volume = {102},
number = {10},
pages = {e209407},
doi = {10.1212/WNL.0000000000209407},
pmid = {38696744},
issn = {1526-632X},
}

@article {pmid38696153,
year = {2024},
author = {Chugunov, DA and Shmilovich, AA and Larina, MR and Goncharenko, SN and Moiseeva, TV and Ryauzova, ES and Fedorova, EV and Bukinich, AA},
title = {[Clinical and psychometric characteristics of cognitive and negative disorders in schizophrenia].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {124},
number = {4. Vyp. 2},
pages = {64-71},
doi = {10.17116/jnevro202412404264},
pmid = {38696153},
issn = {1997-7298},
mesh = {Humans ; Male ; Female ; Adult ; *Schizophrenia/diagnosis/complications ; *Psychometrics ; Middle Aged ; *Schizophrenic Psychology ; Cognition ; Neuropsychological Tests ; Cognition Disorders/diagnosis/etiology ; },
abstract = {OBJECTIVE: To establish the characteristics of clinical manifestations and cognitive tests in patients with schizophrenia, with a predominance of cognitive and negative disorders.

MATERIAL AND METHODS: We examined 76 patients, 66 in the main group, 10 in the comparison group, who were treated in Psychiatric Hospital No. 1 and Psychiatric Hospital No. 4 (Moscow). Clinical-psychopathological, psychometric and statistical methods were used. Features of cognitive functioning were studied using the Frontal Assessment Battery (FAB) and the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS). Emotional intelligence scores were assessed using the Ekman Face Emotion Recognition (EFER) test.

RESULTS: Patients with schizophrenia showed dominance of one of 3 types of deficit symptoms: cognitive, emotional, and volitional. Cognitive functions were significantly reduced in patients with schizophrenia when compared with the comparison group (mean FAB score (M±SD) 13.44±2.97 in patients with schizophrenia vs. 16.10±1.70 in the comparison group; t=4.10; p<0.001). Cognitive functions were particularly reduced in patients with volitional deficit (mean EFER total score 42.40±9.0 in patients with volitional deficit vs. 47.21±633 in patients with cognitive deficit; t=2.12; p=0.039; mean FAB score 12.83±3.29 in patients with volitional deficit vs. 16.10±1.70 in the comparison group; t=4.24; p<0.001; mean ECAS score specific to ALS 78.80±9.07 in patients with volitional deficit vs. 84.50±6.71 in the comparison group; t=2.18; p=0.034).

CONCLUSION: The greatest contribution to the development of cognitive disorders in schizophrenia is made by dysfunction of frontal (especially) and temporal cortex. Executive functions, speech skills and verbal fluency are most severely damaged.},
}

Humans
Male
Female
Adult
*Schizophrenia/diagnosis/complications
*Psychometrics
Middle Aged
*Schizophrenic Psychology
Cognition
Neuropsychological Tests
Cognition Disorders/diagnosis/etiology

@article {pmid38695966,
year = {2024},
author = {Mendes Ferreira, V and Caetano, A and Santos, L and Fernandes, M},
title = {FIG4-associated disease manifesting as rapidly progressive amyotrophic lateral sclerosis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {38695966},
issn = {1590-3478},
}

@article {pmid38695638,
year = {2024},
author = {Fullam, T and Hunt, SL and Han, M and Denesia, J and Chandrashekhar, S and Jawdat, O and Piccione, E and Fernandes, JA and Statland, J},
title = {Outcomes after intervention for enteral nutrition in patients with amyotrophic lateral sclerosis in multidisciplinary clinics.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28103},
pmid = {38695638},
issn = {1097-4598},
support = {10.13039/100000002/NH/NIH HHS/United States ; },
abstract = {INTRODUCTION/AIMS: Patients with amyotrophic lateral sclerosis (ALS) are susceptible to malnutrition, with appropriate management of nutritional interventions an active area of investigation. We sought to determine the impact of gastrostomy tube placement in ALS patients, exploring the correlation between forced vital capacity (FVC), malnutrition, and perioperative complications.

METHODS: A retrospective review was performed of clinically diagnosed ALS patients treated at two multidisciplinary clinics (University of Kansas, University of Nebraska) from January 2009 to September 2020 who were referred for gastrostomy. Data collected included demographics, disease characteristics, and key gastrostomy related dates/outcomes.

RESULTS: Two hundred thirty-nine patients were included with a median age of 65 years and median of 589 days from symptom onset to gastrostomy (interquartile range, 404-943). The population was predominantly Non-Hispanic White with bulbar-onset ALS. 30-day mortality was 4% and 30-day morbidity was 13%. Weight loss, body mass index, and predicted FVC at placement showed no increased 30-day morbidity or mortality association. Bulbar-onset ALS patients exhibited higher overall mortality postplacement than limb onset (odds ratio: 1.85, 95% confidence interval: 1.03-3.33). There was a 5% incidence of symptoms suggestive of refeeding syndrome.

DISCUSSION: Rates of major/minor complications and 30-day mortality related to gastrostomy placement in our population were similar compared with prior studies in ALS. The lack of difference in outcomes based on FVC at procedure may suggest this is not predictive of outcome, or perhaps, high-quality perioperative respiratory management. Alternative reasons may account for the increased morbidity and mortality of gastrostomy placement in the ALS population.},
}

@article {pmid38694387,
year = {2024},
author = {Arora, H and Javed, B and Kutikuppala, LVS and Chaurasia, M and Khullar, K and Kannan, S and Golla, V},
title = {ST2 levels and neurodegenerative diseases: is this a significant relation?.},
journal = {Annals of medicine and surgery (2012)},
volume = {86},
number = {5},
pages = {2812-2817},
pmid = {38694387},
issn = {2049-0801},
abstract = {Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.},
}

@article {pmid38694349,
year = {2024},
author = {Amjadi, N and Mohammadi, S and Paybast, S and Dadkhah, P and Talayeh, M and Asemi, Z},
title = {A pregnant woman with amyotrophic lateral sclerosis from Iran: a case report.},
journal = {Annals of medicine and surgery (2012)},
volume = {86},
number = {5},
pages = {3013-3015},
pmid = {38694349},
issn = {2049-0801},
abstract = {INTRODUCTION AND IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, which is extremely rare during pregnancy. The severity of the disease affects the pregnancy outcome. The present study reports the first Iranian case of a woman with ALS overlapping pregnancy.

CASE PRESENTATION: The 27-year-old lady in her second pregnancy was admitted to the emergency department with labor pain at the 37th gestation week. Following a multidisciplinary team meeting, including a neurologist, maternal-fetal medicine specialist, and anesthesiologist, a decision was made for an emergent cesarean section under spinal anesthesia. The delivery was successful without any maternal or fetal complications. A 5-month follow-up revealed the stable neurologic status of the mother.

CLINICAL DISCUSSION: The combination of ALS and pregnancy is very rare because the disease is more common in elderly men. ALS management involves a multidisciplinary approach. Riluzole is a drug that can increase the survival of the patients. ALS does not affect on motor and sensory nerves of the uterus, so vaginal delivery might be possible. The main cause of cesarean section in patients with ALS is respiratory compromise, but four patients with uncomplicated vaginal deliveries have been reported. The neonatal outcome of most cases resulted in normal healthy infants.

CONCLUSION: Management of ALS in pregnancy is challenging because of respiratory concerns, so multidisciplinary team management is important.},
}

@article {pmid38692734,
year = {2024},
author = {Tartwijk, FWV and Wunderlich, LCS and Mela, I and Makarchuk, S and Jakobs, MAH and Qamar, S and Franze, K and Schierle, GSK and George-Hyslop, PHS and Lin, JQ and Holt, CE and Kaminski, CF},
title = {Mutation of the ALS/FTD-associated RNA-binding protein FUS affects axonal development.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2148-23.2024},
pmid = {38692734},
issn = {1529-2401},
abstract = {Aberrant condensation and localisation of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Changes in RBP function are commonly associated with changes in axonal cytoskeletal organisation and branching in neurodevelopmental disorders. Here, we asked whether branching defects also occur in vivo in a model of FUS-associated disease. We use two reported Xenopus models of ALS/FTD (of either sex), the ALS-associated mutant FUS(P525L) and a mimic of hypomethylated FUS, FUS(16R). Both mutants strongly reduced axonal complexity in vivo. We also observed an axon looping defect for FUS(P525L) in the target area, which presumably arises due to errors in stop cue signalling. To assess whether loss of axon complexity also had a cue-independent component, we assessed axonal cytoskeletal integrity in vitro Using a novel combination of fluorescence and atomic force microscopy, we found that mutant FUS reduced actin density in the growth cone, altering its mechanical properties. Therefore, FUS mutants may induce defects during early axonal development.Significance statement This study demonstrates that mutation of the ALS/FTD (amyotrophic lateral sclerosis/frontotemporal dementia)-associated RNA-binding protein Fused in Sarcoma (FUS) can result in changes in axonal development. These changes occur both axon-autonomously in cytoskeletal organisation during axon extension and context-dependently during axonal branching. This indicates pre-symptomatic, developmental changes in axonal organisation may occur in familial disease variants.},
}

@article {pmid38691665,
year = {2024},
author = {Singh, P and Belliveau, P and Towle, J and Neculau, AE and Dima, L},
title = {Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.},
journal = {American journal of therapeutics},
volume = {31},
number = {3},
pages = {e258-e267},
doi = {10.1097/MJT.0000000000001742},
pmid = {38691665},
issn = {1536-3686},
mesh = {*Edaravone/administration & dosage/pharmacology/therapeutic use ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/administration & dosage/therapeutic use/adverse effects ; Administration, Oral ; Suspensions ; Biological Availability ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.

MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.

PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.

CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.

THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.},
}

*Edaravone/administration & dosage/pharmacology/therapeutic use
Humans
*Amyotrophic Lateral Sclerosis/drug therapy
*Neuroprotective Agents/administration & dosage/therapeutic use/adverse effects
Administration, Oral
Suspensions
Biological Availability

@article {pmid38689650,
year = {2024},
author = {Swindell, WR},
title = {Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords.},
journal = {Frontiers in genetics},
volume = {15},
number = {},
pages = {1385114},
pmid = {38689650},
issn = {1664-8021},
abstract = {INTRODUCTION: ALS is a fatal neurodegenerative disease for which underlying mechanisms are incompletely understood. The motor neuron is a central player in ALS pathogenesis but different transcriptome signatures have been derived from bulk analysis of post-mortem tissue and iPSC-derived motor neurons (iPSC-MNs).

METHODS: This study performed a meta-analysis of six gene expression studies (microarray and RNA-seq) in which laser capture microdissection (LCM) was used to isolate lower motor neurons from post-mortem spinal cords of ALS and control (CTL) subjects. Differentially expressed genes (DEGs) with consistent ALS versus CTL expression differences across studies were identified.

RESULTS: The analysis identified 222 ALS-increased DEGs (FDR <0.10, SMD >0.80) and 278 ALS-decreased DEGs (FDR <0.10, SMD < -0.80). ALS-increased DEGs were linked to PI3K-AKT signaling, innate immunity, inflammation, motor neuron differentiation and extracellular matrix. ALS-decreased DEGs were associated with the ubiquitin-proteosome system, microtubules, axon growth, RNA-binding proteins and synaptic membrane. ALS-decreased DEG mRNAs frequently interacted with RNA-binding proteins (e.g., FUS, HuR). The complete set of DEGs (increased and decreased) overlapped significantly with genes near ALS-associated SNP loci (p < 0.01). Transcription factor target motifs with increased proximity to ALS-increased DEGs were identified, most notably DNA elements predicted to interact with forkhead transcription factors (e.g., FOXP1) and motor neuron and pancreas homeobox 1 (MNX1). Some of these DNA elements overlie ALS-associated SNPs within known enhancers and are predicted to have genotype-dependent MNX1 interactions. DEGs were compared to those identified from SOD1-G93A mice and bulk spinal cord segments or iPSC-MNs from ALS patients. There was good correspondence with transcriptome changes from SOD1-G93A mice (r ≤ 0.408) but most DEGs were not differentially expressed in bulk spinal cords or iPSC-MNs and transcriptome-wide effect size correlations were weak (bulk tissue: r ≤ 0.207, iPSC-MN: r ≤ 0.037).

CONCLUSION: This study defines a robust transcriptome signature from LCM-based motor neuron studies of post-mortem tissue from ALS and CTL subjects. This signature differs from those obtained from analysis of bulk spinal cord segments and iPSC-MNs. Results provide insight into mechanisms underlying gene dysregulation in ALS and highlight connections between these mechanisms, ALS genetics, and motor neuron biology.},
}