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

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

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

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

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

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

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

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

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

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

STUDY DESIGN: Retrospective case series.

SETTING: Single-institution academic center.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.}, } @article {pmid40099353, year = {2025}, author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV}, title = {Cutting-edge insights: LC-OCT and 5% cyclosporine for early lichen sclerosus treatment.}, journal = {Dermatology reports}, volume = {}, number = {}, pages = {}, doi = {10.4081/dr.2025.10279}, pmid = {40099353}, issn = {2036-7392}, abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting genital areas. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. Cyclosporine, a calcineurin inhibitor, has shown efficacy in managing immune-mediated skin diseases and is delivered effectively through the Pentravan® vehicle. [...].}, } @article {pmid32895997, year = {2020}, author = {McElroy, KG and Stalter, AM and Smith, SD}, title = {Association of Community Health Nursing Educators 2020 Research Priorities and Research in Action Model.}, journal = {Public health nursing (Boston, Mass.)}, volume = {37}, number = {6}, pages = {909-924}, doi = {10.1111/phn.12790}, pmid = {32895997}, issn = {1525-1446}, mesh = {*Community Health Nursing/education ; *Education, Nursing, Baccalaureate/methods ; Humans ; Learning ; Public Health Nursing/education ; Research ; *Students, Nursing/psychology ; }, abstract = {OBJECTIVE: The Association of Community/Public Health Nurse Educators (ACHNE) Research Priorities Subcommittee presents a report on the state of the science of public health nursing education.

DESIGN: Whittemore and Knafl's (Journal of Advanced Nursing, 2005, 52, 546) five-step integrative review was used.

SAMPLE: Fifty-two articles were reviewed.

MEASUREMENTS: Braun et al's. (Handbook of research methods in health social sciences, 2019, 843) thematic analysis methods were used.

RESULTS: Four themes emerged: (a) Community/Public Health Nursing Education and teaching strategies/modalities; (b) Clinical teaching and learning partnerships; (c) Environmental health and emergency response; and, (d) Cultural competence and awareness.

CONCLUSIONS: Themes informed the following research priorities: (a) a need for rigorous scientific studies highlighting the impact and effectiveness of Community/Public Health Nursing Education; (b) a need for evidence on faculty development, support and training related to community/public health activities; (c) a need for evidence on impact of Community/Public Health Nursing teaching on communities and students, and (d) a need for evidence on impact of C/PHNE strategies on long-term student knowledge, attitudes or behavior (competencies). Finally, a Research in Action Model is proposed as a means for continued forward movement of the discipline, connecting the three fundamental driving mechanisms.}, } @article {pmid31497116, year = {2019}, author = {Yamada, Y and Ansari, A and Sae-Ngow, T and Tanaka, R and Kawase, T and Kalyan, S and Kato, Y}, title = {Microsurgical Treatment of Paraclinoid Aneurysms by Extradural Anterior Clinoidectomy: The Fujita Experience.}, journal = {Asian journal of neurosurgery}, volume = {14}, number = {3}, pages = {868-872}, pmid = {31497116}, issn = {1793-5482}, abstract = {INTRODUCTION: Paraclinoid aneurysms pose technical difficulty in their approach, mainly because of their close proximity to neurovascular structures, deeper location, and a smaller corridor. Extradural anterior clinoidectomy is a highly beneficial technique in such cases, making more space to deal with these aneurysms. We describe our method of performing extradural anterior clinoidectomy in such patients.

MATERIALS AND METHODS: A total of 33 cases of paraclinoid internal carotid artery aneurysms presenting to Fujita Health University Banbuntane Hospital, Japan, were included. Females comprised the majority with 32 cases; the mean age was 54.8 years (range: 35-74 years). The mean size of the paraclinoid aneurysm was 5.3 mm (range: 3-12 mm).

RESULTS: Nine paraclinoid aneurysms were found projecting dorsally, 7 laterally, and 17 medially (Kazuhiko Kyoshim et al's. classification). An immediate complete occlusion rate of 100% was present. Visual disturbance was found in 6.2% of our patients. One of our patients developed permanent loss of vision.

CONCLUSION: Extradural anterior clinoidectomy enables a better exposure to paraclinoid aneurysms. Precise anatomical knowledge along with microsurgical tactics is required to prevent and manage potential complications to achieve good outcomes.}, } @article {pmid31420835, year = {2019}, author = {Prairie, TM and Wrye, B and Bowman, AS and Weatherby, N and Thareja, G}, title = {Does Location of Practice or Religiosity Predict Negative Physician Attitudes or Beliefs Toward LGB+ Individuals?.}, journal = {Journal of religion and health}, volume = {58}, number = {6}, pages = {2208-2218}, pmid = {31420835}, issn = {1573-6571}, mesh = {Adult ; *Attitude of Health Personnel ; *Bisexuality ; Female ; Health Personnel/*psychology ; Homophobia ; *Homosexuality ; Humans ; Male ; Middle Aged ; Prejudice ; *Professional Practice Location ; *Religion ; Sexual and Gender Minorities ; }, abstract = {The purpose of this study is to extend the Sabin et al's. (Am J Public Health 105(9):1831-1841, 2015. https://doi.org/10.2105/AJPH.2015.302631) findings to examine the extent to which religiosity and/or geographic region is predictive of negative attitudes or beliefs toward lesbian, gay, bisexual, and asexual (LGB+) individuals. Secondary data from the Sexuality Implicit Association Test were analyzed. Data included only participants from 2013 to 2015 who identified "Healthcare - Diagnosing and Treating Practitioners" as their occupation (n = 1376). The results of a factorial ANOVA revealed significant group differences accounting for 22.4% of the variance in attitudes toward LGB+ individuals. Religiosity was a significant factor in determining negative attitudes toward LGB+ individuals. However, the study was underpowered (5.8%) to detect an effect of geographic location in determining negative attitudes toward LGB+ individuals. It is important to validate a tool that can adequately measure the common assumptions associated with both religion and geographic region. Additionally, medical educators need to learn how to recognize and address negative attitudes among their students.}, } @article {pmid28977145, year = {2017}, author = {Fernandes, P and Meiga, C and Peres, AC and Taconeli, CA and Nickel, R and Silvado, C}, title = {Translation of social and occupational functioning scale for epilepsy into Portuguese - Brazil.}, journal = {Arquivos de neuro-psiquiatria}, volume = {75}, number = {9}, pages = {639-648}, doi = {10.1590/0004-282X20170099}, pmid = {28977145}, issn = {1678-4227}, mesh = {Adolescent ; Adult ; Brazil ; Cross-Cultural Comparison ; Epilepsy/*diagnosis/psychology ; Female ; Humans ; Male ; Middle Aged ; Social Behavior ; Socioeconomic Factors ; *Surveys and Questionnaires ; *Translations ; Young Adult ; }, abstract = {Epilepsy has important consequences on functionality and social activities. There are few evaluation tools for this purpose. This study aimed to translate the Social and Occupational Functioning Scale for Epilepsy. It is a translation study, for which Beaton et al's. guidelines were used. Sixty patients over 18 years of age, with a confirmed diagnosis of epilepsy, were evaluated. The analysis of internal consistency (Cronbach's alpha) showed values between 0.55 and 0.72 associated with the original dimensions of the instrument, while the five dimensions identified by the results of an exploratory factor analysis showed values between 0.60 and 0.68, with different grouping of the structures of the original scale. Respondents had no difficulty answering the translated version of the Social and Occupational Functioning Scale for Epilepsy, but the statistics show the need for cultural adaptation to the Brazilian population.}, } @article {pmid25436144, year = {2014}, author = {de Figueiredo Ferreira, M and Detrano, F and Coelho, GM and Barros, ME and Serrão Lanzillotti, R and Firmino Nogueira Neto, J and Portella, ES and Serrão Lanzillotti, H and Soares, Ede A}, title = {Body composition and Basal metabolic rate in women with type 2 diabetes mellitus.}, journal = {Journal of nutrition and metabolism}, volume = {2014}, number = {}, pages = {574057}, pmid = {25436144}, issn = {2090-0724}, abstract = {Objective. The aim of this study was to determine which of the seven selected equations used to predict basal metabolic rate most accurately estimated the measured basal metabolic rate. Methods. Twenty-eight adult women with type 2 diabetes mellitus participated in this cross-sectional study. Anthropometric and biochemical variables were measured as well as body composition (by absorptiometry dual X-ray emission) and basal metabolic rate (by indirect calorimetry); basal metabolic rate was also estimated by prediction equations. Results. There was a significant difference between the measured and the estimated basal metabolic rate determined by the FAO/WHO/UNU (P value < 0.021) and Huang et al. (P value ≤ 0.005) equations. Conclusion. The calculations using Owen et al's. equation were the closest to the measured basal metabolic rate.}, } @article {pmid17372624, year = {2007}, author = {Kim, HK and Capaldi, DM and Crosby, L}, title = {Generalizability of Gottman and Colleagues' Affective Process Models of Couples' Relationship Outcomes.}, journal = {Journal of marriage and the family}, volume = {69}, number = {1}, pages = {55-72}, pmid = {17372624}, issn = {0022-2445}, support = {R01 HD046364-12/HD/NICHD NIH HHS/United States ; R01 DA015485/DA/NIDA NIH HHS/United States ; R01 HD046364/HD/NICHD NIH HHS/United States ; R01 MH037940-25/MH/NIMH NIH HHS/United States ; R01 DA015485-03/DA/NIDA NIH HHS/United States ; R01 MH037940/MH/NIMH NIH HHS/United States ; P30 MH046690/MH/NIMH NIH HHS/United States ; }, abstract = {The generalizability of Gottman et al's. (1998) affective process models was examined using a community-based sample of 85 married or cohabiting couples with at-risk backgrounds. Predictive associations between affective processes assessed at about age 21 years and relationship status and satisfaction approximately 2.5 years later were examined. The major findings of Gottman et al. failed to replicate. In particular, men's rejection of their partners' influence, the lack of men's deescalation of partners' negative affect, and women's negative start up were not predictive of relationship status. Further, differences in affective processes were found when comparing discussion sessions of the men's versus the women's chosen topics. The findings suggested that the validity and utility of the affective process models need further investigation.}, } @article {pmid15742539, year = {2004}, author = {Fisk, JE and Sharp, CA}, title = {Age-related impairment in executive functioning: updating, inhibition, shifting, and access.}, journal = {Journal of clinical and experimental neuropsychology}, volume = {26}, number = {7}, pages = {874-890}, doi = {10.1080/13803390490510680}, pmid = {15742539}, issn = {1380-3395}, mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*physiology ; Aptitude/*physiology ; Cognition Disorders/*physiopathology ; Factor Analysis, Statistical ; Female ; Humans ; *Inhibition, Psychological ; Male ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; Problem Solving/*physiology ; Psychomotor Performance/physiology ; Reading ; }, abstract = {Miyake, Friedman, Emerson, Witzki, Howerter and Wager (2000) have argued that the central executive is fractionated consisting of at least three separable component processes: updating, shifting, and inhibition. The Wisconsin Card Sort Test, random letter generation, Brooks spatial sequences, reading and computation span, word fluency, and a measure of dual task performance were administered to 95 individuals aged between 20 and 81, average age 41.89. The executive measures were factor analyzed, using the oblique rotation method, yielding four factors. The factor structure obtained was broadly consistent with Miyake et al's. However, an additional factor, the only one not to show a significant performance decline with age, was also obtained and was believed to reflect the efficiency of access to long-term memory.}, } @article {pmid11859558, year = {2002}, author = {Williams, T}, title = {Intercessory prayer and its effect on patients with rheumatoid arthritis.}, journal = {Kentucky nurse}, volume = {50}, number = {1}, pages = {16}, pmid = {11859558}, issn = {0742-8367}, mesh = {Aged ; Arthritis, Rheumatoid/nursing/*therapy ; Clinical Trials as Topic ; *Faith Healing ; Female ; Humans ; }, abstract = {Matthews et al's. (2000) study suggested that in person intercessory prayer was useful in the medical treatment of patients with RA, improving overall health. However, distant prayer showed no overall improvement. This study could be used to support a research utilization project to educate nurses on the potential benefits of prayer on the healthcare and health outcomes of patients with certain illnesses. An in-service could be made available for nurses to educate them on potential benefits of prayer. A feasibility issue would be cost. Religion and spiritual beliefs can influence a patient's level of health and self-care behaviors. It is essential for nurses to meet the spiritual needs of their patients. A nurse should also recognize that there are many different religions and not all patients have the same religion and beliefs.}, } @article {pmid40099231, year = {2025}, author = {Hwang, DW and Ser, J and Ziabrev, K and Park, GK and Jo, MJ and Yokomizo, S and Bao, K and Yamashita, A and Cho, H and Henary, M and Kashiwagi, S and Choi, HS}, title = {Image-Guided Monitoring of Mitochondria and Blood-Brain Barrier Dysfunction in Amyotrophic Lateral Sclerosis Mice.}, journal = {Biomaterials research}, volume = {29}, number = {}, pages = {0162}, pmid = {40099231}, issn = {1226-4601}, abstract = {Early detection of amyotrophic lateral sclerosis (ALS) progression is critical for improving disease management and therapeutic outcomes. However, the clinical heterogeneity and variability in ALS symptoms often lead to delayed diagnosis and suboptimal therapeutic interventions. Since mitochondrial dysfunction is a hallmark of ALS, we hypothesized that monitoring mitochondrial function could serve as a reliable strategy for early diagnosis and therapeutic monitoring of ALS. To address this, we synthesized and characterized 2 novel near-infrared fluorophores, ALS04 and ALS05, designed to target mitochondria and lysosomes. Their physicochemical properties, serum protein binding, fluorescence characteristics, photostability, and pharmacokinetics were systematically evaluated. We found that benzothiazole-based fluorophores exhibit excellent mitochondrial targeting, optimal optical properties, biocompatibility, and favorable biodistribution in vivo. Interestingly, ALS04 showed superior mitochondrial accumulation compared to ALS05, despite their similar physicochemical properties. This enhanced accumulation can be attributed to the lower molecular weight and higher lipophilicity of ALS04. Real-time fluorescence imaging revealed a substantial reduction in ALS04 signals in mitochondrial-rich tissues such as brown fat, highlighting its potential for monitoring mitochondrial dysfunction in early-stage ALS. Furthermore, the detection of ALS04 in the mouse brain suggests its ability to monitor blood-brain barrier hyperpermeability, another key feature of ALS pathology. These findings establish ALS04 as a promising noninvasive imaging tool for monitoring biomarkers associated with ALS progression. Its ability to detect early-stage pathophysiological changes in an ALS mouse model highlights its potential for advancing our understanding of ALS mechanisms and facilitating the identification of novel therapeutic targets.}, } @article {pmid40097890, year = {2025}, author = {Dezfouli, MA and Shalilahmadi, D and Shamsaei, G and Esmaeili, A and Majdinasab, N and Rashidi, SK}, title = {Circulating miR-223/NLRP3 axis and IL-1β level in functional disease progression of amyotrophic lateral sclerosis.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {40097890}, issn = {2240-2993}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease identified by progressive motor neuron loss. NLRP3 inflammasomes induce inflammation and pyroptosis, which can lead to neurodegeneration, muscle atrophy, and respiratory decline. miR-223 targets NLRP3 and suppresses inflammasome formation. Here, miR-223, NLRP3 and IL-1β levels were evaluated as plasma biomarkers in the incidence and progression of ALS.

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

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

CONCLUSION: Our results indicated that changes in miR-223, NLRP3 and IL-1β levels may correlate with the occurrence and functional progression of ALS. Additionally, therapeutic approaches based on miR-223 and inflammatory mediators can be proposed as effective strategies against disease progression.}, } @article {pmid40097762, year = {2025}, author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH}, title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40097762}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.}, } @article {pmid40097438, year = {2025}, author = {Ayyadurai, VAS and Deonikar, P and Kamm, RD}, title = {A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.}, journal = {NPJ systems biology and applications}, volume = {11}, number = {1}, pages = {27}, pmid = {40097438}, issn = {2056-7189}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neuromuscular Junction/metabolism/pathology ; Humans ; *Motor Neurons/pathology/metabolism ; Animals ; Systems Biology/methods ; }, abstract = {A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.}, } @article {pmid40097075, year = {2025}, author = {Cuevas, EP and Madruga, E and Martínez, IV and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A}, title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106871}, doi = {10.1016/j.nbd.2025.106871}, pmid = {40097075}, issn = {1095-953X}, abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.}, } @article {pmid40095345, year = {2025}, author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A}, title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40095345}, issn = {1559-1182}, abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.}, } @article {pmid40094392, year = {2025}, author = {Resch, M and Frickel, JS and Dischinger, K and Wen, RCS and Hell, K and Harner, ME}, title = {The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.}, journal = {Journal of cell science}, volume = {}, number = {}, pages = {}, doi = {10.1242/jcs.263661}, pmid = {40094392}, issn = {1477-9137}, support = {413985647//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.}, } @article {pmid40093130, year = {2025}, author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Bae, M and Shao, DD and Sahile, B and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.03.641186}, pmid = {40093130}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10 [-10]). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.}, } @article {pmid40092960, year = {2025}, author = {Liu, Y and Li, XF}, title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {3}, pages = {100463}, pmid = {40092960}, issn = {1948-5204}, abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.}, } @article {pmid40092497, year = {2025}, author = {Fujii, Y and Kanbayashi, T and Takahashi, K and Hamada, Y and Kobayashi, S and Sonoo, M}, title = {Correlation between decremental responses in repetitive nerve stimulation and disease progression rate in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {40-46}, pmid = {40092497}, issn = {2467-981X}, abstract = {OBJECTIVE: Decrement responses in repetitive nerve stimulation (RNS) are theoretically expected to correlate with the disease progression speed in amyotrophic lateral sclerosis (ALS). However, actual results have been controversial. We investigated this issue using ΔFS calculated from the ALS functional rating scale revised version (ALSFRS-R) and the duration of illness.

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

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

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

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

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

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

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

SIGNIFICANCE: The R1', especially when bilateral, could serve as an additional diagnostic biomarker for ALS, although its clinical relevance should be considered within the broader diagnostic context.}, } @article {pmid40091916, year = {2025}, author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F}, title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e78903}, pmid = {40091916}, issn = {2168-8184}, abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.}, } @article {pmid40098659, year = {2023}, author = {Serrano-Giraldo, J and Becerra-Muñoz, MP and Tijaro-Santos, JA and Zarante, I}, title = {[Current situation of rare diseases in Bogotá: Notification to Sivigila from 2019 to 2022].}, journal = {Revista de salud publica (Bogota, Colombia)}, volume = {25}, number = {4}, pages = {107594}, pmid = {40098659}, issn = {2539-3596}, abstract = {OBJECTIVE: To analyze the reports of orphan diseases in Bogotá, in order to describe the epidemiological profile, based on the cases reported to the Public Health System (Sivigila), from January 2019 to March 2022.

METHODS: A descriptive and cross-sectional study was carried out in which the cases reported to Sivigila in Bogotá were analyzed in the period between January 2019 and March 2022. Absolute and relative frequencies, frequency distribution and prevalences and averages of different variables were calculated. notified in the notification sheets.

RESULTS: From January 2019 to March 2022, 10,399 patients with orphan diseases have been notified to Sivigila in Bogotá, of which 56.25% (5,849) are female and 43.75% (4,550) are female. male sex. 87.10% (9,060) of the cases belong to the contributory regime. The town with the highest number of reports was Suba with 15.85% (1,294). The most reported orphan diseases were: multiple sclerosis with 13.1% (1,363), amyotrophic lateral sclerosis with 4.04% (421) and Guillain-Barre syndrome with 3.6% (374). A patient with an orphan disease in Bogotá takes 61.3 months on average from the beginning of their symptoms to obtaining a diagnosis (SD 101.9).

CONCLUSIONS: From the notification to Sivigila in Bogotá, compared to the global prevalence, there is an under-registration of patients with orphan diseases and the delay in the diagnosis of these diseases is evident.}, } @article {pmid9629709, year = {1997}, author = {Forattini, OP and Kakitani, I and Sallum, MA and de Rezende, L}, title = {[Productivity of a breeding place of Aedes albopictus in an urban environment].}, journal = {Revista de saude publica}, volume = {31}, number = {6}, pages = {545-555}, doi = {10.1590/s0034-89101997000700002}, pmid = {9629709}, issn = {0034-8910}, mesh = {*Aedes ; Animals ; Brazil ; *Breeding ; Entomology/methods ; Female ; Humans ; *Insect Vectors ; Male ; Urban Population ; }, abstract = {INTRODUCTION: Aedes albopictus has been found at Cananeia city in the Southeastern State of S. Paulo, Brazil. A study was carried out to evaluate the productivity of its breeding place.

MATERIAL AND METHOD: A container classified as large and permanent was chosen. Water had accumulated at the bottom and was rich in organic matter, mainly of vegetal origin. From November 1996 until May 1997, fortnightly observations were performed, sampling immature stages found in a seventh part of the container's total water volume (nearly 70 litres). Pupae were collected, identified and sexed. The productivity of the breeding place was estimated using Focks et al's. (1981) formula adapted for a single large container. At the same time adults were caught by using human bait and the aspiration of resting places. The first catch was performed at six meters from the breeding place studied. Williams' mean was calculated for the human bait and mean hourly density for the aspiration results of the resting places (Subbarao et al., 1988).

RESULTS: Immature stages of Ae. albopictus represented 44.9% of the total collected through fifteen fortnightly regular samplings (November 1996 to May 1997). The pupae mean was 31.13 and so the emergence index was 2.1. Multiplied by seven the result was 14.7 as the estimated mean number of females per day produced in that container. Adult females caught on human bait gave a general Williams' mean of 30.7, while the mean hour by density was 9.2. According to the accumulated calculated adult number, 22.8 females per day were available to seek human bait, under the conditions of the observations performed.

DISCUSSION: Counting pupae is an efficient method of estimating the productivity of the breeding place of Ae. albopictus. The richness of the organic matter in the water in the container made it quite inappropriate to establish comparisons with water reservoirs for domestic use. Nevertheless, a lack of or deficient maintenance approximate these containers to the one here studied. So cleaning is an important factor and it must be emphasized as necessary to prevent the installation of mosquito breeding. Though it is a distinct species it is reasonable to expect that the application of these study methods to Ae. aegypti would be useful in the attempt being made to eradicate this latter species from our country.}, } @article {pmid40091372, year = {2025}, author = {Jaspers Focks, RJ and Helleman, J and van den Berg, LH and Visser-Meily, JM and Gaytant, MA and Wijkstra, PJ and Beelen, A}, title = {Initiating non-invasive ventilation in patients with Amyotrophic Lateral Sclerosis in The Netherlands: A centralised approach to respiratory care.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251319167}, doi = {10.1177/22143602251319167}, pmid = {40091372}, issn = {2214-3602}, abstract = {BACKGROUND: In the Netherlands a centralised approach to respiratory care for patients with Amyotrophic Lateral Sclerosis is used based on national guidelines. Patients with Amyotrophic Lateral Sclerosis are referred to one of 4 centres for Home Mechanical Ventilation.

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

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

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

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

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

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

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

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

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

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

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

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

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

INTERPRETATION: We identified cognitive impairments in ALS within and beyond the FTD spectrum not captured by existing screening tools. The C-CAS complements the ECAS, improving personalized counseling and research stratification in ALS.}, } @article {pmid40074537, year = {2025}, author = {Mkhize, L and Marimani, M and Duze, ST}, title = {Characterization of Vibrio cholerae from the Jukskei River in Johannesburg South Africa.}, journal = {Letters in applied microbiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/lambio/ovaf036}, pmid = {40074537}, issn = {1472-765X}, abstract = {The current study aimed to isolate and characterize Vibrio cholerae (V. cholerae) isolated from the Jukskei River, one of the largest Rivers in Johannesburg, South Africa. Water samples collected from the Jukskei River were subjected to culture-based methods for the detection and isolation of V. cholerae. Twenty-four V. cholerae were isolated, confirmed using real-time PCR, and sequenced using the MInION portable nanopore-sequencing device. Reference-based genome assemblies were constructed from the raw reads using the EPI2ME software followed by bioinformatics analysis using the Centre for Genomic Epidemiology website. All the V. cholerae isolates isolated from the Jukskei River were classified as non-O1/ non-O139 and none of the isolates harbored the cholera toxin gene, ctxA. All 24 V. cholerae isolates belonged to sequence type 741, virulent genes including toxR, vspD, als, hlyA, makA, and rtxA as well as the Vibrio pathogenicity island 2 were detected amongst the isolates. Antimicrobial resistance genes (parC, varG, and gyrA) were detected in 83% of isolates. Although V. cholerae non-O1/non-O139 are not associated with epidemic cholera they can still cause mild to life-threatening illnesses. Therefore, increased surveillance should be considered to better understand the public health risks to the local community.}, } @article {pmid40074390, year = {2025}, author = {Cappa, SF}, title = {Hemispheric asymmetry in neurodegenerative diseases.}, journal = {Handbook of clinical neurology}, volume = {208}, number = {}, pages = {101-112}, doi = {10.1016/B978-0-443-15646-5.00009-9}, pmid = {40074390}, issn = {0072-9752}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; *Functional Laterality/physiology ; Brain/pathology/physiopathology ; }, abstract = {Hemispheric asymmetry in pathologic involvement is frequently observed in neurodegenerative disorders (NDD) and is responsible for differences in cognitive and motor clinical manifestations in individual patients. While asymmetry is modest in typical Alzheimer disease (AD), atypical AD presentations with prominent language impairment [logopenic/phonologic variant of primary progressive aphasia (L/Phv-PPA)] are associated with prevalent involvement of the language-dominant hemisphere. Similarly, in the frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, the semantic (Sv) and nonfluent/agrammatic (Nf/Av) variants of PPA are due to asymmetric pathology involving the language-dominant hemisphere. A reversed (typically right-sided) pattern of asymmetry is often found in conditions associated with prominent disorders of behavior and social cognition (i.e., behavioral variant of frontotemporal degeneration-Bv FTD). Asymmetry is generally modest and less consistent in NDD with prevalent motor manifestations, such as Parkinson disease (PD). Overall, the pattern of hemispheric involvement reflects the network-specific selectivity of NDD and is compatible with the spreading of pathology along connection pathways.}, } @article {pmid40073860, year = {2025}, author = {Zhang, Z and Fu, X and Wright, N and Wang, W and Ye, Y and Asbury, J and Li, Y and Zhu, C and Wu, R and Wang, S and Sun, S}, title = {PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.02.005}, pmid = {40073860}, issn = {1097-4199}, abstract = {The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.}, } @article {pmid40073394, year = {2025}, author = {Janes, WE and Marchal, N and Song, X and Popescu, M and Mosa, ASM and Earwood, JH and Jones, V and Skubic, M}, title = {Integrating Ambient In-Home Sensor Data and Electronic Health Record Data for the Prediction of Outcomes in Amyotrophic Lateral Sclerosis: Protocol for an Exploratory Feasibility Study.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e60437}, doi = {10.2196/60437}, pmid = {40073394}, issn = {1929-0748}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnosis ; *Electronic Health Records ; *Feasibility Studies ; Machine Learning ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to rapid physiological and functional decline before causing untimely death. Current best-practice approaches to interdisciplinary care are unable to provide adequate monitoring of patients' health. Passive in-home sensor systems enable 24×7 health monitoring. Combining sensor data with outcomes extracted from the electronic health record (EHR) through a supervised machine learning algorithm may enable health care providers to predict and ultimately slow decline among people living with ALS.

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

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

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

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

DERR1-10.2196/60437.}, } @article {pmid40072375, year = {2025}, author = {Gong, Z and Ba, L and Li, Z and Hou, H and Zhang, M}, title = {CD16[-]CD56[bright] NK Cells: A Protective NK Cell Subset for Progression and Prognosis in Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1597}, pmid = {40072375}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a non-neuron-autonomous disease where peripheral immune dysregulation significantly impacts disease progression. However, the immunopathological mechanisms of natural killer (NK) cells in ALS remain largely unexplored. This study enrolled 241 ALS patients and 102 healthy controls (HC), analyzing lymphocyte subsets, including T cells, B cells, and NK cells. A sub-cohort of 81 ALS patients was followed up for one year at three-month intervals. Linear mixed and Cox proportional hazards models were used to evaluate the association between lymphocyte subsets and ALS progression and prognosis. Our results revealed significant reductions in total T cells, helper T cells (Th), and NK cells in ALS patients compared to HC (P &;lt 0.05). Slow-progressing ALS patients exhibited higher counts of total T cells, Th, CD16-CD56[bright] NK cells, and CD16[+]CD56[bright] NK cells, while showing lower counts of CD16[+]CD56[dim] NK cells compared to fast-progressing ALS patients (P &;lt 0.05). ALS patients with lower CD16[-]CD56[bright] NK cell counts experienced a faster decline in motor function than those with higher counts (P &;lt 0.05). Elevated CD16[-]CD56[bright] NK cell counts were associated with improved ALS prognosis (HR, 0.73; 95% CI: 0.60-0.90; P &;lt 0.05). This study suggests that CD16[-]CD56[bright] NK cells play a protective role in ALS progression and prognosis, offering a potential therapeutic target for ALS.}, } @article {pmid40072076, year = {2025}, author = {Calvo, B and Schembri-Wismayer, P and Durán-Alonso, MB}, title = {Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective.}, journal = {Cells}, volume = {14}, number = {5}, pages = {}, doi = {10.3390/cells14050347}, pmid = {40072076}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Aging/pathology ; Animals ; Stem Cells/metabolism ; Neurogenesis ; }, abstract = {Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.}, } @article {pmid40070688, year = {2025}, author = {Hosseini Faradonbeh, SM and Seyedalipour, B and Keivan Behjou, N and Rezaei, K and Baziyar, P and Hosseinkhani, S}, title = {Structural insights into SOD1: from in silico and molecular dynamics to experimental analyses of ALS-associated E49K and R115G mutants.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1532375}, pmid = {40070688}, issn = {2296-889X}, abstract = {Protein stability is a crucial characteristic that influences both protein activity and structure and plays a significant role in several diseases. Cu/Zn superoxide dismutase 1 (SOD1) mutations serve as a model for elucidating the destabilizing effects on protein folding and misfolding linked to the lethal neurological disease, amyotrophic lateral sclerosis (ALS). In the present study, we have examined the structure and dynamics of the SOD1 protein upon two ALS-associated point mutations at the surface (namely, E49K and R115G), which are located in metal-binding loop IV and Greek key loop VI, respectively. Our analysis was performed through multiple algorithms on the structural characterization of the hSOD1 protein using computational predictions, molecular dynamics (MD) simulations, and experimental studies to understand the effects of amino acid substitutions. Predictive results of computational analysis predicted the deleterious and destabilizing effect of mutants on hSOD1 function and stability. MD outcomes also indicate that the mutations result in structural destabilization by affecting the increased content of β-sheet structures and loss of hydrogen bonds. Moreover, comparative intrinsic and extrinsic fluorescence results of WT-hSOD1 and mutants indicated structural alterations and increased hydrophobic surface pockets, respectively. As well, the existence of β-sheet-dominated structures was observed under amyloidogenic conditions using FTIR spectroscopy. Overall, our findings suggest that mutations in the metal-binding loop IV and Greek key loop VI lead to significant structural and conformational changes that could affect the structure and stability of the hSOD1 molecule, resulting in the formation of toxic intermediate species that cause ALS.}, } @article {pmid40069959, year = {2025}, author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C}, title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2475893}, pmid = {40069959}, issn = {2167-9223}, abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.}, } @article {pmid40069809, year = {2025}, author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H}, title = {Nursing contribution to end-of-life care decision-making in patients with neurological diseases on an acute hospital ward: documentation of signs and symptoms.}, journal = {BMC nursing}, volume = {24}, number = {1}, pages = {271}, pmid = {40069809}, issn = {1472-6955}, support = {71545//Icelandic Nurses Association/ ; }, abstract = {BACKGROUND: Recognizing impending death in patients with neurological diseases presents challenges for nurses and other healthcare professionals. This study aimed to identify nursing contribution to end-of-life (EOL) care decision-making for patients with neurological diseases in an acute hospital ward and to compare signs and symptoms among subgroups of patients.

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

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

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

CLINICAL TRIAL NUMBER: Not applicable.}, } @article {pmid40069360, year = {2025}, author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X}, title = {Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {40069360}, issn = {1546-1726}, support = {2019YFA0508701//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; 2022YFA1303300//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in many genes of diverse functions, the underlying pathogenic mechanisms of ALS, especially in sporadic ALS (sALS), are largely unknown. Notably, about half of the cases with sALS showed defects in mitochondrial respiratory complex IV (CIV). To determine the causal role of this defect in ALS, we used transcription activator-like effector-based mitochondrial genome editing to introduce mutations in CIV subunits in rat neurons. Our results demonstrate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance in understanding and therapeutic development of sALS.}, } @article {pmid40067829, year = {2025}, author = {O'Neill, K and Shaw, R and Bolger, I and , and Tam, OH and Phatnani, H and Gale Hammell, M}, title = {ALS molecular subtypes are a combination of cellular and pathological features learned by deep multiomics classifiers.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115402}, doi = {10.1016/j.celrep.2025.115402}, pmid = {40067829}, issn = {2211-1247}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this heterogeneity, large-scale genomics studies revealed that ALS postmortem samples can be grouped into a small number of subtypes, defined by transcriptomic signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or TDP-43 pathology and associated transposable elements (ALS-TE). In this study, we present a deep ALS neural net classifier (DANCer) for ALS molecular subtypes. Applying DANCer to an expanded cohort from the NYGC ALS Consortium highlights two subtypes that strongly correlate with disease duration: ALS-TE in cortex and ALS-Glia in spinal cord. Finally, single-nucleus transcriptomes demonstrate that ALS subtypes are recapitulated in neurons and glia, with both ALS-wide and subtype-specific alterations in all cell types. In summary, ALS molecular subtypes represent a combination of cellular and pathological features that correlate with clinical features of ALS.}, } @article {pmid40067821, year = {2025}, author = {, and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , }, title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.27643}, pmid = {40067821}, issn = {1538-3598}, abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.

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

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

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

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

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

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

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.}, } @article {pmid40067755, year = {2025}, author = {, and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , }, title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.26429}, pmid = {40067755}, issn = {1538-3598}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.

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

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

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

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

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

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

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.}, } @article {pmid40067754, year = {2025}, author = {, and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S and , }, title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2024.5249}, pmid = {40067754}, issn = {2168-6157}, abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.

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

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

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

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

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

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

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

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

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

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

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

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

DISCUSSION: Our single-center findings demonstrate a large racial difference in time to clinical events for Black versus White ALS patients referred for NIV, AAC, hospice, and wheelchair, suggesting more advanced disease at the time of presentation or more rapid progression.}, } @article {pmid40065553, year = {2025}, author = {Boddy, SL and Simpson, RM and Walters, SJ and Walsh, T and McDermott, CJ and , and , }, title = {Further development of a patient-reported outcome measure to assess the impact of oral secretion problems in people living with MND.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2469721}, pmid = {40065553}, issn = {2167-9223}, abstract = {Objective: Oral secretion problems are common yet poorly managed in people living with MND (plwMND). A validated patient-reported outcome for measuring saliva symptoms in this patient group would facilitate better monitoring of individuals. This study aimed to assess the validity, reliability and sensitivity to change of a revised version of the clinical saliva score for MND (CSS-MNDr). Methods: Data were collected as part of a longitudinal, observational saliva management study. The CSS-MNDr, ALS Functional Rating Scale, a Global Rating of Change questionnaire and saliva-specific modified Likert scale were completed at each study visit, each of which probed the severity of saliva symptoms. Construct validity, test-retest reliability and sensitivity of the CSS-MNDr were assessed and the minimal important difference of the instrument was estimated. Results: The CSS-MNDr showed excellent test-retest reliability (intraclass correlation coefficient >0.9). Construct validity showed the CSS-MNDr performed as expected, with bulbar-onset participants scoring significantly higher than those who reported limb-onset across all visits (group mean scores). Strong correlation of total scores with the ALSFRS-R saliva question was demonstrated (-0.8), with the thick subscore correlating less well (-0.5). A minimal important difference in the range of -2.5 to -3.6 over 3 months was estimated for worsening symptoms. Conclusions: The CSS-MNDr has been validated as a reliable patient reported outcome for measuring saliva problems in plwMND. With separate scores for thick and thin secretion problems, the CSS-MNDr is the most comprehensive tool for assessing salivary problems in plwMND reported to date.}, } @article {pmid40065552, year = {2025}, author = {Shibata, N and Kataoka, I and Okamura, Y and Murakami, K and Kato, Y and Yamamoto, T and Masui, K}, title = {Implications for soluble iron accumulation, oxidative stress, and glial glutamate release in motor neuron death associated with sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/neup.13033}, pmid = {40065552}, issn = {1440-1789}, abstract = {Oxidative stress in sporadic amyotrophic lateral sclerosis (ALS) has been evidenced by accumulation of oxidatively modified products of nucleic acids, lipids, sugars, and proteins in the motor neuron system of brains and spinal cords obtained at autopsy from the patients. We recently demonstrated soluble iron accumulation in activated microglia of sporadic ALS spinal cords. This finding could indicate that iron-mediated Fenton reaction is most likely to be responsible for oxidative stress associated with this disease. The excitatory amino acid neurotoxicity hypothesis for sporadic ALS has been proposed based on increased glutamate and aspartate concentrations in cerebrospinal fluid from the patients. Initially, the increase in extracellular excitatory amino acid levels was considered to reflect excessive release from the axon terminal of upper motor neurons. However, it is a question of whether the damaged upper motor neurons continue releasing glutamate even in advanced stage of this disease. To address this issue, we hypothesized that glial cells might be a glutamate release source. Our immunohistochemical analysis on autopsied human spinal cords revealed that ferritin, hepcidin, ferroportin, aconitase 1, tumor necrosis factor-α (TNF-α), TNF-α-converting enzyme (TACE), and glutaminase-C (GAC) were expressed mainly in microglia and that cystine/glutamate antiporter (xCT) was expressed mainly in astrocytes. We next performed cell culture experiments. Cultured microglia treated with soluble iron over-released glutamate and TNF-α via aconitase 1 and TACE, respectively. Cultured microglia treated with TNF-α over-released glutamate via GAC. Cultured microglia treated with hepcidin, of which expression is known to be upregulated by TNF-α, showed downregulated expression of ferroportin. Cultured astrocytes treated with hydrogen peroxide over-released glutamate via xCT. These observations provide in vivo and in vitro evidence that microglia and astrocytes are glutamate suppliers in response to soluble iron overload and oxidative stress, respectively, in sporadic ALS.}, } @article {pmid40064496, year = {2025}, author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ}, title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.}, journal = {eNeuro}, volume = {}, number = {}, pages = {}, doi = {10.1523/ENEURO.0329-24.2025}, pmid = {40064496}, issn = {2373-2822}, abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.}, } @article {pmid40064491, year = {2025}, author = {Izumi, Y and Nakayama, Y}, title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {3}, pages = {259-263}, doi = {10.11477/mf.188160960770030259}, pmid = {40064491}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Communication ; Patient Care Team ; }, abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.}, } @article {pmid40063887, year = {2025}, author = {Hayden, CD and Murphy, BP and Gilsenan, D and Nasseroleslami, B and Hardiman, O and Murray, D}, title = {Clinical validation of a novel hand dexterity measurement device.}, journal = {PLOS digital health}, volume = {4}, number = {3}, pages = {e0000744}, pmid = {40063887}, issn = {2767-3170}, abstract = {The lack of sensitive objective outcome measures for hand dexterity is a barrier for clinical assessment of neurological conditions and has negatively affected clinical trials. Here, we clinically validate a new method for measuring hand dexterity, a novel hand worn sensor that digitises the Finger Tapping Test. The device was assessed in a cohort of 180 healthy controls and 51 people with Amyotrophic Lateral Sclerosis (ALS) and compared against rating scales and traditional measures (Nine Hole Peg test and grip dynamometry). 14 features were extracted from the device and using a logistic regression algorithm, a 0-100 dexterity performance score was generated for each participant, which accounted for age/sex differences. The device returned objective ratings of a participant's hand dexterity (dominant, non-dominant and overall score). The average overall dexterity performance score in all healthy participants was 88 ± 17 (mean ± standard deviation). The overall dexterity score was statistically significantly worse in participants with ALS (age/sex matched healthy subset: 80 ± 20, ALS: 45 ± 32, p-value < 0.0001). The device also had a higher completion rate, (94% dominant hand) compared to the traditional measures (82% dominant hand). This test and scoring system have been validated and the regression model was developed using a framework that is potentially applicable to any relevant condition. This device could act as an objective outcome measure in clinical trials and may be useful in improving patient care.}, } @article {pmid40063831, year = {2025}, author = {Kubinski, S and Claus, L and Schüning, T and Zeug, A and Kalmbach, N and Staege, S and Gschwendtberger, T and Petri, S and Wegner, F and Claus, P and Hensel, N}, title = {Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf020}, pmid = {40063831}, issn = {1460-2083}, support = {ZE994//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs). SGs assemble and dissolve dependent on the cellular condition. However, it has been suggested that transition from reversible SGs to irreversible aggregates contributes to the toxic properties of ALS-related mutated proteins. Sequestration of additional proteins within these aggregates may then result in downstream toxicity. While the exact downstream mechanisms remain elusive, rare ALS-causing mutations in the actin binding protein profilin 1 suggest an involvement of the actin cytoskeleton. Here, we hypothesize that profilin isoforms become sequestered in aggregates of ALS-associated proteins which induce subsequent dysregulation of the actin cytoskeleton. Interestingly, localization of neuronal profilin 2 in SGs was more pronounced compared with the ubiquitously expressed profilin 1. Accordingly, FUS and C9orf72 aggregates prominently sequestered profilin 2 but not profilin 1. Moreover, we observed a distinct sequestration of profilin 2 and G-actin to C9orf72 aggregates in different cellular models. On the functional level, we identified dysregulated actin dynamics in cells with profilin 2-sequestering aggregates. In summary, our results suggest a more common involvement of profilins in ALS pathomechanisms than indicated from the rarely occurring profilin mutations.}, } @article {pmid40061974, year = {2025}, author = {Zhang, ZN and Hao, L and Han, S and Li, SS and Lin, SX and Miao, YD}, title = {Harnessing the prognostic power of preoperative systemic immune-inflammation index/albumin ratio in hepatocellular carcinoma resection.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {102261}, pmid = {40061974}, issn = {1948-9366}, abstract = {The recent study by Chen et al, published in the World Journal of Gastroenterology, introduces a groundbreaking assessment tool-the preoperative systemic immune-inflammation index/albumin (SII/ALB) ratio-for patients with hepatocellular carcinoma (HCC) undergoing curative resection. This study not only establishes the independent prognostic significance of the SII/ALB ratio but also incorporates it into a predictive nomogram, enhancing its utility for clinical decision-making. The SII/ALB ratio, by integrating inflammatory and nutritional biomarkers, offers a novel lens through which the prognosis of HCC patients can be viewed, suggesting a more tailored approach to patient management. The development of the nomogram, validated for its accuracy in predicting patient outcomes, marks a pivotal advance, potentially guiding surgical decisions and postoperative care. However, the study's focus on a single-center cohort prompts the need for validation in a broader, more diverse patient population to ensure its applicability across various clinical settings. Moreover, longitudinal studies could elucidate the dynamic changes in SII/ALB post-surgery, offering insights into its potential as a continuous monitor for recurrence and long-term survival. This abstract aim to underscore the critical findings of Chen et al's study while calling for further research to explore the full potential of the SII/ALB ratio in the global management of hepatocellular carcinoma.}, } @article {pmid40061972, year = {2025}, author = {Yi, XM and Cai, HQ and Jiao, Y}, title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {100257}, pmid = {40061972}, issn = {1948-9366}, abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.}, } @article {pmid40061966, year = {2025}, author = {Wang, H and Jiao, Y and Ma, Q and Liu, YH}, title = {Overview of endoscopic biliary stenting in malignant obstructive jaundice.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {103378}, pmid = {40061966}, issn = {1948-9366}, abstract = {This article discusses Wang et al's essay. Endoscopic biliary stenting, a less invasive alternative to surgery, is effective for malignant obstructive jaundice. This article summarizes the pathophysiology of biliary obstruction, the technical aspects of stenting, and the clinical outcomes. By comparison of endoscopic stenting with percutaneous biliary drainage, improvements and complications are focused on. Additionally, patient selection for stenting and future advancements in stent technology are important. Overall, endoscopic biliary stenting is a valuable palliative option for patients with malignant jaundice, especially those ineligibles for surgery.}, } @article {pmid40060668, year = {2025}, author = {Axakova, A and Ding, M and Cote, AG and Subramaniam, R and Senguttuvan, V and Zhang, H and Weile, J and Douville, SV and Gebbia, M and Al-Chalabi, A and Wahl, A and Reuter, J and Hurt, J and Mitchell, A and Fradette, S and Andersen, PM and van Loggerenberg, W and Roth, FP}, title = {Landscapes of missense variant impact for human superoxide dismutase 1.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.25.640191}, pmid = {40060668}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene SOD1 . Diagnosis based on SOD1 sequencing can not only be definitive but also indicate specific therapies available for SOD1 -associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUS). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging, given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over two thousand SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting 'missense variant effect maps' not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUS, offering the potential to identify additional patients who would benefit from therapy approved for SOD1-ALS.}, } @article {pmid40060539, year = {2025}, author = {Petrescu, J and Roque, CG and Jackson, CA and Daly, A and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and McDade, K and Gregory, JM and Smith, C and Phatnani, H}, title = {Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.26.640433}, pmid = {40060539}, issn = {2692-8205}, abstract = {Half of all amyotrophic lateral sclerosis (ALS) patients demonstrate a spectrum of cognitive and behavioral changes over the course of the disease, but the mechanisms underlying this heterogeneity remain unclear. We assemble a high-resolution cellular map of prefrontal cortex regions of the ALS brain by integrating spatial and single-nucleus transcriptomic profiles of a cognitively stratified ALS patient cohort that includes non-neuropathological controls. We find cellular programs characteristic of ALS, including a frequent gliotic response. We also find that executive and language cognitive impairments differ from ALS without cognitive impairment, and from each other, in the extent and pattern of neuronal dysregulation and neuron-glial interactions across different brain regions. These findings reveal a relationship between cognitive phenotype and prefrontal cortex dysfunction in ALS.}, } @article {pmid40060442, year = {2025}, author = {Deng, X and Bradshaw, G and Kalocsay, M and Mitchison, T}, title = {Tubulin Regulates the Stability and Localization of STMN2 by Binding Preferentially to Its Soluble Form.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.27.640326}, pmid = {40060442}, issn = {2692-8205}, abstract = {Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic lateral sclerosis (ALS) but how it protects neurons is not known. STMN2 is known to turn over rapidly and accumulate at axotomy sites. We confirmed fast turnover of STMN2 in U2OS cells and iPSC-derived neurons and showed that degradation occurs mainly by the ubiquitin-proteasome system. The membrane targeting N-terminal domain of STMN2 promoted fast turnover, whereas its tubulin binding stathmin-like domain (SLD) promoted stabilization. Proximity labeling and imaging showed that STMN2 localizes to trans-Golgi network membranes and that tubulin binding reduces this localization. Pull-down assays showed that tubulin prefers to bind to soluble over membrane-bound STMN2. Our data suggest that STMN2 interconverts between a soluble form that is rapidly degraded unless bound to tubulin and a membrane-bound form that does not bind tubulin. We propose that STMN2 is sequestered and stabilized by tubulin binding, while its neuroprotective function depends on an unknown molecular activity of its membrane-bound form.}, } @article {pmid40060160, year = {2025}, author = {Mangalindan, KE and Wyatt, TR and Brown, KR and Shapiro, M and Maggio, LA}, title = {Investigating the Road to Equity: A Scoping Review of Solutions to Mitigate Implicit Bias in Assessment within Medical Education.}, journal = {Perspectives on medical education}, volume = {14}, number = {1}, pages = {92-106}, pmid = {40060160}, issn = {2212-277X}, mesh = {Humans ; *Education, Medical/methods ; Bias ; Educational Measurement/methods ; }, abstract = {INTRODUCTION: In medical education, assessments have high-stakes implications. Yet, assessments are rife with unconscious bias, which contributes to inequitable social structures. Implicit bias in assessment must be addressed because medical educators use assessments to guide learning and promote development of physicians' careers. In this scoping review, the authors map the literature on implicit bias in assessment, as it applies to: 1) the types of implicit bias addressed, 2) the targets and types of interventions studied or proposed, and 3) how publications describe intervention efficacy.

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

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

DISCUSSION: This scoping review showed that more work is necessary to address different types of implicit biases, move scholarship beyond single-institution studies, refine existing interventions, and evaluate how efficacy is defined.}, } @article {pmid40059194, year = {2025}, author = {Shang, Q and Zhou, J and Ye, J and Chen, M}, title = {Adverse events reporting of edaravone: a real-world analysis from FAERS database.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {8148}, pmid = {40059194}, issn = {2045-2322}, mesh = {*Edaravone/adverse effects/therapeutic use ; Humans ; *Adverse Drug Reaction Reporting Systems ; *Databases, Factual ; United States ; United States Food and Drug Administration ; Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Drug-Related Side Effects and Adverse Reactions ; Female ; Male ; }, abstract = {For individuals with amyotrophic lateral sclerosis (ALS), intravenous edaravone is approved as a disease-modifying medication; yet, there have been many reports of adverse events (AEs). We examined the AEs associated with edaravone in this study using actual data from the FDA's (Food and Drug Administration) adverse event reporting system (FAERS). By extracting large-scale data from the FAERS database, this study used the signals of edaravone-associated AEs were quantified using the multiitem gamma Poisson shrinker (MGPS) method based on disproportionality, the Bayesian confidence propagation neural network (BCPNN), the reporting odds ratio (ROR), and the proportional reporting ratio (PRR). In the FAERS database, this study extracted data between April 2017 and March 2024, and edaravone was identified as the "primary suspect (PS)" in 2,986 AE reports. AEs associated with edaravone specifically targeted 27 system organ types (SOCs). Unexpectedly serious AEs that weren't mentioned in the drug insert, include abnormal hepatic function, catheter site thrombosis, pain, cerebral hemorrhage, infection, cerebral infarction, poor venous access, disseminated intravascular coagulation, vein collapse and cerebral venous sinus thrombosis. Our research found possible signals of new AEs that may offer substantial backing for clinical surveillance and edaravone risk assessment, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instruction.}, } @article {pmid40057796, year = {2025}, author = {Mitra, J and Kodavati, M and Dharmalingam, P and Guerrero, EN and Rao, KS and Garruto, RM and Hegde, ML}, title = {Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {54}, pmid = {40057796}, issn = {2051-5960}, support = {R03AG064266/AG/NIA NIH HHS/United States ; R03AG064266/AG/NIA NIH HHS/United States ; RF1NS112719/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Disease Models, Animal ; *DNA Repair ; *Gene Knock-In Techniques ; *Cellular Senescence/physiology ; Motor Neurons/metabolism/pathology ; Mice, Transgenic ; Inflammation/metabolism/pathology/genetics ; DNA Ligase ATP/metabolism/genetics ; }, abstract = {TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage TDP-43 proteinopathy. To complement these models and to study the early-stage motor neuron-specific pathology during pre-symptomatic phases of disease progression, we generated a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43∆NLS variant of mouse Tdp-43. This variant is expressed either in the whole body (WB) or specifically in the motor neurons (MNs) in two distinct models. These mice exhibit loss of nuclear Tdp-43, with concomitant cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation, and associated cellular senescence. Notably, unlike WT Tdp-43, which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43∆NLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mouse brain. The mutant mice also exhibit myogenic degeneration in hindlimb soleus muscles and distinct motor deficits, consistent with the characteristics of motor neuron disease (MND). Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.}, } @article {pmid40057753, year = {2025}, author = {Sharbafshaaer, M and Siciliano, M and Passaniti, C and Sant'Elia, V and Silvestro, M and Russo, A and Esposito, S and Tedeschi, G and Trojano, L and Trojsi, F}, title = {Screening of visuospatial abilities in amyotrophic lateral sclerosis (ALS): a pilot study using the battery for visuospatial abilities (BVA).}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {110}, pmid = {40057753}, issn = {1750-1172}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Neuropsychological Tests ; Visual Perception/physiology ; }, abstract = {BACKGROUND: Cognitive deficits related to frontotemporal dysfunction are common in Amyotrophic Lateral Sclerosis (ALS). Visuospatial deficits, related to posterior cerebral regions, are often underestimated in ALS, though they play a crucial role in attending daily living activities. Our pilot study aims at assessing visuospatial abilities using a domain-specific tool in ALS patients compared to healthy controls (HC).

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

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

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

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

CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.}, } @article {pmid40056296, year = {2025}, author = {Li, Z and Fan, J and Gong, Z and Tang, J and Yang, Y and Liu, M and Zhang, M}, title = {Association between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {}, number = {}, pages = {}, pmid = {40056296}, issn = {1619-1560}, support = {82271478//the National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; }, abstract = {PURPOSE: The aim of this study was to investigate the relationship between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis (ALS).

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

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

CONCLUSIONS: Patients with ALS with cognitive impairment demonstrated reduced cardiac autonomic modulations and altered cognitive autonomic associations. Cognitive impairment was linked to reduced survival, with baseline SDNN ≤ 100 ms identified as a potential marker.}, } @article {pmid40056685, year = {2025}, author = {Jakhar, M and Barone, V}, title = {Single atom catalysts adsorbed on reduced monolayers for enhanced kinetics in Al-S batteries.}, journal = {Journal of colloid and interface science}, volume = {689}, number = {}, pages = {137226}, doi = {10.1016/j.jcis.2025.03.015}, pmid = {40056685}, issn = {1095-7103}, abstract = {Rechargeable aluminum-sulfur (Al-S) batteries have attracted significant attention as potential next-generation energy storage devices due to their safety, the natural abundance of the elemental components, and high theoretical energy density. However, their utilization is hindered by sluggish reaction kinetics and poor reversibility. Introducing single-atom catalysts (SACs) can promote redox processes at the cathode and help in mitigating the shuttle effect of Al polysulfides (Al2Sx). While the electrochemical, thermodynamic, and thermal stabilities of SACs (Co, Fe, Ir, Ni, Pt, and Rh) have been explored in previous studies, this work focuses on their potential role in enhancing reaction kinetics in Al-S batteries. Our calculations indicate that SACs-based substrates exhibit more robust binding energies for capturing Al2Sx than the bare surfaces. Additionally, SACs lower the free energies associated with the rate-determining step during discharging and exhibit lower decomposition barriers during charging. Moreover, the interaction of soluble Al2Sx with the electrolyte reveals that SAC supported polysulfides are less likely to dissolve in the electrolyte than their pristine counterparts. The analysis of the underlying mechanisms of the interaction of molecules and the Co@ substrate reveals the ability of this substrate to accommodate large volume changes and support a sulfur loading up to 53.37 wt% during the charging and discharging cycles, without causing fractures. The mechanism driving this enhanced performance is extensively investigated through charge transfer, bond strength, and d-band center analyses. Our findings present an effective strategy for designing SACs substrates to improve the electrochemical performance of Al-S cathodes.}, } @article {pmid40056552, year = {2025}, author = {Newell, ME and Babbrah, A and Aravindan, A and Kulkarni, S and Ellershaw, A and Dupati, A and Rathnam, R and Shaffer, G and Estrada, L and Curtis, C and Leneaux, J and Driver, EM and Halden, RU}, title = {Wastewater-borne markers of neurodegenerative disease: β-methylamino-L-alanine and aminomethylphosphonic acid.}, journal = {The Science of the total environment}, volume = {970}, number = {}, pages = {179032}, doi = {10.1016/j.scitotenv.2025.179032}, pmid = {40056552}, issn = {1879-1026}, abstract = {Exposure to toxic organic chemicals such as β-methylamino-L-alanine (BMAA) and glyphosate has been associated with neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). We explored the utility of BMAA and glyphosate's metabolite aminomethylphosphonic acid (AMPA) for serving as potential markers of NDDs by comparing levels of wastewater-borne BMAA and AMPA with regional U.S. rates of NDD prevalence. Newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were applied to U.S. wastewater samples (n = 87) and resultant concentrations of putative biomarkers were statistically compared to NDD prevalence rates in conjunction with environmental data on algal blooms and agricultural glyphosate use. Locations of algal blooms were found to be significantly associated (p = 0.01) with ALS prevalence rates per 100,000 people. BMAA levels in wastewater were highly correlated (p < 0.0001) with ALS prevalence rates by region. BMAA in wastewater typically peaked in summer months. We conclude that NDD biomarker detection in wastewater holds potential value, with BMAA outperforming AMPA. Furthermore, prevalence data for NDDs may have to be reported to the Centers for Disease Control and Prevention at a higher geospatial resolution to further enhance the value for the present type of analysis. Further method development is needed for AMPA to be quantified using LC-MS/MS. Future method developments focusing on metabolites (e.g., AMPA) may enable epidemiologists to determine human exposure levels rather than the mere occurrence of toxic organic chemicals in the environment.}, } @article {pmid40056503, year = {2025}, author = {Zhan, A and Zhong, K and Zhang, K}, title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151582}, doi = {10.1016/j.bbrc.2025.151582}, pmid = {40056503}, issn = {1090-2104}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.}, } @article {pmid40056413, year = {2025}, author = {Kahn, OI and Dominguez, SL and Glock, C and Hayne, M and Vito, S and Sengupta Ghosh, A and Adrian, M and Burgess, BL and Meilandt, WJ and Friedman, BA and Hoogenraad, CC}, title = {Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115382}, doi = {10.1016/j.celrep.2025.115382}, pmid = {40056413}, issn = {2211-1247}, abstract = {Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.}, } @article {pmid40056187, year = {2025}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Correction: Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {259}, doi = {10.1007/s00415-025-12952-1}, pmid = {40056187}, issn = {1432-1459}, } @article {pmid40055545, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Author Correction: Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41593-025-01926-1}, pmid = {40055545}, issn = {1546-1726}, } @article {pmid40054065, year = {2025}, author = {Tserennadmid, B and Nam, MK and Park, JH and Rhim, H and Kang, S}, title = {HAP/ClpP-mediated disaggregation and degradation of Mutant SOD1 aggregates: A potential therapeutic strategy for Amyotrophic lateral sclerosis (ALS).}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151533}, doi = {10.1016/j.bbrc.2025.151533}, pmid = {40054065}, issn = {1090-2104}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by the accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) protein aggregates in motor neurons, leading to progressive motor dysfunction and ultimately death. While the molecular chaperone heat shock protein 104 (Hsp104) has been shown to reduce protein misfolding by disaggregating protein aggregates, fully degrading these disaggregated proteins remains a significant challenge. In this study, we have investigated the effects of Hsp104 and its hyperactive variant, HAP, in combination with caseinolytic protease P (CIpP), on the disaggregation and degradation of SOD1 aggregates. Using laser confocal microscopy, fluorescence loss in photobleaching (FLIP), and biomolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assays, we demonstrate that Hsp104 effectively disaggregates SOD1 aggregates across 14 different G93 mutants, classified based on the properties of substituted amino acids, thus restoring protein mobility. Notably, the HAP/CIpP system not only disaggregates ALS-associated SOD1[G93A] aggregates but also promotes their proteolytic degradation, as evidenced by a significant reduction in high-order oligomers observed through BiFC and FRET assays. This dual mechanism of action presents. the HAP/CIpP system holds significant therapeutic potential for ALS and other neurodegenerative diseases characterized by protein aggregates, as it enables both effective disaggregation and degradation of toxic protein aggregates, thereby maintaining protein homeostasis.}, } @article {pmid40053600, year = {2025}, author = {Nie, Y and Szebényi, K and Wenger, LMD and Lakatos, A and Chinnery, PF}, title = {Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.}, journal = {Science advances}, volume = {11}, number = {10}, pages = {eadr0690}, pmid = {40053600}, issn = {2375-2548}, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA, Mitochondrial/genetics ; *Organoids/metabolism/pathology ; *Mutation ; *Brain/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Astrocytes/metabolism/pathology ; Mitochondria/genetics/metabolism ; DNA Repeat Expansion/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.}, } @article {pmid40053462, year = {2025}, author = {Fazzini, L and Martis, A and Pateri, MI and Maccabeo, A and Borghero, G and Puligheddu, M and Montisci, R and Marchetti, MF}, title = {Long-term outcomes and worse clinical course in Takotsubo syndrome patients with amyotrophic lateral sclerosis.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {26}, number = {4}, pages = {184-190}, doi = {10.2459/JCM.0000000000001711}, pmid = {40053462}, issn = {1558-2035}, mesh = {Humans ; *Takotsubo Cardiomyopathy/mortality/epidemiology/complications/physiopathology/diagnosis/therapy ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/complications/epidemiology/therapy/physiopathology ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; Time Factors ; Prevalence ; Aged, 80 and over ; Hospital Mortality ; Risk Factors ; Prognosis ; Cause of Death ; Risk Assessment ; Respiration, Artificial/statistics & numerical data ; Shock, Cardiogenic/mortality/epidemiology/etiology/therapy/diagnosis ; }, abstract = {AIMS: Takotsubo syndrome (TTS) is usually triggered by either physical/psychological stressors or comorbidities, neurological among others. The prevalence of amyotrophic lateral sclerosis (ALS) among TTS and whether it has a worse clinical course is not known. We aim to describe ALS prevalence and its impact on clinical presentation, clinical course, and long-term mortality.

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

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

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

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

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

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

CONCLUSION: This international study examining physician knowledge, attitudes, and practices related to medical cannabis revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is a wide variability in willingness to recommend medical cannabis, which is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.}, } @article {pmid40050936, year = {2025}, author = {Jeejan, J and Rao, L and Sadasivan, S and Lopes, R and Dsouza, N}, title = {Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis.}, journal = {Genomics & informatics}, volume = {23}, number = {1}, pages = {7}, pmid = {40050936}, issn = {1598-866X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease prevalent in American and European populations, with its onset and progression significantly influenced by mutations in the superoxide dismutase 1 (SOD1) protein. While previous studies have highlighted the effects of mutations in the metal-binding region and catalytic region and dimerisation of SOD1, the impact of mutations involving the Cysteine residue at the N-terminal end remains unexplored. This study investigates the effects of Cysteine-to-Trp, Phe, Ser, and Gly mutations at the 6th position of SOD1's N-terminal end on its structural dynamics and functional impairment. Our computational analysis using PolyPhen-2, PROVEAN, Meta-SNP, and PhD-SNP predicted mutations to be deleterious, with their negative impacts likely contributing to disease development. Furthermore, stability studies and bonding pattern changes due to the mutations, analysed by mCSM, SDM, DUET, Dynamut2, and PremPS revealed changes in free energy and disruption in intramolecular interactions. The molecular dynamics studies revealed distinct changes in stability patterns among the mutations, particularly in Cys6Trp and Cys6Phe. All the mutations primarily altered the catalytic region of the protein; additionally, Cys6Phe and Cys6Gly caused disruption in the metal-binding region. The impact of mutations on the dimerisation of SOD1, analysed using MM/PBSA showed destabilisation due to Cys6Phe mutation. These findings provide molecular insights into the clinical symptoms observed in patients, highlighting the critical impact of the Cys6Phe mutation on the metal-binding and catalytic loops of SOD1 along with destabilisation of dimer formation. Overall, our analysis offers valuable insights into the molecular mechanisms driving structural changes in SOD1 due to mutations, contributing to a deeper understanding of their role in ALS pathogenicity.}, } @article {pmid40050651, year = {2025}, author = {Gregorio-Sanz, MÁ and Marzo-Campos, JC and Segura-Heras, JV}, title = {Effects of nursing music intervention on cardiovascular patients transferred in advanced life support ambulances.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7919}, pmid = {40050651}, issn = {2045-2322}, support = {PROMETEO/2021/063//Generalitat Valenciana/ ; }, mesh = {Humans ; Male ; Female ; Aged ; *Ambulances ; *Music Therapy/methods ; *Cardiovascular Diseases/therapy/prevention & control ; Middle Aged ; Case-Control Studies ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Blood Pressure ; }, abstract = {Patients with acute cardiovascular disease require out-of-hospital care during the most critical and vulnerable periods of their illness. This study aims to evaluate the influence of musical intervention in patients with acute cardiovascular disease during transfer in Advanced Life Support (ALS) ambulances using an analytical randomized controlled case-control experimental study conducted according to CONSORT guidelines. Forty-one subjects took part in the study. The patients required the administration of nitrates/antiarrhythmics (n = 11, 26.8%), (n = 5, 12.2%) antiemetics, and (n = 7, 17.1%) opioids. Statistically significant differences were found for blood pressure and the variable cardiovascular drugs between groups. The use of music therapy to complement other health measures in ALS ambulances lowers blood pressure values and reduces the need to administrate cardiovascular drugs, thus avoiding their possible side effects. It is easy to implement, has a low cost and should be monitored and controlled as a specific nursing intervention, included in the care of patients transferred by ambulances on a routine basis.}, } @article {pmid40050016, year = {2025}, author = {Martin, J and Johnson, R and Yemane, L and Unaka, N and Ebo, C and Hippolyte, J and Jones, M and Quinn, M and Barber, A and Floyd, B and Blankenburg, R and Hilgenberg, SL}, title = {Multi-institutional exploration of pediatric residents' perspectives on anti-racism curricula: a qualitative study.}, journal = {Medical education online}, volume = {30}, number = {1}, pages = {2474134}, doi = {10.1080/10872981.2025.2474134}, pmid = {40050016}, issn = {1087-2981}, mesh = {Humans ; *Internship and Residency ; *Curriculum ; *Qualitative Research ; *Focus Groups ; *Pediatrics/education ; *Racism/psychology ; United States ; Male ; Female ; Attitude of Health Personnel ; Antiracism ; }, abstract = {BACKGROUND: Anti-racism curricula are increasingly being recognized as an integral component of medical education. To our knowledge, there has not yet been a publication exploring resident perspectives from multiple institutions and explicitly representing both underrepresented in medicine (UIM) and non-UIM perspectives.

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

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

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

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

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

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

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

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

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

CONCLUSION: This study provides evidence of a causal relationship between gut microbiota and neuropsychiatric disorders, suggesting lipids as mediators. These findings offer new insights into the mechanisms by which gut microbiota may influence neuropsychiatric disorders.}, } @article {pmid40049292, year = {2025}, author = {Faure-De Baets, J and Besnard, J and Banville, F and Cassereau, J and Allain, P}, title = {Effects of virtual reality mindfulness on cognition and well-being in ALS: A randomized trial protocol.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107876}, doi = {10.1016/j.cct.2025.107876}, pmid = {40049292}, issn = {1559-2030}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons but also leading to significant non-motor symptoms, including cognitive impairments, anxiety, depression, and behavioral changes, which severely impact quality of life. While mindfulness-based interventions (MBIs) have shown promise in alleviating psychological distress, their accessibility is often limited due to patients' physical impairments. Virtual reality (VR) could enhance engagement and immersion, offering a novel, more inclusive therapeutic approach. This randomized controlled trial (RCT) aims to evaluate the efficacy of a VR-based MBI compared to traditional mindfulness for ALS patients. Forty-six participants will be randomly assigned to an eight-week mindfulness program delivered either via VR or in a conventional format. The primary outcome is quality of life, assessed using the ALS-Specific Quality of Life Scale (ALSSQOL-R). Secondary outcomes include cognitive function, anxiety, depression, behavioral changes, and mindfulness propensity, evaluated at baseline, post-intervention, and three-month follow-up. The study will also examine VR usability and potential accessibility challenges for ALS patients. By addressing a critical gap in non-pharmacological psychological care, this study will provide key insights into the feasibility and benefits of VR-based MBIs. If effective, VR mindfulness could offer an innovative, scalable solution to improve emotional well-being and quality of life in ALS, making psychological support more accessible for patients with severe physical limitations.}, } @article {pmid40049153, year = {2025}, author = {Cho, HW and Jung, S and Park, KH and Choi, JW and Heo, JS and Kim, J and Yun, H and Yu, D and Son, J and Choi, BM}, title = {Deep Learning-based Multi-class Classification for Neonatal Respiratory Diseases on Chest Radiographs in Neonatal Intensive Care Units.}, journal = {Neonatology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000545107}, pmid = {40049153}, issn = {1661-7819}, abstract = {Objective Accurate and timely interpretation of chest radiographs is essential for assessing respiratory distress and guiding clinical management to improve outcomes of critically ill newborns. This study aimed to introduce a deep learning-based automated algorithm designed to classify various neonatal respiratory diseases and healthy lungs using a large dataset of high-quality, multi-class labeled chest X-ray images from neonatal intensive care units (NICUs). Methods Portable supine chest X-ray images for six common conditions (healthy lung, respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), air leak syndrome (ALS), atelectasis, and bronchopulmonary dysplasia (BPD)) and demographic variables (gestational age and birth weight) were retrospectively collected from 10 university hospitals in Korea. Ground truth for manual classification of these conditions was generated by 20 neonatologists and validated by others from different hospitals. The dataset, consisting 34,598 for training, 4,370 for validation, and 4,370 for testing, was used to train a modified ResNet50-based deep-learning model for automatic classification. Results The automatic classification algorithm showed high concordance with human-annotated classifications, achieving an overall testing accuracy of 83.96% and an F1-score of 83.68%. The F1-score for each condition was 87.38% for "healthy lung", and 92.19% for "BPD", 90.65% for "ALS", 90.30% for "RDS", 86.56% for "atelectasis", and 70.84% for "TTN". Conclusion We introduced a deep learning-based automated algorithm to classify neonatal respiratory diseases using a large dataset of high-quality, multi-class labeled chest X-ray images, incorporating non-imaging data, which could support neonatologists in making timely and accurate decisions for critically ill newborns.}, } @article {pmid40048825, year = {2025}, author = {Kacker, K and Chetty, N and Feldman, AK and Bennett, J and Yoo, PE and Fry, A and Lacomis, D and Harel, N and Nogueira, RG and Majidi, S and Opie, NL and Collinger, J and Oxley, T and Putrino, D and Weber, DJ}, title = {Motor activity in gamma and high gamma bands recorded with a Stentrode from the human motor cortex in two people with ALS.}, journal = {Journal of neural engineering}, volume = {}, number = {}, pages = {}, doi = {10.1088/1741-2552/adbd78}, pmid = {40048825}, issn = {1741-2552}, abstract = {This study examined the strength and stability of motor signals in low gamma and high gamma bands of vascular electrocorticograms (VECoG) recorded with endovascular stent-electrode arrays (Stentrodes) implanted in the superior sagittal sinus of two participants with severe paralysis due to Amyotrophic Lateral Sclerosis. Methods: VECoG signals were recorded from two participants in the COMMAND trial, an Early Feasibility Study of the Stentrode brain-computer interface (BCI) (NCT05035823). The participants performed attempted movements of their ankles or hands. The signals were band-pass filtered to isolate low gamma (30-70 Hz) and high gamma (70-200 Hz) components. The strength of VECoG motor activity was measured as signal-to-noise ratio (SNR) and the percentage change in signal amplitude between the rest and attempted movement epochs, which we termed depth of modulation (DoM). We trained and tested classifiers to evaluate the accuracy and stability of detecting motor intent. Results: Both low gamma and high gamma were modulated during attempted movements. For Participant 1, the average DoM across channels and sessions was 125.41 ± 17.53 % for low gamma and 54.23 ± 4.52 % for high gamma, with corresponding SNR values of 6.75 ± 0.37 dB and 3.69 ± 0.28 dB. For Participant 2, the average DoM was 22.77 ± 4.09 % for low gamma and 22.53 ± 2.04 % for high gamma, with corresponding SNR values of 1.72 ± 0.25 dB and 1.73 ± 0.13 dB. VECoG amplitudes remained significantly different between rest and move periods over the 3 - month testing period, with > 90 % accuracy in discriminating attempted movement from rest epochs for both participants. For Participant 1, the average DoM was strongest during attempted movements of both ankles, while for Participant 2, the DoM was greatest for attempted movement of the right hand. The overall classification accuracy was 91.43 % for Participant 1 and 70.37 % for Participant 2 in offline decoding of multiple attempted movements and rest conditions. Significance: By eliminating the need for open brain surgery, the Stentrode offers a promising BCI alternative, potentially enhancing access to BCIs for individuals with severe motor impairments. This study provides preliminary evidence that the Stentrode can detect discriminable signals indicating motor intent, with motor signal modulation observed over the 3 - month testing period reported here.}, } @article {pmid40048117, year = {2025}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Increased risk of ischemic stroke in amyotrophic lateral sclerosis: a nationwide cohort study in South Korea.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40048117}, issn = {1590-3478}, support = {HI20C1073//Ministry of Health and Welfare/ ; }, abstract = {BACKGROUND: We investigated the risk of ischemic stroke in ALS and analyzed the effect of ALS-related physical disability using the Korean National Health Insurance Service database.

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

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

CONCLUSIONS: Our findings suggest that ALS patients have an increased risk of ischemic stroke compared with controls, but the risk did not differ by the presence of disability in ALS.}, } @article {pmid40047927, year = {2025}, author = {Ludolph, A and Klose, V and Dreyhaupt, J and Del Tredici, K and Braak, H}, title = {The deltoid muscle and the pattern of paresis in ALS.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {253}, pmid = {40047927}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Deltoid Muscle/physiopathology/pathology ; Male ; Female ; Middle Aged ; Aged ; *Paresis/etiology/physiopathology ; Adult ; Prospective Studies ; Muscle, Skeletal/physiopathology ; Pyramidal Tracts/physiopathology/pathology ; Electromyography ; Aged, 80 and over ; }, abstract = {There is neuroanatomical and clinical evidence that the corticospinal tract governs the patterns of pareses in sporadic ALS. These patterns are mirrored by phylogenetically young monosynaptic corticomotor neuronal connections. It is well known that, clinically, dysfunction of the deltoid muscle contributes considerably to the early disability of the ALS patient. In this study, we prospectively compared the degree of pareses of the deltoid muscle with the triceps and biceps brachii in N = 71 patients (426 muscles). We could show that the extent of involvement of the deltoid muscle early in the disease process resembles that of the biceps rather than the triceps brachii. This pattern is consistent with functional data of the corticospinal monosynaptic connectivity of all three muscles.}, } @article {pmid40047382, year = {2025}, author = {Murray, D and Rooney, J and Meldrum, D and Al-Chalabi, A and Bunte, TM and Chiwera, T and Choudhury, M and Chio, A and Fenton, L and Fortune, J and Maidment, L and Manera, U and McDermott, CJ and Meyjes, M and Tattersall, R and Torrieri, MC and Van Damme, P and Vanderlinden, E and Wood, C and Van Den Berg, LH and Hardiman, O}, title = {Respiratory measurements, respiratory symptoms, and quality of life in ALS: results from the REVEALS study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2025.2471421}, pmid = {40047382}, issn = {2167-9223}, abstract = {Objective: Progressing respiratory weakness throughout the course of amyotrophic lateral sclerosis (ALS) is clinically associated with distressing symptoms, including dyspnea, orthopnea, and difficulty clearing secretions. Fatigue, poor sleep, and reduced quality of life are also considered to be associated with declining respiratory function. Respiratory measurements guide prescription of interventions, which aim to alleviate symptoms. The relationships between respiratory measurements and patient reported symptoms are currently unclear. Method: The REVEALS study was a longitudinal, observational, multisite study of decline in respiratory function in people with ALS attending six European centers. Respiratory measures (forced and slow vital capacity (F/SVC), sniff nasal inspiratory pressure (SNIP), and peak cough flow) were collected, as were the presence of respiratory symptoms and simple quality of life, fatigue and sleep measures. We used Bayesian's multivariate models to explore the associations of the respiratory measures with outcome variables. Results: Two hundred and eighty participants completed in-person assessments over a median of 8 (IQR 2.3, 14.1) months, with 974 data collection timepoints. The probability of reporting symptoms including dyspnea, orthopnea, and difficulty clearing secretions increased with decreasing respiratory measurement scores. The probability of reporting moderately low quality of life and moderate fatigue also increased with decreasing test scores, but reported sleep quality was not associated with respiratory scores. Conclusion: Respiratory weakness in people with ALS was associated with symptoms including dyspnea, orthopnea, and difficulty clearing secretions. The probability of reporting symptoms increased incrementally as respiratory weakness increased, supporting the use of both respiratory measurements and the presence of symptoms in making decisions about clinical interventions.}, } @article {pmid40046336, year = {2025}, author = {Öztürk, MM and Emgård, J and García-Revilla, J and Fernández-Calle, R and Yang, Y and Deierborg, T and Roos, TT}, title = {The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf087}, pmid = {40046336}, issn = {2632-1297}, abstract = {Numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis share a neuropathological hallmark: aberrant protein aggregation in the CNS. Microglia, the brain's innate immune cells, also play a pivotal role in the pathogenesis of these disorders. Multiple studies indicate that these pathological aggregates can propagate throughout the brain in a prion-like manner. A protein/peptide that adopts a prion-like conformation can induce homologous proteins to misfold into a prion-like conformation through templated seeding, enabling cell-to-cell spread and accelerating protein aggregation throughout the brain. Two important questions in the prion-like paradigm are where the prion-like misfolding occurs and how the prion-like aggregates are spread throughout the CNS. Here, we review the role of microglia and associated inflammation in the prion-like spread of pathologically aggregated proteins/peptides in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that microglia can internalize prion-like proteins and transport them to neighbouring neurons and other glial cells. Microglia may also influence the potential seeding of proteins in neurons and induce inflammatory pathways in their microenvironment. This review aims to broaden the understanding of the role of microglia in the prion-like spread of protein aggregation.}, } @article {pmid40045432, year = {2025}, author = {Blair, K and Martinez-Serra, R and Gosset, P and Martín-Guerrero, SM and Mórotz, GM and Atherton, J and Mitchell, JC and Markovinovic, A and Miller, CCJ}, title = {Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {49}, pmid = {40045432}, issn = {2051-5960}, support = {MR/X021858/1//UK Research and Innovation/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Endoplasmic Reticulum/metabolism ; *Vesicular Transport Proteins/metabolism ; Animals ; *Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Protein Tyrosine Phosphatases/metabolism ; }, abstract = {Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many of the seemingly disparate physiological functions that are damaged in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer's disease, Parkinson's disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.}, } @article {pmid40044663, year = {2025}, author = {Abu-Rumeileh, S and Scholle, L and Mensch, A and Großkopf, H and Ratti, A and Kölsch, A and Stoltenburg-Didinger, G and Conrad, J and De Gobbi, A and Barba, L and Steinacker, P and Klafki, HW and Oeckl, P and Halbgebauer, S and Stapf, C and Posa, A and Kendzierski, T and Silani, V and Hausner, L and Ticozzi, N and Froelich, L and Weishaupt, JH and Verde, F and Otto, M}, title = {Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2019}, pmid = {40044663}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; *tau Proteins/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; Phosphorylation ; *Biomarkers/blood ; *Alzheimer Disease/blood/metabolism/pathology/diagnosis ; Muscle, Skeletal/metabolism/pathology ; Case-Control Studies ; Biopsy ; Aged, 80 and over ; Adult ; Cohort Studies ; }, abstract = {Blood phosphorylated (p)-tau 181 and p-tau 217 have been proposed as accurate biomarkers of Alzheimer's disease (AD) pathology. However, blood p-tau 181 is also elevated in amyotrophic lateral sclerosis (ALS) without a clearly identified source. We measured serum p-tau 181 and p-tau 217 in a multicentre cohort of ALS (n = 152), AD (n = 111) cases and disease controls (n = 99) recruited from four different centres. Further, we investigated the existence of both p-tau species using immunohistochemistry (IHC) and mass spectrometry (MS) in muscle biopsies of ALS cases (IHC: n = 13, MS: n = 5) and disease controls (IHC: n = 14, MS: n = 5) from one cohort. Serum p-tau 181 and p-tau 217 were higher in AD and ALS patients compared to disease controls. IHC and MS analyses revealed the presence of p-tau 181 and 217 in muscle biopsies from both ALS cases and disease controls, with ALS samples showing increased p-tau reactivity in atrophic muscle fibres. Blood p-tau species could potentially be used to diagnose both ALS and AD.}, } @article {pmid40044193, year = {2025}, author = {Ross, WT and Buday, S and Yakel, E and Khabele, D and Balls-Berry, J and As-Sanie, S and Colditz, G and Baumann, AA}, title = {Does interdisciplinary group care for the treatment of endometriosis improve pain interference: protocol for a pilot randomised controlled trial at an urban academic medical centre.}, journal = {BMJ open}, volume = {15}, number = {3}, pages = {e097372}, doi = {10.1136/bmjopen-2024-097372}, pmid = {40044193}, issn = {2044-6055}, mesh = {Humans ; Female ; Pilot Projects ; *Endometriosis/complications/therapy ; *Quality of Life ; *Pelvic Pain/therapy/etiology ; Academic Medical Centers ; Pain Management/methods ; Adult ; Randomized Controlled Trials as Topic ; Patient Care Team/organization & administration ; Pain Measurement ; }, abstract = {INTRODUCTION: Endometriosis affects 10-15% of people assigned female at birth and can cause chronic pelvic pain and impair many domains of quality of life, such as fertility, mood and bladder, bowel and sexual function. Current treatments often fail, leading to recurrent pain and the need for reintervention. As endometriosis negatively affects many domains of life, a variety of non-pharmacological treatments modestly improve symptoms. To bundle these interventions into accessible packaging, our interdisciplinary team developed a novel endometriosis intervention titled 'Peer-Empowered Endometriosis Pain Support (PEEPS)', an 8-week integrative group care intervention. Here, we present the protocol for a pilot randomised controlled trial (RCT) to evaluate the effectiveness and implementation of PEEPS for people with endometriosis-associated pain refractory to surgical management. We hypothesise that patients who complete the PEEPS programme will show a greater decrease in pain interference in daily activities at intervention completion as compared with baseline than those in the education arm.

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

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

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

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

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

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

HIGHLIGHTS: The pathogenic variant of annexin A11 (ANXA11I) is linked to frontotemporal dementia (FTD) syndrome. ANXA11 (p.D40G) may be one of the possible genetic causes of semantic variant primary progressive aphasia (svPPA). ANXA11 (p.D40G) may enhance heteromeric amyloid filaments of annexin A11 and TDP-43, promoting frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) type C.}, } @article {pmid40041912, year = {2025}, author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB}, title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {1}, pages = {15-34}, pmid = {40041912}, issn = {2211-3835}, abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.}, } @article {pmid40039939, year = {2024}, author = {Udhayakumar, R and Gopakumar, S and Rahman, S and Karmakar, C}, title = {Nonlinear Assessment of Gait Signal Complexity in Neurodegenerative Disorders.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781711}, pmid = {40039939}, issn = {2694-0604}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; *Algorithms ; *Gait/physiology ; Nonlinear Dynamics ; Entropy ; Signal Processing, Computer-Assisted ; Male ; Female ; Middle Aged ; Aged ; }, abstract = {The human gait cycle undergoes discernible alterations upon the onset of neurodegenerative diseases (NDD) such as Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. Each specific neurodegenerative disorder imparts a distinct influence on human gait dynamics, and precise quantification of these changes holds the potential for accurate methods of NDD detection.Nonlinear entropy algorithms, such as sample entropy (SampEn), find widespread use in physiological signal analysis. SampEn gauges signal complexity by identifying pattern matches within windowed sub-segments of the signal. However, traditional SampEn is notably dependent on user-defined parameters, particularly the tolerance parameter r, leading to inaccuracies in complexity information.SampEn profiling emerges as an alternative concept, eliminating the need for an input r parameter. This data-driven algorithm autonomously generates a set of 'r' values based on the signal's dynamics, yielding a comprehensive SampEn profile. The SampEn profile, containing extensive information about the signal's complexity, serves as a valuable resource for extracting secondary entropy features.In this study, we have contrasted the efficacy of traditional SampEn with SampEn profile-based secondary features such as Total SampEn (TSE) and Median SampEn (MSE), in identifying neurological states. Our findings consistently reveal that secondary features derived from the reduced-parametric SampEn profiling method outperform the traditional parametric SE in distinguishing control cohorts from specific Neurodegenerative Disease (NDD) cohorts.}, } @article {pmid40039399, year = {2024}, author = {Rechichi, I and Amprimo, G and Cicolin, A and Olmo, G}, title = {Predicting Amyotrophic Lateral Sclerosis Progression: an EMG-based Survival Analysis.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782485}, pmid = {40039399}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; Humans ; *Electromyography/methods ; *Disease Progression ; Male ; Female ; Middle Aged ; Survival Analysis ; Aged ; Sleep, REM ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease, ultimately leading to muscle inefficiency and death. A vast majority of people with ALS also suffer from sleep disorders. Previous studies highlighted the presence of REM Sleep Without Atonia (RSWA) in an ALS cohort, and suggested its strong correlation with the disease severity. This study investigates the ability of electromyography (EMG) parameters recorded during Rapid-eye Movement (REM) sleep to predict disease progress and outcome rapidity in ALS. Survival models trained on a cohort of 45 ALS patients undergoing a longitudinal study, revealed a promising predictive power for the proposed EMG-derived metrics (c-index ≥ 0.65) and encouraging goodness of fit (through c-index and χ[2]). These results suggest the possibility of employing the trained model in follow-up procedures, based on non-invasive, lightweight EMG metrics, which would significantly ease disease monitoring and help personalized symptomatic care.}, } @article {pmid40039278, year = {2024}, author = {Murphy, EK and Doussan, A and Verga, S and Stommel, EW and McIlduff, C and Halter, RJ and Rutkove, SB}, title = {Assessing Pulmonary Function in ALS using Electrical Impedance Tomography.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781742}, pmid = {40039278}, issn = {2694-0604}, mesh = {Humans ; *Electric Impedance ; *Tomography/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Respiratory Function Tests/methods ; Male ; Female ; Middle Aged ; Lung/diagnostic imaging/physiopathology ; Algorithms ; Case-Control Studies ; Aged ; Adult ; }, abstract = {This study aimed to determine an optimal model involving thoracic electrical impedance tomography (EIT) metrics and patient geometric information to best correlate to standard pulmonary function test (PFT) measures in a cohort of 32 ALS patients and 32 age-matched healthy controls. Thoracic EIT is a non-invasive technology in which an electrode belt chest allows for real-time impedance imaging of respiratory function. The optimal form of the model was determined via a genetic algorithm a novel technique for model generation in EIT applications. Combining multiple metrics yielded optimal r[2] values of 0.62 and 0.66 for 1- and 2-term regression models optimized. The results appear very promising and further refinement of the technology appears warranted.}, } @article {pmid40038221, year = {2025}, author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK}, title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.}, journal = {Journal of neurovirology}, volume = {}, number = {}, pages = {}, pmid = {40038221}, issn = {1538-2443}, abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.}, } @article {pmid40037468, year = {2025}, author = {Peck, A and Dadi, A and Yavarow, Z and Alfano, LN and Anderson, D and Arkin, MR and Chou, TF and D'Ambrosio, ES and Diaz-Manera, J and Dudley, JP and Elder, AG and Ghoshal, N and Hart, CE and Hart, and Huryn, and Johnson, AE and Jones, KB and Kimonis, V and Kiskinis, E and Lee, EB and Lloyd, TE and Mapstone, M and Martin, A and Meyer, H and Mozaffar, T and Onyike, CU and Pfeffer, G and Pindon, A and Raman, M and Richard, I and Rubinsztein, DC and Schiava, M and Schütz, AK and Shen, PS and Southworth, DR and Staffaroni, AM and Taralio-Gravovac, M and Weihl, CC and Yao, Q and Ye, Y and Peck, N}, title = {2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106861}, doi = {10.1016/j.nbd.2025.106861}, pmid = {40037468}, issn = {1095-953X}, abstract = {Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach. The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.}, } @article {pmid40037332, year = {2025}, author = {Belbasis, L and Morris, S and van Duijn, C and Bennett, D and Walters, R}, title = {Mendelian randomization identifies proteins involved in neurodegenerative diseases.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf018}, pmid = {40037332}, issn = {1460-2156}, support = {203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; //NIHR/ ; //NHS/ ; /DH_/Department of Health/United Kingdom ; }, abstract = {Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.}, } @article {pmid39971247, year = {2025}, author = {Zhang, H and Sun, Y}, title = {Response to Chen et al's "Incorporating regional variability and demographic insights into melanoma public health strategies".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.02.029}, pmid = {39971247}, issn = {1097-6787}, } @article {pmid39952435, year = {2025}, author = {Truel, JS and Novice, M and Shapiro, J and Lo Sicco, KI}, title = {Response to Folliat et al's "Characteristics of pruritus in lichen planopilaris and frontal fibrosing alopecia: A cohort study in a French hospital".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.11.084}, pmid = {39952435}, issn = {1097-6787}, } @article {pmid40036711, year = {2025}, author = {Nguyen, ML and Haddad, A and Law-Ye, B and Hesters, A}, title = {Uncommon Spinal Cord MRI Findings in a Patient With Early-Onset Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Neurology}, volume = {104}, number = {7}, pages = {e213503}, doi = {10.1212/WNL.0000000000213503}, pmid = {40036711}, issn = {1526-632X}, } @article {pmid40036368, year = {2025}, author = {Ervilha Pereira, P and De Bleecker, JL and Bogaert, E and Dermaut, B}, title = {Myopathic aggregation-prone variants in the TDP-43 prion-like domain: genetics paving the way.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf076}, pmid = {40036368}, issn = {1460-2156}, abstract = {While neuropathological and genetic studies have established the crucial involvement of TDP-43 proteinopathy in the pathogenesis of ALS (Amyotrophic Lateral Sclerosis), FTD (Frontotemporal Dementia) and related neurodegenerative disorders, multiple studies have described the presence of TDP-43 inclusions in muscular disorders, including inclusion body myositis but also other related rimmed vacuole myopathies. In addition, TDP-43 has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury. However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing. In the present review we highlight recent landmark discoveries linking novel pathogenic TDP-43 variants [p.(W385IfsX10) and p.(G376V)] within the prion-like domain with unusual aggregation-propensity and muscle rather than neuronal pathology. We discuss these studies in the context of known TDP-43-related pathways in ALS/FTD pathogenesis and show how they challenge some widely accepted views such as ALS as a pure neurogenic presynaptic neuromuscular disease and the direct correlation between TDP-43 aggregation-propensity and neurotoxicity. Finally, we discuss TDP-43 as part of a growing list of RNA-binding proteins including hnRNPA2B1 and hnRNPA1 as genetic causes of myopathies and relate this to the idea of 'multisystem proteinopathy'.}, } @article {pmid40034872, year = {2025}, author = {Wagner, H and Mlček, M and Krupičková, P and Popkova, M and Mejstrik, A and Boucek, T and Michálek, P and Kittnar, O and Belohlavek, J}, title = {Adrenaline has a limited effect on myocardial microvascular blood flow: A randomised experimental study in a porcine cardiac arrest model.}, journal = {Resuscitation plus}, volume = {22}, number = {}, pages = {100893}, pmid = {40034872}, issn = {2666-5204}, abstract = {BACKGROUND: Adrenaline (ADR) is a cornerstone of advanced life support (ALS) in cardiac arrest (CA), although its neurologically favourable survival outcomes remain unclear. ADR increases coronary perfusion pressure (CPP), with levels >15 mmHg associated with successful defibrillation. This study aimed to elucidate the relationship between ADR, myocardial microvascular blood flow, and resuscitation outcomes using a porcine CA model simulating refractory ventricular fibrillation (VF).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.}, } @article {pmid40032505, year = {2025}, author = {Callegaro, S and Manera, U and Canosa, A and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and De Mattei, F and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A and Vasta, R}, title = {Another brick in our knowledge of ALS causes: a population-based study of residential clustering.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335670}, pmid = {40032505}, issn = {1468-330X}, } @article {pmid40032262, year = {2025}, author = {Mick, P and Sehmsdorf, K and Lehner, B and Geisbüsch, A and Renkawitz, T and Hariri, M and Doll, J and Tsitlakidis, S}, title = {Perfusion based malignancy assessment of soft tissue tumors by contrast-enhanced ultrasound (CEUS): a comprehensive analysis of 187 cases.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2549-6101}, pmid = {40032262}, issn = {1438-8782}, support = {IIS-DE-0080//Bracco Imaging/ ; }, abstract = {English Purpose This study aimed to examine the perfusion characteristics of benign and malignant soft-tissue tumors (STT) using contrast-enhanced ultrasound (CEUS) and correlate STT microperfusion with malignancy. Findings were compared with patient characteristics, clinical presentations, MRI findings, and histopathological outcomes. Methods This prospective single-center study involved patients with unclear STTs who were scheduled for STT biopsy. Clinical assessments and preoperative MRI were conducted along with CEUS. Perfusion quantification was performed, and perfusion parameters (Peak Enhancement (PE), Rise Time, Wash-in Perfusion Index, and Wash-out Rate) were calculated. Perfusion characteristics of different STT were compared. Results 187 patients were included in the final analysis. Significant differences in CEUS perfusion between benign and non-benign STT were demonstrated. Non-benign tumors showed significantly higher tumor perfusion and differences were also significant when comparing semi-malignant, malignant, and metastatic STTs. (PE-Benign 107.74 (34.65-345.62); PE-Semimalignant 166.06 (60.14-374.47); PE-Malignant 1042.24 (358.15-4917.74); PE-Metastasis 2632.37 (2249.46-3788.94). ROC analysis demonstrated a sensitivity of 80% and a PPV of 69% for malignant tumor detection using a cut-off value for Peak Enhancement of 137 [a.u.]. Conclusion CEUS appears to be a promising tool for primary STT evaluation in addition to MRI. Furthermore, it can detect vital areas within the tumor tissue and could be utilized to increase biopsy accuracy. Abstract Deutsch Ziel Es erfolgte eine Analyse der Perfusionscharakteristika verschiedener gutartiger und bösartiger Weichteiltumoren (WTT) mittels kontrastverstärkten Ultraschalls (CEUS). Die Tumor-Mikroperfusion wurde neben MRT-Bildgebung auch mit den histopathologischen Befunden nach Biopsie korreliert, um die prädiktive Qualität des CEUS zur präoperativen Diagnostik unklarer WTT zu untersuchen. Material & Methoden Es wurden Patienten mit unklarem WTT und geplanter offener Biopsie inkludiert. Klinische Untersuchungen und präoperative MRT-Bildgebung wurden durch eine CEUS-Untersuchung ergänzt. Die WTT-Mikroperfusion wurde mittels CEUS quantifiziert und Perfusionsparameter (Peak Enhancement (PE), Rise Time, Wash-in Perfusion Index und Wash-out Rate) berechnet. Die Perfusionscharakteristika verschiedener WTT wurden verglichen. Ergebnisse 187 Patienten wurden inkludiert. Es zeigten sich unter benignen WTT signifikant niedrigere Perfusionsparameter als unter nicht-benignen WTT. Auch im Vergleich von benignen, semimalignen, malignen WTT und Metastasen zeigten sich charakteristische Unterschiede der CEUS-Mikroperfusion (PE-Benigne 107,74 (34,65-345,62); PE-Semi-Maligne 166,06 (60,14-374,47); PE-Maligne 1042,24 (358,15-4917,74); PE-Metastase 2632,37 (2249,46-3788,94). Für die Detektion eines malignen Tumors ergab sich eine Sensitivität von 80% und ein PPV von 69% bei einem Cut-off von PE=137 [a.u.]. Schlussfolgerungen CEUS erscheint als vielversprechendes Instrument zur WTT-Diagnostik in Ergänzung zur MRT. Darüber hinaus kann es vitale Bereiche innerhalb eines WTT identifizieren und so womöglich in Zukunft die Präzision einer offenen oder ultraschallgestützten Biopsie erhöhen.}, } @article {pmid40032118, year = {2025}, author = {Dang, M and Wu, L and Zhang, X}, title = {Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {141677}, doi = {10.1016/j.ijbiomac.2025.141677}, pmid = {40032118}, issn = {1879-0003}, abstract = {Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.}, } @article {pmid40031506, year = {2024}, author = {Guo, J and Chen, D and Zeng, X and Liu, X and Wang, X and Teng, S and Ye, K and Sun, X and Zhang, S and He, J and Fan, D and Liu, Y}, title = {A Multi-branch Attention-based Deep Learning Method for ALS Identification with sMRI Data.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782847}, pmid = {40031506}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/diagnosis ; *Deep Learning ; Humans ; *Spinal Cord/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Algorithms ; Image Processing, Computer-Assisted/methods ; }, abstract = {The structural Magnetic resonance imaging (sMRI) of spinal cord plays a significant role in the clinical diagnosis of Amyotrophic Lateral Sclerosis (ALS). But due to small cross-sectional area in the axial plane and long sagittal/coronal expansion of spinal cord, the diagnosis of ALS using sMRI of spinal cord has remained largely at the stage of morphological observation. In this study, a Multi-branch attention-based deep learning method is proposed to solve this problem. Multi-branch framework is utilized to extract general features of all levels of spinal cord for challenging of long sagittal and coronal expansion of spinal cord, and attention module coupled with multi-scale module in each branch is applied to extract multi-scale features and pay more attention to the important regions of the spinal cord in the axial plane. Experiments show that the proposed method obtains better performance in ALS identification, which implies that the proposed method can extract features of important region in the spinal cord and could be helpful to find more regions sensitive for ALS disease identification.}, } @article {pmid40030850, year = {2025}, author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L}, title = {Transcranial focused ultrasound modifies disease progression in SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TUFFC.2024.3525143}, pmid = {40030850}, issn = {1525-8955}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD1[G93A]) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. Additionally, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography. Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using Hematoxylin-eosin and Gomori Aldehyde-Fuchsin staining. The number of neurons and the phenotype of microglia in the motor cortex was observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD1[G93A] mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD1[G93A] mice. These results revealed the neuroprotective effects of ultrasound against disease pathogenesis of SOD1[G93A] mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.}, } @article {pmid40030617, year = {2024}, author = {Jiang, Y and Li, K and Liang, Y and Chen, D and Tan, M and Li, Y}, title = {Daily Assistance for Amyotrophic Lateral Sclerosis Patients Based on a Wearable Multimodal Brain-Computer Interface Mouse.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2024.3520984}, pmid = {40030617}, issn = {1558-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease that mainly causes damage to upper and lower motor neurons. This leads to a progressive deterioration in the voluntary mobility of the upper and lower extremities in ALS patients, which underscores the pressing need for an assistance system to facilitate communication and body movement without relying on neuromuscular function. In this paper, we developed a daily assistance system for ALS patients based on a wearable multimodal brain-computer interface (BCI) mouse. The system comprises two subsystems: a mouse system assisting the upper extremity and a wheelchair system based on the mouse system assisting the lower extremity. By wearing a BCI headband, ALS patients can control a computer cursor on the screen with slight head rotation and eye blinking, and further operate a computer and drive a wheelchair with specially designed graphical user interfaces (GUIs). We designed operating tasks that simulate daily needs and invited ALS patients to perform the tasks. In total, 15 patients with upper extremity limitations performed the mouse system task and 9 patients with lower extremity mobility issues performed the wheelchair system task. To our satisfaction, all the participants fully accomplished the tasks and average accuracies of 83.9% and 87.0% for the two tasks were achieved. Furthermore, workload evaluation using NASA Task Load Index (NASA-TLX) revealed that the participants experienced a low workload when using the system. The experimental results demonstrate that the proposed system provides ALS patients with effective daily assistance and shows promising long-term application prospects.}, } @article {pmid40030616, year = {2024}, author = {Bista, S and Coffey, A and Mitchell, M and Fasano, A and Dukic, S and Buxo, T and Giglia, E and Heverin, M and Muthuraman, M and Carson, RG and Lowery, M and Manus, LM and Hardiman, O and Nasseroleslami, B}, title = {Abnormal EEG spectral power and coherence measures during pre-motor stage in Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2024.3523109}, pmid = {40030616}, issn = {1558-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive motor decline. Studies of electroencephalographic (EEG) activity during rest and motor execution have captured network changes in ALS. However, the nature of network-level impairment in the pre-motor activity in ALS remains unclear. Assessing the (dys)function of motor networks engaged prior to motor output is essential for understanding the motor pathophysiology in ALS. We recorded EEG in 22 people with ALS (PwALS) and 16 age-matched healthy controls during rest and isometric pincer-grip tasks. EEG spectral power and coherence were calculated during rest, pre-motor stage, and motor execution. In PwALS, significantly higher event-related spectral perturbations were observed compared to controls over electrodes representing a) contralateral prefrontal and parietal regions in theta band during pre-motor stage, b) contralateral parietal and ipsilateral motor regions in high-beta band during motor execution. Similarly, spectral coherence revealed abnormal EEG connectivity within 1) sensorimotor network during rest in theta band, 2) (pre)motor networks during pre-motor stage in low-alpha and high-beta bands, 3) Fronto-parietal networks during execution in high-beta band. Furthermore, the abnormal EEG connectivity during rest and execution (but not during pre-motor stage) showed significant negative correlation with clinical ALS-functional-rating-scale scores. Combining abnormal EEG connectivity from rest, pre-motor, and execution stages provided more powerful discrimination between patients and controls with a uniquely higher contribution of measures pertaining to the pre-motor stage. The results indicate that pre-motor functional activity reflects a different and unique aspect of network impairment, with potential for inclusion as biomarker candidates in ALS.}, } @article {pmid40030411, year = {2024}, author = {Mishra, S and Chatterjee, D and Kanekar, N}, title = {Topological Gait Analysis: A New Framework and Its Application to the Study of Human Gait.}, journal = {IEEE journal of biomedical and health informatics}, volume = {28}, number = {12}, pages = {7040-7053}, doi = {10.1109/JBHI.2024.3427700}, pmid = {40030411}, issn = {2168-2208}, mesh = {Humans ; *Gait Analysis/methods ; Adult ; Male ; Middle Aged ; Female ; Gait/physiology ; Aged ; Parkinson Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Signal Processing, Computer-Assisted ; Huntington Disease/physiopathology ; Algorithms ; }, abstract = {OBJECTIVE: This study introduces a physiologically driven topological gait analysis (TGA) framework to gain insights into pathological gait.

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

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

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

SIGNIFICANCE: TGA offers characterization of gait at a hitherto uncharted level, potentially serving neuromotor markers for early diagnosis and personalized rehabilitation protocols.}, } @article {pmid40030015, year = {2025}, author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB}, title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2402117122}, doi = {10.1073/pnas.2402117122}, pmid = {40030015}, issn = {1091-6490}, support = {AG061708//HHS | National Institutes of Health (NIH)/ ; AG050492//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Neurons/metabolism/drug effects ; Mice ; Hippocampus/metabolism/pathology ; Alzheimer Disease/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Protein Aggregation, Pathological/metabolism/drug therapy ; Autophagy/drug effects ; }, abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.}, } @article {pmid40029926, year = {2025}, author = {Panda, P and Mohanty, S and Gouda, SR and Baral, TC and Mohanty, A and Nayak, J and Mohapatra, R}, title = {Advanced strategies for enhancing the neuroprotective potential of curcumin: delivery systems and mechanistic insights in neurodegenerative disorders.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-26}, doi = {10.1080/1028415X.2025.2472773}, pmid = {40029926}, issn = {1476-8305}, abstract = {Background: Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits significant neuroprotective potential due to its diverse pharmacological properties.Objective: This review explores curcumin's role in modulating key pathological mechanisms underlying neurodegenerative disorders such as Alzheimer's, Parkinson's diseases, Amyotrophic Lateral Sclerosis, Huntington's Disease and Prion Disease.Methods: A comprehensive analysis of curcumin's molecular interactions, including its effects on amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal-induced neurotoxicity, was conducted. Additionally, strategies to overcome its low bioavailability and blood-brain barrier (BBB) permeability were evaluated.Results: Curcumin inhibits Aβ aggregation and promotes disaggregation, reducing amyloid plaque formation in Alzheimer's disease. It modulates glial cell activity, attenuating neuroinflammation and fostering a neuroprotective environment. By interacting with tau proteins, curcumin prevents hyperphosphorylation and neurofibrillary tangle formation. As a potent antioxidant, it scavenges reactive oxygen species, mitigating oxidative stress-related neuronal damage. Its metal-chelating properties further diminish neurotoxicity by sequestering iron and copper ions. Despite its limited bioavailability and BBB permeability, curcumin's therapeutic efficacy can be enhanced using nanocarriers such as nanoparticles, liposomes, and micelles, which improve solubility, stability, and brain penetration.Conclusion: Curcumin's multifaceted neuroprotective mechanisms make it a promising candidate for preventing or slowing neurodegenerative disease progression. Advanced drug delivery systems hold potential for overcoming its pharmacokinetic limitations, paving the way for future clinical applications.}, } @article {pmid40029669, year = {2025}, author = {Carroll, E and Scaber, J and Huber, KVM and Brennan, PE and Thompson, AG and Turner, MR and Talbot, K}, title = {Drug repurposing in amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on drug discovery}, volume = {}, number = {}, pages = {}, doi = {10.1080/17460441.2025.2474661}, pmid = {40029669}, issn = {1746-045X}, abstract = {INTRODUCTION: Identifying treatments that can alter the natural history of amyotrophic lateral sclerosis (ALS) is challenging. For years, drug discovery in ALS has relied upon traditional approaches with limited success. Drug repurposing, where clinically approved drugs are reevaluated for other indications, offers an alternative strategy that overcomes some of the challenges associated with de novo drug discovery. Whilst not a new concept, the potential of drug repurposing in ALS is yet to be fully realized.

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

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

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

CONCLUSION: This report expands the phenotypic spectrum of ATP13A2-related disorders, highlighting the potential overlap of symptoms associated with KRS, ALS, and HSP.}, } @article {pmid40027730, year = {2025}, author = {Pant, DC and Lone, MA and Parameswaran, J and Ma, F and Dutta, P and Wang, Z and Park, J and Verma, S and Hornemann, T and Jiang, J}, title = {Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.18.638951}, pmid = {40027730}, issn = {2692-8205}, abstract = {Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS - linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1 , we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 ΔExon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.}, } @article {pmid40027671, year = {2025}, author = {Woo, E and Tasnim, F and Kawamata, H and Manfredi, G and Konrad, C}, title = {Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.13.637962}, pmid = {40027671}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms of ALS (fALS) account for approximately 10% of cases and are associated with mutations in numerous genes. Alterations of mitochondrial functions have been proposed to contribute to disease pathogenesis. Here, we employed a direct conversion (DC) technique to generate induced motor neurons (iMN) from skin fibroblasts to investigate mitochondrial phenotypes in a patient-derived disease relevant cell culture system. We converted 7 control fibroblast lines and 17 lines harboring the following fALS mutations, SOD1 [A4V] , TDP-43 [N352S] , FUS [R521G] , CHCHD10 [R15L] , and C9orf72 repeat expansion. We developed new machine learning approaches to identify iMN, analyze their mitochondrial function, and follow their fate longitudinally. Mitochondrial and energetic abnormalities were observed, but not all fALS iMN lines exhibited the same alterations. SOD1 [A4V] , C9orf72, and TDP-43 [N352S] iMN had increased mitochondrial membrane potential, while in CHCHD10 [R15L] cells membrane potential was decreased. TDP-43 [N352S] iMN displayed changes in mitochondrial morphology and increased motility. SOD1 [A4V] , TDP-43 [N352S] , and CHCHD10 [R15L] iMN had increased oxygen consumption rates and altered extracellular acidification rates, reflecting a hypermetabolic state similar to the one described in sporadic ALS fibroblasts. FUS [R521G] mutants had decreased ATP/ADP ratio, suggesting impaired energy metabolism. We then tested the viability of iMN and found decreases in survival in SOD1 [A4V] , C9orf72, and FUS [R521G] , which were corrected by small molecules that target mitochondrial stress. Together, our findings reinforce the role of mitochondrial dysfunction in ALS and indicate that fibroblast-derived iMN may be useful to study fALS metabolic alterations. Strengths of the DC iMN approach include low cost, speed of transformation, and the preservation of epigenetic modifications. However, further refinement of the fibroblasts DC iMN technique is still needed to improve transformation efficiency, reproducibility, the relatively short lifespan of iMN, and the senescence of the parental fibroblasts.}, } @article {pmid40027590, year = {2025}, author = {Untalan, LGV and Malanog, JPD and Jamora, RDG}, title = {Evaluating YouTube as a source of information on amyotrophic lateral sclerosis.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251324439}, pmid = {40027590}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that leads to progressive motor weakness and eventual death. Recent years have seen an increase in online information on ALS, with the popular video platform YouTube becoming a prominent source. We aimed to evaluate the quality, reliability, actionability, and understandability of ALS videos on YouTube.

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

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

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

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

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

CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.}, } @article {pmid40024058, year = {2025}, author = {Baumgarten, BR and Freye, CE}, title = {Use of Fisher's Ratio assisted multivariate curve resolution- alternating least squares for discovery-based analysis using ultrahigh pressure liquid chromatography-high resolution mass spectrometry.}, journal = {Journal of chromatography. A}, volume = {1747}, number = {}, pages = {465812}, doi = {10.1016/j.chroma.2025.465812}, pmid = {40024058}, issn = {1873-3778}, abstract = {Non-targeted analysis of complex chemical mixtures can be difficult considering the convoluted nature of the matrix and the potential unknown chemical differences between samples or classes of samples. Ultrahigh pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF) is an ideal technique to probe chemical differences for a wide variety of samples. While UHPLC-QTOF can discover minute chemical differences down to low part per billion (ppb) concentrations with a high degree of confidence, the application of high-resolution mass spectrometry can yield massive amounts of information (∼ 10 gb per sample) that cannot be analyzed manually. Therefore, the application of chemometric techniques is mandatory for the interrogation of complex samples. Fisher's ratio (FR) assisted multivariate curve resolution-alternating least squares (MCR-ALS) was used to the discover and identify the chemical differences between two classes of materials: 1) a pond water matrix and 2) the matrix spiked with a pharmaceutical standard mix containing 17 compounds. Thirteen of the seventeen spiked compounds were discovered using FR analysis, and then five were successfully deconvoluted using MCR-ALS wherein the number of curves chosen were automatically determined using singular value decomposition (SVD). The use of an automated FR assisted MCR-ALS will aid in discovering trace levels of chemical components without the need for the researcher to provide potentially biased input which will aid in non-targeted workflow.}, } @article {pmid40022663, year = {2025}, author = {Buckett, LE and Holdom, CJ and Howe, SL and McCombe, PA and Henderson, RD and Al-Chalabi, A and Steyn, FJ and Ngo, ST}, title = {Persistent high levels of perceived fatigue are not associated with hypermetabolism in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2471429}, pmid = {40022663}, issn = {2167-9223}, abstract = {Objective: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Little is known about factors that contribute to fatigue, and whether levels of fatigue change throughout disease course. We aimed to determine associations between self-reported perceived fatigue and metabolic and clinical features of ALS, and perceived fatigue over the course of disease. Methods: This prospective study was conducted between July 2017 and March 2024. Baseline measures of self-reported perceived fatigue, metabolic rate, and clinical measures of disease were assessed in 117 participants with clinically definite or probable ALS. For comparison, fatigue and metabolic rate were collected from 107 control participants. Perceived fatigue was determined using the Fatigue Severity Scale (FSS). Metabolic rate was assessed using indirect calorimetry. Functional capacity and clinical progression were assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Results: Baseline levels of perceived fatigue were greater in people living with ALS (plwALS) when compared to controls (5.44 vs. 2.55; p < 0.01). Perceived fatigue was higher in plwALS with lower ALSFRS-R scores and was not associated with measures of metabolism. For most plwALS, perceived fatigue remained high as functional capacity worsened. Conclusion: Our findings confirm higher prevalence of perceived fatigue in plwALS, with persistently high FSS scores reported by most patients during follow-up. High levels of fatigue were not associated with hypermetabolism, suggesting that metabolic rate is unlikely to be a primary contributor. Results highlight a need for further research to identify factors that contribute to fatigue in ALS, and options for improved fatigue management.}, } @article {pmid40022581, year = {2025}, author = {Galvin, M and Heverin, M and Mac Domhnaill, É and Mcfarlane, R and Meldrum, D and Murray, D and Bolger, A and Connelly, J and Flynn, K and Fox, E and Gibbons, F and Hederman, L and Impey, S and O'Keefe, I and O'Meara, C and McKibben, D and Nicholson, M and Stephens, G and Van Dijk, J and Van Den Berg, L and Hardiman, O}, title = {Challenges and solutions to complex data governance issues in cross-national, cross-sectoral, multidisciplinary real world health research: a descriptive overview.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2428927}, pmid = {40022581}, issn = {2167-9223}, abstract = {Real-world clinical data is generated during clinical engagements. The collection and further processing and mining of clinical information requires consents and navigation of necessary and important data governance processes. PRECISION ALS is an academic industry programme that collects, collates and analyses clinical and para-clinical data from patients with ALS across 10 European sites. The infrastructure of PRECISION ALS represents a complex interplay of the clinical, governance, and technical frameworks. Incorporation of infrastructural and operational measures enables sophisticated cross-national, cross-sectoral and cross disciplinary health research. PRECISION ALS has established a range of domain expertise, technologies, governance and clinical data management practices that can be applied throughout the life cycle of patient data from generation, collation, delivery and secure storage for advanced analytics. PRECISION ALS is designed to move the field of ALS research to a true Precision Medicine based approach toward new and more effective therapeutics.}, } @article {pmid39956201, year = {2025}, author = {Potestio, L and Martora, F and Megna, M}, title = {Response to Sood et al's "Real-world experience of bimekizumab for plaque psoriasis in adult patients with prior exposure to interleukin-17 inhibitors: A 16-week multicenter retrospective review".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.10.129}, pmid = {39956201}, issn = {1097-6787}, } @article {pmid40020551, year = {2025}, author = {Tafuri, B and Giugno, A and Nigro, S and Zoccolella, S and Barone, R and Tamburrino, L and Gnoni, V and Urso, D and Rollo, E and De Blasi, R and Logroscino, G}, title = {Radiomic alterations and clinical correlates of hypothalamic nuclei in ALS.}, journal = {Computers in biology and medicine}, volume = {189}, number = {}, pages = {109906}, doi = {10.1016/j.compbiomed.2025.109906}, pmid = {40020551}, issn = {1879-0534}, abstract = {OBJECTIVE: The aim of this study is to analyze hypothalamic changes and clinical/metabolic correlates with a radiomic approach in Amyotrophic Lateral Sclerosis (ALS).

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

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

CONCLUSIONS: These results support the hypothesis that a degenerative process affecting hypothalamus in ALS extends beyond the atrophy process. Intriguingly, the close relationship between the entropy of left Anterior-Inferior nucleus and the higher BMI may further demonstrate the critical role of hypothalamus in eating abnormalities. Furthermore, the inhomogeneity of the right Inferior-Tubular subunit reflects a more severe clinical condition by ALSFRS-R. This work represents a significant advancement in the study of ALS and its association with hypothalamic changes through a novel radiological approach, uncovering new associations between sub-hypothalamic radiomic changes, anthropometric measures, and disease outcomes.}, } @article {pmid40021952, year = {2025}, author = {Hao, Y and Li, Z and Du, X and Xie, Q and Li, D and Lei, S and Guo, Y}, title = {Characterization and chemoproteomic profiling of protein O-GlcNAcylation in SOD1-G93A mouse model.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {31}, number = {1}, pages = {82}, pmid = {40021952}, issn = {1528-3658}, support = {92478109//National Natural Science Foundation of China/ ; 82471451//National Natural Science Foundation of China/ ; ZR2024QB108//Shandong Provincial Natural Science Foundation/ ; 7222082//Beijing Municipal Natural Science Foundation，China/ ; }, mesh = {Animals ; *Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mice ; *Mice, Transgenic ; *Proteomics/methods ; *Acetylglucosamine/metabolism ; *Spinal Cord/metabolism ; Glycosylation ; Superoxide Dismutase-1/metabolism/genetics ; Protein Processing, Post-Translational ; Humans ; Proteome/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been found to affect the processing of several important proteins implicated in ALS. However, the overall level and cellular localization of O-GlcNAc during ALS progression are incompletely understood, and large-scale profiling of O-GlcNAcylation sites in this context remains unexplored.

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

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

CONCLUSION: These data provide a valuable resource for dissecting the functional role of O-GlcNAcylation in ALS and shed light on promising therapeutic avenues for ALS. The chemoenzymatic labeling-based chemoproteomic approach is applicable for probing O-GlcNAc dynamics in various pathological processes.}, } @article {pmid40019593, year = {2025}, author = {Dobroniak, CC and Lesche, V and Olgemöller, U and Beck, P and Lehmann, W and Spering, C}, title = {Surgical strategy for chest wall reconstruction secondary to cardiopulmonary resuscitation versus post-traumatic.}, journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society}, volume = {51}, number = {1}, pages = {122}, pmid = {40019593}, issn = {1863-9941}, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; Male ; Female ; Retrospective Studies ; Middle Aged ; *Thoracic Wall/injuries/surgery ; *Flail Chest/surgery/etiology ; *Rib Fractures/surgery ; *Sternum/injuries/surgery ; Germany ; Plastic Surgery Procedures/methods ; Aged ; Fracture Fixation, Internal/methods ; Adult ; Length of Stay/statistics & numerical data ; Bone Plates ; }, abstract = {PURPOSE: In mechanically cardiopulmonary resuscitated (CPR) patients, chest compressions at the level of the 3rd to 5th rib on the sternum result in reproducibly similar injury patterns: parasternal osteochondral dissociation (OCS) on both sides in combination with a sternal fracture with or without an additional serial rib fracture in the anterolateral column (ALS). This injury biomechanically impairs physiological breathing, resulting in an inverse breathing pattern. Trauma patients, on the other hand, often show a mixed pattern depending on the location of the main energy. The aim of the study was to evaluate the surgical technique of chest wall reconstruction (CWR) using transsternal refixation of the 5th rib on both sides in combination with plate osteosynthesis of the sternum and to analyze its success in comparison to the surgical strategy of CWR in the context of a traumatic genesis.

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

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

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

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

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

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

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

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

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

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

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

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

SCHLUSSFOLGERUNG: Die gezielte pränatale Echokardiografie konnte in einer Niedrigrisikopopulation eine Prävalenz von 18,9 % für Varianten der Abgänge des Aortenbogen identifizieren. Zukünftige Studien sind erforderlich, um die klinischen Auswirkungen unserer Ergebnisse auf Neugeborene mit angeborenen Herzfehlern zu bewerten.}, } @article {pmid40014834, year = {2025}, author = {Gusovsky Chevalier, AV and Lin, CC and Kerber, K and Reynolds, EL and Callaghan, BC and Burke, JF}, title = {Cost Trends of New-To-Market Neurologic Medications: An Insurance Claims Database Analysis.}, journal = {Neurology}, volume = {104}, number = {6}, pages = {e213428}, doi = {10.1212/WNL.0000000000213428}, pmid = {40014834}, issn = {1526-632X}, mesh = {Humans ; Male ; Female ; United States ; Middle Aged ; *Databases, Factual ; Aged ; Adult ; Nervous System Diseases/drug therapy/economics ; Insurance Claim Review/trends ; Drug Costs/trends ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: Costs for neurologic medications have increased considerably in recent years. Since 2014, more than 30 neurologic medications have been approved by the US Food and Drug Administration (FDA) for neurologic conditions. This study aims to characterize recent trends in annual costs and aggregate spending from 2012 to 2021 for new-to-market (NTM) medications for 9 neurologic conditions.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CONCLUSION: A novel drug delivery system has been developed and characterized, demonstrating enhanced CNS biodistribution of riluzole, which shows promise as efficient therapeutic tool for motor neuron diseases, including amyotrophic lateral sclerosis.}, } @article {pmid40006958, year = {2025}, author = {Mielcarska, MB and Rouse, BT}, title = {Viruses and the Brain-A Relationship Prone to Trouble.}, journal = {Viruses}, volume = {17}, number = {2}, pages = {}, doi = {10.3390/v17020203}, pmid = {40006958}, issn = {1999-4915}, mesh = {Humans ; *Brain/virology ; Animals ; Viruses/pathogenicity/genetics ; Antiviral Agents/therapeutic use/pharmacology ; Virus Diseases/virology ; Neurodegenerative Diseases/virology ; }, abstract = {Neurological disorders, some of which are associated with viral infections, are growing due to the aging and expanding population. Despite strong defenses of the central nervous system, some viruses have evolved ways to breach them, which often result in dire consequences. In this review, we recount the various ways by which different viruses can enter the CNS, and we describe the consequences of such invasions. Consequences may manifest as acute disease, such as encephalitis, meningitis, or result in long-term effects, such as neuromuscular dysfunction, as occurs in poliomyelitis. We discuss evidence for viral involvement in the causation of well-known chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as vascular dementia in the elderly. We also describe the approaches currently available to control a few of the neural viral infections. These include antivirals that are effective against human immunodeficiency virus and herpes simplex virus, as well as vaccines valuable for controlling rabies virus, poliomyelitis virus, and some flavivirus infections. There is an urgent need to better understand, at a molecular level, how viruses contribute to acute and, especially, chronic neurological diseases and to develop more precise and effective vaccines and therapies.}, } @article {pmid40006784, year = {2025}, author = {Ji, M and Yu, H and Cui, H and Chen, J and Yu, J and Li, X}, title = {A New Pro-197-Ile Mutation in Amaranthus palmeri Associated with Acetolactate Synthase-Inhibiting Herbicide Resistance.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/plants14040525}, pmid = {40006784}, issn = {2223-7747}, support = {CARS25//China Agriculture Research System/ ; }, abstract = {Palmer amaranth (Amaranthus palmeri S. Watson), native to North America, is one of the most prominent invasive weed species on agricultural land. Acetolactate synthase (ALS)-resistant A. palmeri (Amaranthus palmeri) is widespread, while the research focus on resistance pattern and molecular basis of A. palmeri to imazethapyr is seldom documented in China. An A. palmeri population that survived the recommended rate of imazethapyr was collected in Shandong Province, China. The resistant mechanism and pattern of A. palmeri to imazethapyr was investigated. Dose-response assay showed that the resistant (R) population displayed a high resistance level (292.5-fold) to imazethapyr compared with the susceptible (S) population. Sequence analysis of the ALS gene revealed that nucleotide mutations resulted in three resistance-conferring amino acid substitutions, Pro-197-Ile, Trp-574-Leu, and Ser-653-Asp, in the individual plants of the R population. An in vitro enzyme assay indicated that the ALS was relatively unsusceptible to imazethapyr in the R population, showing a resistance index of 88.6-fold. ALS gene expression and copy number did not confer resistance to imazethapyr in the R population. Pro-197-Ile is the first reported amino acid substitution conferring ALS resistance to A. palmeri. This is the first case of an imazethapyr-resistant A. palmeri biotype in China.}, } @article {pmid40004464, year = {2025}, author = {Liu, Z and Song, SY}, title = {Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases.}, journal = {Genes}, volume = {16}, number = {2}, pages = {}, doi = {10.3390/genes16020135}, pmid = {40004464}, issn = {2073-4425}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/diagnosis ; *Transcriptome/genetics ; Prognosis ; *Genome-Wide Association Study/methods ; Genomics/methods ; Gene Expression Profiling/methods ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Genetic Predisposition to Disease ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.}, } @article {pmid40004056, year = {2025}, author = {Yan, B and Suen, MC and Xu, N and Lu, C and Liu, C and Zhu, G}, title = {G-Quadruplex Structures Formed by Human Telomere and C9orf72 GGGGCC Repeats.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, doi = {10.3390/ijms26041591}, pmid = {40004056}, issn = {1422-0067}, support = {32071188//National Scientific Foundation of China/ ; 16101120, 161011121, AoE/M-403-16, AoE/M-401/20//Research Grants Council of the Hong Kong Special Administrative Region, China/ ; BGF.2023.019//Hong Kong University of Science and Technology, China/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation, China/ ; 32301012//Young Scientists Fund of the National Natural Science Foundation of China/ ; }, mesh = {*G-Quadruplexes ; Humans ; *Telomere/genetics ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {G-quadruplexes (G4s) are unique nucleic acid structures composed of guanine-rich (G-rich) sequences that can form diverse topologies based on the arrangement of their four strands. G4s have attracted attention for their potential roles in various biological processes and human diseases. In this review, we focus on the G4 structures formed by human telomeric sequences, (GGGTTA)n, and the hexanucleotide repeat expansion, (GGGGCC)n, in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene, highlighting their structural diversity and biological significance. Human telomeric G4s play crucial roles in telomere retention and gene regulation. In particular, we provide an in-depth summary of known telomeric G4s and focus on our recently discovered chair-type conformation, which exhibits distinct folding patterns. The chair-type G4s represent a novel folding pattern with unique characteristics, expanding our knowledge of telomeric G4 structural diversity and potential biological functions. Specifically, we emphasize the G4s formed by the (GGGGCC)n sequence of the C9orf72 gene, which represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The thorough structural analysis in this review advances our comprehension of the disease mechanism and provides valuable insights into developing targeted therapeutic strategies in ALS/FTD.}, } @article {pmid40002740, year = {2025}, author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, doi = {10.3390/biomedicines13020327}, pmid = {40002740}, issn = {2227-9059}, support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; }, abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.}, } @article {pmid40002527, year = {2025}, author = {Eisen, A and Kiernan, MC}, title = {The Neonatal Microbiome: Implications for Amyotrophic Lateral Sclerosis and Other Neurodegenerations.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, doi = {10.3390/brainsci15020195}, pmid = {40002527}, issn = {2076-3425}, abstract = {Most brain development occurs in the "first 1000 days", a critical period from conception to a child's second birthday. Critical brain processes that occur during this time include synaptogenesis, myelination, neural pruning, and the formation of functioning neuronal circuits. Perturbations during the first 1000 days likely contribute to later-life neurodegenerative disease, including sporadic amyotrophic lateral sclerosis (ALS). Neurodevelopment is determined by many events, including the maturation and colonization of the infant microbiome and its metabolites, specifically neurotransmitters, immune modulators, vitamins, and short-chain fatty acids. Successful microbiome maturation and gut-brain axis function depend on maternal factors (stress and exposure to toxins during pregnancy), mode of delivery, quality of the postnatal environment, diet after weaning from breast milk, and nutritional deficiencies. While the neonatal microbiome is highly plastic, it remains prone to dysbiosis which, once established, may persist into adulthood, thereby inducing the development of chronic inflammation and abnormal excitatory/inhibitory balance, resulting in neural excitation. Both are recognized as key pathophysiological processes in the development of ALS.}, } @article {pmid40002476, year = {2025}, author = {Raymond, J and Howard, IM and Berry, J and Larson, T and Horton, DK and Mehta, P}, title = {Head Injury and Amyotrophic Lateral Sclerosis: Population-Based Study from the National ALS Registry.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, doi = {10.3390/brainsci15020143}, pmid = {40002476}, issn = {2076-3425}, support = {n/a/CC/CDC HHS/United States ; }, abstract = {Background/Objectives: To examine if head injury (HI) is associated with age at ALS diagnosis in the United States. Methods: In this cross-sectional populationf-based analysis, we identified patients with ALS who were registered from 2015 to 2023 who completed the Registry's head trauma survey module. The association between HI and age at ALS diagnosis was assessed using multivariate analysis. Results: Of the 3424 respondents, 56.6% had experienced a HI. The adjusted odds ratio (aOR) for an ALS diagnosis before age 60 years for patients with a HI was 1.24 (95% CI, 1.07-1.45). One or two HIs had an aOR of 1.15 (95% CI, 0.97-1.36), and five or more HIs had an aOR of 1.58 (95% CI, 1.19-2.09). HI before age 18 years yielded an aOR of 2.03 (95% CI, 1.53-2.70) as well as HI between the ages of 18 and 30 years (aOR = 1.48, 95% CI: 1.06-2.06)). When narrowing the analysis to patients with HI before age 18 compared with patients with no HI, we found an association with HI that led to an emergency department or hospital visit (aOR = 1.50 (95% CI: 1.21-1.86)). Conclusions: In this cross-sectional analysis of ALS patients, HIs occurring in childhood and early adulthood and the number of HIs increased the odds of being diagnosed before age 60 years. These results suggest that HI continues to be a risk factor for ALS and could be associated with a younger age of diagnosis.}, } @article {pmid40002468, year = {2025}, author = {Dawoody Nejad, L and Pioro, EP}, title = {Modeling ALS with Patient-Derived iPSCs: Recent Advances and Future Potentials.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, doi = {10.3390/brainsci15020134}, pmid = {40002468}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal complex neurodegenerative disease, with 10-15% of cases being familial and the majority being sporadic with no known cause. There are no animal models for the 85-90% of sporadic ALS cases. More creative, sophisticated models of ALS disease are required to unravel the mysteries of this complicated disease. While ALS patients urgently require new medications and treatments, suitable preclinical in vitro models for drug screening are lacking. Therefore, human-derived induced pluripotent stem cell (hiPSC) technology offers the opportunity to model diverse and unreachable cell types in a culture dish. In this review, we focus on recent hiPSC-derived ALS neuronal and non-neuronal models to examine the research progress of current ALS 2D monocultures, co-cultures, and more complex 3D-model organoids. Despite the challenges inherent to hiPSC-based models, their application to preclinical drug studies is enormous.}, } @article {pmid40002444, year = {2025}, author = {Okoh, C and Mayall, L and Makin, SM and Chen, C and Zarotti, N}, title = {Non-Pharmacological Interventions for Caregivers of People with Motor Neurone Disease: A Scoping Review of Psychosocial Outcomes.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, doi = {10.3390/brainsci15020112}, pmid = {40002444}, issn = {2076-3425}, abstract = {Objective: Caregivers of individuals with motor neurone disease (MND) face a wide range of psychosocial difficulties. To address these, non-pharmacological interventions have been trialled, showing promising results. However, no clear characterisation of the breadth of psychosocial constructs examined by the interventions is currently available, resulting in the lack of a core outcome set (COS). The present review explored the types of psychosocial outcomes investigated in studies that adopted non-pharmacological interventions with caregivers of people with MND. Methods: A scoping review was conducted across four major databases (Academic Search Ultimate, CINAHL, PsycINFO, and MEDLINE) from inception to the 1 March 2024. Results: From an initial return of 4802 citations, 10 were considered eligible for inclusion. A total of 10 main psychosocial outcomes were identified: anxiety and depression, psychological distress, resilience, caregiver burden, caregiver preparedness, self-efficacy, quality of life, spiritual wellbeing, and mindfulness. Conclusions: Caregiver burden and symptoms of anxiety and depression represent pivotal outcomes, but caution is advised with regard to caregiver burden's potential multidimensional structure. Psychological distress and quality of life are also commonly investigated, but clearer consensus is needed on their conceptualisation. There is a paucity of studies characterising important psychosocial outcomes such as resilience, problem-solving, self-efficacy, and mindfulness, while no investigations are available for relevant outcomes such as coping, isolation, and loneliness. Further research is warranted to address these gaps to improve our insight into non-pharmacological support for MND caregivers and ultimately lead to the development of a core psychosocial outcome set in this population.}, } @article {pmid40001624, year = {2025}, author = {Ma, B and Ren, J and Qian, X}, title = {Study on the Polarization of Astrocytes in the Optic Nerve Head of Rats Under High Intraocular Pressure: In Vitro.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, doi = {10.3390/bioengineering12020104}, pmid = {40001624}, issn = {2306-5354}, support = {12472309 12072210//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes, the most common glial cells in the optic nerve head (ONH), provide support and nutrition to retinal ganglion cells. This study aims to investigate the polarization types of astrocytes in the ONH of rats under high intraocular pressure (IOP) and explore signaling pathways potentially associated with different types of polarized astrocytes. The rat models with chronic high IOP were established. High IOP lasted for 2, 4, 6, and 8 weeks. Astrocytes were extracted from the ONH of rats using the tissue block cultivation method. Western blot was used to detect the expression of proteins associated with astrocyte polarization. Proteomics was employed to identify differential proteins associated with astrocyte polarization. Astrocytes polarized into A2 astrocytes after 2, 4, 6, and 8 weeks of high IOP, while polarization into A1 astrocytes began only after 8 weeks of high IOP. The differential proteins associated with A1 astrocyte polarization are primarily enriched in pathways of neurodegeneration with respect to multiple diseases, while the differential proteins associated with A2 astrocyte polarization are primarily enriched in pathways of spliceosome in amyotrophic lateral sclerosis. Our findings could provide a better understanding of the role of ONH astrocytes in the pathogenesis of glaucoma and offer new perspectives for glaucoma treatment.}, } @article {pmid40001529, year = {2025}, author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML}, title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, doi = {10.3390/biom15020225}, pmid = {40001529}, issn = {2218-273X}, support = {GM125082/GF/NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Inositol Phosphates/metabolism ; Animals ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Signal Transduction ; Inositol/metabolism ; }, abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.}, } @article {pmid40001370, year = {2025}, author = {Silva Ortíz, YL and de Sousa, TC and Kruklis, NE and Galeano García, P and Brango-Vanegas, J and Soller Ramada, MH and Franco, OL}, title = {The Role of Amphibian AMPs Against Oxidative Stress and Related Diseases.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, doi = {10.3390/antibiotics14020126}, pmid = {40001370}, issn = {2079-6382}, abstract = {Amphibians use their skin as an effective defense mechanism against predators and microorganisms. Specialized glands produce antimicrobial peptides (AMPs) that possess antioxidant properties, effectively reducing reactive oxygen species (ROS) levels. These peptides are promising candidates for treating diseases associated with oxidative stress (OS) and redox imbalance, including neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), as well as age-related conditions, like cardiovascular diseases and cancer. This review highlights the multifaceted roles of AMPs and antioxidant peptides (AOPs) in amphibians, emphasizing their protective capabilities against oxidative damage. They scavenge ROS, activate antioxidant enzyme systems, and inhibit cellular damage. AOPs often share structural characteristics with AMPs, suggesting a potential evolutionary connection and similar biosynthetic pathways. Peptides such as brevinin-1FL and Cath-KP demonstrate neuroprotective effects, indicating their therapeutic potential in managing oxidative stress-related diseases. The antioxidant properties of amphibian-derived peptides pave the way for novel therapeutic developments. However, a deeper understanding of the molecular mechanisms underlying these peptides and their interactions with oxidative stress is essential to addressing ROS-related diseases and advancing therapeutic strategies in clinical practice.}, } @article {pmid40000803, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {40000803}, issn = {1546-1726}, support = {NS132836//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS123242//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, abstract = {Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.}, } @article {pmid40000618, year = {2025}, author = {Ru, Q and Li, Y and Zhang, X and Chen, L and Wu, Y and Min, J and Wang, F}, title = {Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.}, journal = {Bone research}, volume = {13}, number = {1}, pages = {27}, pmid = {40000618}, issn = {2095-4700}, support = {82071970//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072506//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31970689//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32330047//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024AFB971//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Homeostasis ; *Iron/metabolism ; *Muscular Diseases/metabolism/therapy/pathology/physiopathology ; Animals ; }, abstract = {The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.}, } @article {pmid39999835, year = {2025}, author = {Saxena, S and Liebscher, S}, title = {Boosting the X factor: Increasing XBP1s-mediated ER stress signaling protects motor neurons in ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2025.02.005}, pmid = {39999835}, issn = {1525-0024}, } @article {pmid39999167, year = {2025}, author = {Wang, HV and Xiang, JF and Yuan, C and Veire, AM and Gendron, TF and Murray, ME and Tansey, MG and Hu, J and Gearing, M and Glass, JD and Jin, P and Corces, VG and McEachin, ZT}, title = {pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex of C9orf72 ALS/FTD patients.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {9}, pages = {e2419818122}, doi = {10.1073/pnas.2419818122}, pmid = {39999167}, issn = {1091-6490}, support = {R35 GM139408/GM/NIGMS NIH HHS/United States ; R35 NS111602/NS/NINDS NIH HHS/United States ; F32 ES031827/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Prefrontal Cortex/metabolism/pathology ; *Microglia/metabolism/pathology ; Male ; *DNA-Binding Proteins/metabolism/genetics ; Female ; Middle Aged ; Aged ; DNA Repeat Expansion/genetics ; Neurons/metabolism/pathology ; Phosphorylation ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.}, } @article {pmid39998997, year = {2025}, author = {García-Casanova, PH and Vázquez-Costa, JF}, title = {Advances in the early diagnosis of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1080/14737175.2025.2471556}, pmid = {39998997}, issn = {1744-8360}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Despite rapid disease progression, diagnostic delay of 10-16 months persists, influenced by disease-specific factors and healthcare systems. Reducing it is crucial for early intervention, multidisciplinary care planning, and patient participation in clinical trials.

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

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

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

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

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

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

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

CONCLUSION: These findings suggest current collars do not fully meet the needs of people living with ALS, emphasizing the importance of improved treatment options. Future research should explore innovative technologies to improve cervical support, function, and quality of life.}, } @article {pmid39997929, year = {2025}, author = {Newell, ME and Aravindan, A and Babbrah, A and Halden, RU}, title = {Epigenetic Biomarkers Driven by Environmental Toxins Associated with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the United States: A Systematic Review.}, journal = {Toxics}, volume = {13}, number = {2}, pages = {}, doi = {10.3390/toxics13020114}, pmid = {39997929}, issn = {2305-6304}, support = {GF000000002135//Glen Swette Memorial Fund/ ; }, abstract = {Environmental toxins and epigenetic changes have been linked to neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). This paper aimed to (i) identify environmental toxins associated with AD, PD, and ALS, (ii) locate potential industrial sources of toxins in the United States (U.S.), and (iii) assess epigenetic changes driven by exposure to toxins reported by patients. Environmental factors and epigenetic biomarkers of neurodegeneration were compiled from 69 studies in the literature using Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) and geographic information system approaches. Some 127 environmental toxins have been associated or putatively associated with AD, PD, or ALS, with four toxic metals (As, Cd, Mn, and Hg) common to all three of these neurodegenerative diseases. Environmental toxins associated with epigenetic changes (e.g., DNA methylation) in patients include air pollutants, metals, and organic chemicals (e.g., pesticides, mycotoxins, and cyanotoxins). Geographic analysis showed that study locations (e.g., U.S., Europe, and East Asia) were selected by researchers based on convenience of access rather than exposure risk and disease prevalence. We conclude that several toxins and epigenetic markers shared among neurodegenerative diseases could serve as attractive future targets guiding environmental quality improvements and aiding in early disease detection.}, } @article {pmid39996748, year = {2025}, author = {Yang, HM}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/cells14040276}, pmid = {39996748}, issn = {2073-4409}, support = {2020R1A2C1011311//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Oxidative Stress ; Mitochondrial Dynamics ; Mitophagy ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial dysfunction represents a pivotal characteristic of numerous neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions, distinguished by unique clinical and pathological features, exhibit shared pathways leading to neuronal damage, all of which are closely associated with mitochondrial dysfunction. The high metabolic requirements of neurons make even minor mitochondrial deficiencies highly impactful, driving oxidative stress, energy deficits, and aberrant protein processing. Growing evidence from genetic, biochemical, and cellular investigations associates impaired electron transport chain activity and disrupted quality-control mechanisms, such as mitophagy, with the initial phases of disease progression. Furthermore, the overproduction of reactive oxygen species and persistent neuroinflammation can establish feedforward cycles that exacerbate neuronal deterioration. Recent clinical research has increasingly focused on interventions aimed at enhancing mitochondrial resilience-through antioxidants, small molecules that modulate the balance of mitochondrial fusion and fission, or gene-based therapeutic strategies. Concurrently, initiatives to identify dependable mitochondrial biomarkers seek to detect pathological changes prior to the manifestation of overt symptoms. By integrating the current body of knowledge, this review emphasizes the critical role of preserving mitochondrial homeostasis as a viable therapeutic approach. It also addresses the complexities of translating these findings into clinical practice and underscores the potential of innovative strategies designed to delay or potentially halt neurodegenerative processes.}, } @article {pmid39996723, year = {2025}, author = {Deecke, L and Ohlei, O and Goldeck, D and Homann, J and Toepfer, S and Demuth, I and Bertram, L and Pawelec, G and Lill, CM}, title = {Peripheral Immune Profiles in Individuals at Genetic Risk of Amyotrophic Lateral Sclerosis and Alzheimer's Disease.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/cells14040250}, pmid = {39996723}, issn = {2073-4409}, support = {#16SV5536K, #16SV5537, #16SV5538, #16SV5837, #01UW0808,01GL1716A, and 01GL1716B//Bundesministerium für Bildung und Forschung/ ; LI 2654/4-1//German Research Foundation/ ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; *Alzheimer Disease/genetics/immunology ; Male ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Aged ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide/genetics ; Multifactorial Inheritance/genetics ; CD8-Positive T-Lymphocytes/immunology ; }, abstract = {The immune system plays a crucial role in the pathogenesis of neurodegenerative diseases. Here, we explored whether blood immune cell profiles are already altered in healthy individuals with a genetic predisposition to amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD). Using multicolor flow cytometry, we analyzed 92 immune cell phenotypes in the blood of 448 healthy participants from the Berlin Aging Study II. We calculated polygenic risk scores (PGSs) using genome-wide significant SNPs from recent large genome-wide association studies on ALS and AD. Linear regression analyses were then performed of the immune cell types on the PGSs in both the overall sample and a subgroup of older participants (>60 years). While we did not find any significant associations between immune cell subtypes and ALS and AD PGSs when controlling for the false discovery rate (FDR = 0.05), we observed several nominally significant results (p < 0.05) with consistent effect directions across strata. The strongest association was observed with CD57+ CD8+ early-memory T cells and ALS risk (p = 0.006). Other immune cell subtypes associated with ALS risk included PD-1+ CD8+ and CD57+ CD4+ early-memory T cells, non-classical monocytes, and myeloid dendritic cells. For AD, naïve CD57+ CD8+ T cells and mature NKG2A+ natural killer cells showed nominally significant associations. We did not observe major immune cell changes in individuals at high genetic risk of ALS or AD, suggesting they may arise later in disease progression. Additional studies are required to validate our nominally significant findings.}, } @article {pmid39996599, year = {2025}, author = {Chowdhury, RN and Azam, MA and Azam, SA and Lana, S and Culver, EN and Garruto, RM and Wander, K}, title = {Elevated Serum MCP-2 and TARC Associated With Increased Risk of Death in Guamanian ALS Patients.}, journal = {European journal of neurology}, volume = {32}, number = {3}, pages = {e70088}, doi = {10.1111/ene.70088}, pmid = {39996599}, issn = {1468-1331}, support = {//Sigma Xia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality ; Female ; Male ; Middle Aged ; Aged ; Guam/epidemiology ; Biomarkers/blood ; Adult ; Chemokine CCL2/blood ; }, abstract = {BACKGROUND: This study explores the relationship between inflammation and longevity in a high-incidence focus of amyotrophic lateral sclerosis (ALS) in post-WWII Guam. Characteristics of this focus include the sudden appearance of the disease in high numbers and the unusually long lifespan (without medical interventions) seen in some cases. We used bio-banked specimens to evaluate the relationship between serum immunoregulators and survival time.

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

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

DISCUSSION: Like sporadic ALS cases worldwide, inflammation is associated with a shortened lifespan in Guamanian ALS; more specifically, our findings suggest serum levels of MCP-2 and TARC at onset may predict disease duration. Further investigation is needed to determine the role of these immunoregulators in disease prognosis and as targets for diagnostic and therapeutic interventions.}, } @article {pmid39996130, year = {2025}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {Neurology. Genetics}, volume = {11}, number = {2}, pages = {e200246}, pmid = {39996130}, issn = {2376-7839}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.}, } @article {pmid39995927, year = {2025}, author = {McDonald, TS and Cui, CS and Lerskiatiphanich, T and Marallag, J and Lee, JD}, title = {Metabolic rate and insulin-independent glucose uptake increase in a TDP-43[Q331K] mouse model of amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e42482}, pmid = {39995927}, issn = {2405-8440}, abstract = {Impaired glucose regulation is increasingly recognised in amyotrophic lateral sclerosis (ALS), yet the precise mechanisms remain unclear. Here, we investigated energy balance and glucose control in TAR DNA-binding protein 43 (TDP-43)[Q331K] mice, a model of ALS, at both the early and late symptomatic stages of disease. Mutant TDP-43[Q331K] mice and non-transgenic controls underwent indirect calorimetry, as well as intraperitoneal glucose, insulin, and glucagon tolerance testing. We also examined plasma hormone levels and quantified α- and β-cell areas in pancreatic islets. Throughout disease progression, TDP-43[Q331K] mice exhibited elevated metabolic rates, with a transient increase in food intake at the early stages. At the later stages of disease, heightened glucose uptake was observed despite unchanged insulin secretion or tolerance, indicating mechanisms independent of insulin. Notably, TDP-43[Q331K] mice maintained fasting blood glucose levels even when circulating glucagon levels were reduced, suggesting that alternative pathways contribute to preserving euglycemia. These findings reveal a distinct metabolic profile in TDP-43[Q331K] mice, underscoring the complexity of glucose dyshomeostasis in ALS.}, } @article {pmid39995125, year = {2025}, author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV}, title = {ISR Modulators in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X361653250213114821}, pmid = {39995125}, issn = {1875-6190}, abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.}, } @article {pmid39995102, year = {2025}, author = {Perdikakis, M and Papadimitrakis, D and Floros, N and Tzavellas, E and Piperi, C and Gargalionis, AN and Papavassiliou, AG}, title = {Diagnostic role of circulating cell-free DNA in schizophrenia and neuro-degenerative disorders.}, journal = {Biomarkers in medicine}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/17520363.2025.2468151}, pmid = {39995102}, issn = {1752-0371}, abstract = {Over the past few years, circulating cell-free DNA (cfDNA) research has grown exponentially. Several studies have associated the release of cfDNA in the bloodstream, cerebrospinal fluid, and other body fluids with increased apoptosis and cell death. Therefore, their possible use as biomarkers for cancer and other diseases has emerged. The diagnosis of pathological entities such as schizophrenia and neurodegenerative diseases involves many challenges and requires ruling out conditions with similar symptoms. In this context, cfDNA could serve as a valuable diagnostic biomarker. This study encompasses the recent bibliography and research regarding the utilization of circulating cfDNA for diagnostic purposes in schizophrenia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. This minimally invasive method has provided important evidence regarding the diagnosis of the aforementioned diseases although further research is necessary.}, } @article {pmid39995075, year = {2025}, author = {Manco, C and Righi, D and Primiano, G and Romano, A and Luigetti, M and Leonardi, L and De Stefano, N and Plantone, D}, title = {Peripherin, A New Promising Biomarker in Neurological Disorders.}, journal = {The European journal of neuroscience}, volume = {61}, number = {4}, pages = {e70030}, doi = {10.1111/ejn.70030}, pmid = {39995075}, issn = {1460-9568}, mesh = {Humans ; *Peripherins/metabolism/genetics ; *Biomarkers/metabolism ; Animals ; *Nervous System Diseases/metabolism ; }, abstract = {Peripherin is a class III intermediate filament protein that has recently gained attention as a potential biomarker for axonal damage in the peripheral nervous system. This review examines peripherin gene expression, protein structure, and its functions in both healthy and diseased states. Peripherin is predominantly expressed in the peripheral nervous system, especially in motor and sensory neurons, and plays a critical role in neurite growth, stability, and axonal transport during myelination. Its expression is regulated by various cytokines and undergoes several post-transcriptional modifications. Peripherin interacts with multiple proteins, including neurofilaments and kinases, influencing cytoskeletal dynamics and neuronal functions. The review also explores peripherin involvement in several neurological disorders, such as Amyotrophic Lateral Sclerosis, where its abnormal expression and aggregation contribute to disease pathology. Additionally, peripherin has been linked to polyneuropathies, traumatic axonal injury, and diabetic neuropathy, suggesting its broader relevance as a biomarker in these conditions. The potential of peripherin as a biomarker is further supported by recent studies using ultrasensitive detection methods, which have identified elevated peripherin levels in the serum of patients with neurological diseases. Despite the promising findings, the application of peripherin as a biomarker in clinical settings remains limited, primarily due to challenges in its detection and the need for further validation in diverse patient populations. Future research directions include the development of more sensitive assays and the exploration of peripherin's role in non-neuronal tissues, which may expand its diagnostic and therapeutic potential.}, } @article {pmid39994742, year = {2025}, author = {Djukic, S and Zhao, Z and Jørgensen, LMH and Bak, AN and Jensen, DB and Meehan, CF}, title = {TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {42}, pmid = {39994742}, issn = {2051-5960}, support = {R370-2021-1109//The Lundbeck Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/physiopathology/genetics ; Animals ; *Motor Neurons/pathology/metabolism/physiology ; *DNA-Binding Proteins/metabolism/genetics ; *Mice, Transgenic ; *Disease Models, Animal ; *Neuronal Plasticity/physiology ; *Axon Initial Segment/metabolism/physiology ; Spinal Cord/pathology/metabolism ; Mice ; Male ; Humans ; Female ; Action Potentials/physiology ; Mice, Inbred C57BL ; }, abstract = {A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated in the disease pathogenesis. What drives this hyperexcitability in the vast majority of patients is unknown. This is important to know as existing treatments simply reduce all neuronal excitability and fail to distinguish between pathological changes and important homeostatic changes. Understanding what drives the initial pathological changes could therefore provide better treatments. One challenge is that patients represent a heterogeneous population and the vast majority of cases are sporadic. One pathological feature that almost all (~97%) cases (familial and sporadic) have in common are cytoplasmic aggregates of the protein TDP-43 which is normally located in the nucleus. In our experiments we investigated whether this pathology was sufficient to increase neuronal excitability and the mechanisms by which this occurs. We used the TDP-43(ΔNLS) mouse model which successfully recapitulates this pathology in a controllable way. We used in vivo intracellular recordings in this model to demonstrate that TDP-43 pathology is sufficient to drive a severe hyper-excitability of spinal motoneurones. Reductions in soma size and a lengthening and constriction of axon initial segments were observed, which would contribute to enhanced excitability. Resuppression of the transgene resulted in a return to normal excitability parameters by 6-8 weeks. We therefore conclude that TDP-43 pathology itself is sufficient to drive a severe but reversible hyperexcitability of spinal motoneurones.}, } @article {pmid39994160, year = {2025}, author = {Dubey, PR and Kaur, G and Shukla, R}, title = {Nano-mediated Management of Metal Toxicity-induced Neurodegeneration: A Critical Review.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39994160}, issn = {1559-1182}, abstract = {Heavy metals, omnipresent in the environment, though imperative in trace quantities for human physiology, become a serious health hazard due to their toxicity. Copper, arsenic, lead, iron, and mercury are some examples of the heavy metals responsible for oxidative stress, which is one of the primary factors behind neurodegenerative diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Neurodegeneration is caused by toxicity due to environmental exposure to these toxic substances or genetic variation. Conventional therapies, relying on chelation and antioxidants, suffer from the broader perspective of metal removal in a non-selective manner and poor targeting of the brain. In this respect, treatments based on nanotechnology that employ nanoparticles such as dendrimers, micelles, and liposomes constitute a promising interest in enhancing drug delivery with minimal neurotoxicity. The present review outlines the heavy metals responsible for neurodegenerative diseases, their pathophysiology, management strategies available at present, and the scope of nanotechnology intervention in overcoming shortcomings of conventional therapies. The genetic influence of heavy metals on neurological health is also part of this article.}, } @article {pmid39993605, year = {2025}, author = {David Wu, CH and Whelan, TJ and Swaminath, A}, title = {Response to: Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {}, number = {}, pages = {110804}, doi = {10.1016/j.radonc.2025.110804}, pmid = {39993605}, issn = {1879-0887}, } @article {pmid39993604, year = {2025}, author = {Huertas, A and Moghanaki, D and Siva, S}, title = {Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {}, number = {}, pages = {110805}, doi = {10.1016/j.radonc.2025.110805}, pmid = {39993604}, issn = {1879-0887}, } @article {pmid39992908, year = {2025}, author = {Nemeth, T and Zarnocki, A and Ladanyi, A and Papp, C and Ayaydin, F and Szebeni, GJ and Gacser, A}, title = {PCR-based CRISPR/Cas9 system for fluorescent tagging: A tool for studying Candida parapsilosis virulence.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0312948}, doi = {10.1371/journal.pone.0312948}, pmid = {39992908}, issn = {1932-6203}, mesh = {*CRISPR-Cas Systems ; Mice ; *Candida parapsilosis/genetics/pathogenicity ; Animals ; Virulence/genetics ; Polymerase Chain Reaction/methods ; Macrophages/microbiology ; Humans ; }, abstract = {Candida parapsilosis is persistent in a hospital environment hence it is often associated with nosocomial infections especially amongst low-birth weight neonates. Genetic modification is therefore important to characterise the physiological and virulence related properties of this fungus. A PCR-based CRISPR/Cas9 system has been adopted to facilitate the generation of fluorescent tagged prototroph isolates. We examined a total of eight fluorescent protein coding genes, out of which three were found to be applicable for simultaneous utilisation. We investigated three clinical isolates of C. parapsilosis in terms of their adherence to silicone and their uptake by J774.2 murine macrophages in competition assays. Interestingly, we found significant differences between them in both experiments where GA1 isolate was significantly less resistant to macrophage uptake and CDC317 was significantly more adherent to silicone material. In silico analysis of the agglutinin-like sequences (Als) exposed remarkable diversity in this protein family and additionally, the thorough analysis of the ALS genes revealed evidence of formation of a new gene by intrachromosomal recombination in the GA1 isolate. Finally, we provide a step by step protocol for the application of the PCR-based CRISPR/Cas9 system for fluorescently labelling C. parapsilosis isolates.}, } @article {pmid39992655, year = {2025}, author = {Liu, X and Shang, H and Wei, Q and Yao, X and Lian, L and Dang, J and Jia, R and Wu, Z and Li, H and Niu, Q and Cheng, X and Zou, Z and Chen, S and Zhang, M and Liu, Y and Liu, Y and Liu, Q and Huang, X and Wang, H and Feng, H and Wang, S and Fan, D and , }, title = {Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2461055}, doi = {10.1001/jamanetworkopen.2024.61055}, pmid = {39992655}, issn = {2574-3805}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Pyrazines/therapeutic use/adverse effects ; Double-Blind Method ; Aged ; Treatment Outcome ; China ; Nitrogen Oxides ; }, abstract = {IMPORTANCE: Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

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

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

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

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

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

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

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

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

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

CONCLUSION: This study maps the global clinical research landscape of intracranial application of nicardipine for aSAH from 1994 to 2024, providing valuable references and guidance for future research.}, } @article {pmid39551156, year = {2025}, author = {Chen, LC and Martin, A and Senna, MM}, title = {Response to Truel J. et al's "Response to 'Topical tofacitinib for patients with lichen planopilaris and/or frontal fibrosing alopecia'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e69}, doi = {10.1016/j.jaad.2024.11.011}, pmid = {39551156}, issn = {1097-6787}, } @article {pmid39990425, year = {2025}, author = {Chakraborty, A and Mitra, J and Maloji Rao, VH and Kodavati, M and Mandal, SM and Gill, SK and Sreenivasmurthy, SG and Vasquez, V and Mankevich, M and Krishnan, B and Ghosh, G and Hegde, ML and Hazra, T}, title = {Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.13.623464}, pmid = {39990425}, issn = {2692-8205}, abstract = {TAR DNA-binding protein 43 (TDP-43) proteinopathy plays a critical role in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). In our recent discovery, we identified that TDP-43 plays an essential role in DNA double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. Here, we found persistent DNA damage in the brains of ALS/FTD patients, primarily in the transcribed regions of the genome. We further investigated the underlying mechanism and found that polynucleotide kinase 3'-phosphatase (PNKP) activity was severely impaired in the nuclear extracts of both patient brains and TDP-43-depleted cells. PNKP is a key player in DSB repair within the transcribed genome, where its 3'-P termini processing activity is crucial for preventing persistent DNA damage and neuronal death. The inactivation of PNKP in ALS/FTD was due to reduced levels of its interacting partner, phosphofructo-2-kinase fructose 2,6 bisphosphatase (PFKFB3), and its biosynthetic product, fructose-2,6-bisphosphate (F2,6BP), an allosteric modulator of glycolysis. Recent work from our group has shown that F2,6BP acts as a positive modulator of PNKP activity in vivo . Notably, exogenous supplementation with F2,6BP restored PNKP activity in nuclear extracts from ALS/FTD brain samples and patient-derived induced pluripotent stem (iPS) cells harboring pathological mutations. Furthermore, we demonstrate that supplementation of F2,6BP restores genome integrity and partially rescues motor phenotype in a Drosophila model of ALS. Our findings underscore the possibility of exploring the therapeutic potential of F2,6BP or its analogs in TDP-43 pathology-associated motor neuron diseases.}, } @article {pmid39990107, year = {2025}, author = {Zhao, S and Chen, R and An, Y and Zhang, Y and Ma, C and Gao, Y and Lu, Y and Yang, F and Bai, X and Zhang, J}, title = {Optineurin overexpression ameliorates neurodegeneration through regulating neuroinflammation and mitochondrial quality in a murine model of amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1522073}, pmid = {39990107}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons (MNs). Genetic mutations in Optineurin (OPTN) and Superoxide Dismutase 1 (SOD1) have been identified as causal factors for ALS. OPTN immunopositive inclusions have been confirmed in the cases of ALS with SOD1 mutations. However, the role of the OPTN gene in ALS caused by SOD1 mutations is ambiguous.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CONCLUSIONS: cfDNA methylation is a powerful tool for assessing age-related changes and ALS-specific molecular dysregulation by revealing perturbed locus, genes, and the proportional contributions of different tissues/cells to the plasma. This technique holds promise for clinical application in biomarker discovery across a broad spectrum of neurodegenerative disorders.}, } @article {pmid39979261, year = {2025}, author = {Liu, D and Webber, HC and Bian, F and Xu, Y and Prakash, M and Feng, X and Yang, M and Yang, H and You, IJ and Li, L and Liu, L and Liu, P and Huang, H and Chang, CY and Liu, L and Shah, SH and La Torre, A and Welsbie, DS and Sun, Y and Duan, X and Goldberg, JL and Braun, M and Lansky, Z and Hu, Y}, title = {Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1789}, pmid = {39979261}, issn = {2041-1723}, support = {EY024932//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY034353//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; 1F32EY029567//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY026877//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY032518//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; EY023295//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; }, mesh = {Animals ; *Cell Cycle Proteins/metabolism/genetics ; *Membrane Transport Proteins/metabolism/genetics ; *Mitochondria/metabolism ; *Axons/metabolism ; *Retinal Ganglion Cells/metabolism/pathology ; Mice ; Humans ; *Microtubules/metabolism ; Nerve Regeneration ; Optic Nerve/metabolism/pathology ; Neuroprotection ; Disease Models, Animal ; Axonal Transport ; Kinesins/metabolism/genetics ; Mice, Inbred C57BL ; Transcription Factor TFIIIA/metabolism/genetics ; Low Tension Glaucoma/metabolism/genetics/pathology ; Male ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; }, abstract = {Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.}, } @article {pmid39978484, year = {2025}, author = {Hülsmeier, AJ}, title = {Glycosphingolipids in neurodegeneration - Molecular mechanisms, cellular roles, and therapeutic perspectives.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106851}, doi = {10.1016/j.nbd.2025.106851}, pmid = {39978484}, issn = {1095-953X}, abstract = {Neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal loss and pose significant global health challenges. Glycosphingolipids (GSLs), critical components of neuronal membranes, regulate signal transduction, membrane organization, neuroinflammation, and lipid raft functionality. This review explores GSL roles in neural development, differentiation, and neurogenesis, along with their dysregulation in neurodegenerative diseases. Aberrations in GSL metabolism drive key pathological features such as protein aggregation, neuroinflammation, and impaired signaling. Specific GSLs, such as GM1, GD3, and GM3, influence amyloid-beta aggregation in AD, α-synuclein stability in PD, and mutant huntingtin toxicity in HD. Therapeutic strategies targeting GSL metabolism, such as GM1 supplementation and enzyme modulation, have demonstrated potential to mitigate disease progression. Further studies using advanced lipidomics and glycomics may support biomarker identification and therapeutic advancements. This work aims to highlight the translational potential of GSL research for diagnosing and managing devastating neurodegenerative conditions.}, } @article {pmid39977915, year = {2024}, author = {Linares, A and Li, X and Satterwhite, L and Sun, Y and Bedlack, R}, title = {A Retrospective Analysis of ALS Clusters Near Algae Blooms in North Carolina (P5-11.019).}, journal = {Neurology}, volume = {102}, number = {7_supplement_1}, pages = {3353}, doi = {10.1212/WNL.0000000000205080}, pmid = {39977915}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/genetics ; North Carolina/epidemiology ; Humans ; Retrospective Studies ; *Harmful Algal Bloom ; Female ; Male ; }, abstract = {OBJECTIVE: To examine clinical differences between individuals with amyotrophic lateral sclerosis (ALS) who live near and far from harmful algal blooms (HABs) in North Carolina.

BACKGROUND: While 10% of ALS cases are associated with genetic mutations, the rest may have environmental causes. Higher than expected numbers of ALS cases have been identified near HABs in North Carolina using data from death certificates between 1999 and 2020 (unpublished). It is not clear why there might be more ALS cases near HABs. Blue-green algae produce toxins, such as β-methylamino-L-alanine, which are associated with neurotoxicity and ALS. We hypothesize that there might be clinical differences in HAB-associated ALS and non-HAB-associated ALS, which may help to understand why this correlation exists and better manage HAB-associated ALS.

DESIGN/METHODS: We will perform two retrospective cohort analyses comparing individuals with ALS who live far from HABs (more than 50 miles) and individuals with ALS who live near HABs (less than 50 miles). We will first analyze differences in demographics, genetic testing, and symptom onset using an existing RedCap database. We will analyze ALS progression using ALS Functional Rating Scale scores, forced vital capacity, and weight over time. For the second analysis using the Duke electronic medical record, we will examine the percentage of patients with ALS in each region and compare family history, comorbidities, medications, and socioeconomic status.

RESULTS: Preliminary results reveal that 16.3% of patients with ALS who live far from HABs have a family history of ALS or dementia, compared with 11.8% of those living near HABs.

CONCLUSIONS: This association suggests that higher than expected rates of ALS near HABs are not caused by genetic mutations. Additional analyses are underway which we hope will shed light on the etiology of HAB-associated ALS and eventually lead to new treatments and methods of prevention. Disclosure: Ms. Linares has nothing to disclose. Dr. Li has nothing to disclose. Dr. Satterwhite has nothing to disclose. Dr. Sun has nothing to disclose. Dr. Bedlack has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Guidepoint Global. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for New Biotic. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Woolsey Pharma. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amylyx. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ITF Pharma. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Mitsubishi Tanabe America. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Orphazyme. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AB Scicence. Dr. Bedlack has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for ALS Association. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Adept Field Solutions. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Apellis. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Black Swan. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clarivate. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clearview. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clean. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CM Group. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Corcept. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Health Advances. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MT Pharma America. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MJH Healthcare. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Maple Health Care. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for National Association of Managed Care Physicians. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Projects in Knowledge. Dr. Bedlack has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Shinkei Pharma. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Webb MD/Medscape. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Pharma. Dr. Bedlack has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Brainstorm Cell. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mallinkrodt. Dr. Bedlack has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion . Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurosense. Dr. Bedlack has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC Therapeutics. Dr. Bedlack has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amylyx. Dr. Bedlack has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for GenieUS. The institution of Dr. Bedlack has received research support from Cytokinetics. The institution of Dr. Bedlack has received research support from Orion. The institution of Dr. Bedlack has received research support from Ultragenyx. The institution of Dr. Bedlack has received research support from MediciNova. The institution of Dr. Bedlack has received research support from Healey Center. Dr. Bedlack has received publishing royalties from a publication relating to health care.}, } @article {pmid39977838, year = {2025}, author = {Chang, JH and Tschannen, D}, title = {An Integrative Review of Quality Improvement Competence and Engagement Among Frontline Nurses.}, journal = {Journal of nursing care quality}, volume = {40}, number = {2}, pages = {173-180}, pmid = {39977838}, issn = {1550-5065}, mesh = {Humans ; *Quality Improvement ; *Leadership ; Clinical Competence/standards ; }, abstract = {BACKGROUND: Nurses providing direct care have firsthand knowledge of gaps in practice and thus must actively engage in quality improvement (QI) to enhance patient outcomes.

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

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

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

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

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

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

INTERPRETATION: Our findings suggest metabolomic changes primarily involving different lipid classes and carnitine metabolism may underscore ALS severity and progression. ANN NEUROL 2025.}, } @article {pmid39976261, year = {2025}, author = {Menendez-Gonzalez, M}, title = {Implementing a tridimensional diagnostic framework for personalized medicine in neurodegenerative diseases.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14591}, doi = {10.1002/alz.14591}, pmid = {39976261}, issn = {1552-5279}, support = {PI21/00467//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/diagnosis/genetics ; *Biomarkers ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant challenge in modern medicine due to their clinical heterogeneity, multifactorial etiologies, and frequent co-pathologies. Traditional diagnostic systems, based on clinical symptoms and post mortem findings, are limited in capturing the complex interactions among genetic, molecular, and neuroanatomical factors. This manuscript introduces a novel tridimensional diagnostic framework that integrates these factors across three key axes: etiology (genetic and environmental influences), molecular markers (primary and secondary biomarkers), and neuroanatomoclinical correlations. Through case studies, we demonstrate the framework's ability to synthesize incomplete datasets, stratify patients, and guide precision medicine. By incorporating omics technologies, neuroimaging, and AI-driven probabilistic modeling, the framework enhances diagnostic accuracy and clinical relevance. This approach may contribute to overcoming the limitations of traditional nosologies, offering a scalable and adaptable tool for both clinical practice and research and advancing the field of precision medicine in NDD management. HIGHLIGHTS: Tridimensional diagnostic system: We propose a new framework that incorporates three axes - etiology, molecular markers, and neuroanatomical-clinical correlations - to enhance diagnostic accuracy for NDDs. Personalized medicine: The tridimensional system enables the integration of genetic, molecular, and clinical data, allowing for highly personalized treatment strategies tailored to individual patients. Proteinopathies as key biomarkers: This diagnostic system emphasizes the use of primary proteinopathies (amyloid, tau, synuclein) and secondary biomarkers (eg, NfL, GFAP) to monitor disease progression and treatment efficacy. Addressing clinical heterogeneity: The framework accommodates the complexity and heterogeneity of NDDs, offering an adaptable diagnostic approach for classical conditions like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ALS. Case studies and real-world application: Practical case studies illustrate how this system can be implemented in clinical practice, enabling the combination of DMTs with symptomatic treatments.}, } @article {pmid39976178, year = {2025}, author = {Canosa, A and Manera, U and Vasta, R and Zocco, G and Di Pede, F and Cabras, S and De Mattei, F and Palumbo, F and Iazzolino, B and Minerva, E and Sbaiz, L and Brunetti, M and Gallone, S and Grassano, M and Matteoni, E and Polverari, G and Fuda, G and Casale, F and Salamone, P and De Marco, G and Marchese, G and Moglia, C and Calvo, A and Pagani, M and Chiò, A}, title = {Brain Metabolic Features of FUS-ALS: A 2-[[18]F]FDG-PET Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27201}, pmid = {39976178}, issn = {1531-8249}, support = {//A.S.D. Polisportiva U.I.C.I Torino Onlus (Oltre la Vista, Oltre la SLA)/ ; PRIN 2017//Ministero dell'Università e della Ricerca/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran (INSPIRED)/ ; RF-2016- 02362405//Ministero della Salute (The Italian Ministry of Health [Ricerca Sanitaria Finalizzata])/ ; 259867//European Commission's Health Seventh Framework Programme (FP7/2007-2013)/ ; GA101017598//Horizon 2020 Framework Programme (BRAINTEASER [Bringing Artificial Intelligence Home for a Better Care of Amyotrophic Lateral Sclerosis and Multiple Sclerosis])/ ; 101137074//Horizon 2020 Framework Programme/ ; }, abstract = {OBJECTIVE: We aimed at evaluating the brain metabolic features of fused in sarcoma amyotrophic lateral sclerosis (FUS-ALS) compared with sporadic ALS (sALS), using 2-[fluorine-18] fluoro-2-deoxy-D-glucose positron emission tomography (2-[[18]F]FDG-PET).

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

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

INTERPRETATION: Patients with FUS-ALS show relative preservation of motor cortex metabolism compared with those with sALS, possibly reflecting the prevalence of lower motor neuron impairment in their phenotype. Prospective studies are necessary to investigate the possible role of 2-[[18]F]FDG-PET as a biomarker to track disease spreading in clinical trials. ANN NEUROL 2025.}, } @article {pmid39975337, year = {2025}, author = {Zinn, KM and McLaren, MW and Imai, MT and Jayaram, MM and Rothstein, JD and Elrick, MJ}, title = {Enterovirus D68 2A protease causes nuclear pore complex dysfunction and motor neuron toxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.23.632178}, pmid = {39975337}, issn = {2692-8205}, abstract = {The picornavirus Enterovirus D68 (EV-D68) is an important pathogen associated with acute flaccid myelitis (AFM). The pathogenesis of AFM involves infection of spinal motor neurons and motor neuron death, however the mechanisms linking EV-D68 infection to selective neurotoxicity are not well understood. Dysfunction of the nuclear pore complex (NPC) has been implicated in motor neuron injury in neurodegenerative diseases such as amyotrophic lateral sclerosis, and the NPC is also modified by picornavirus proteases during the course of infection. We therefore sought to determine the impact of EV-D68 proteases on NPC structure and function and their role in motor neuron toxicity. We demonstrate widespread disruption of NPC composition by EV-D68 2A and 3C proteases via the direct cleavage of a relatively small number of nucleoporins, notably Nup98 and POM121 by 2A [pro] . Using reporter systems, we demonstrate that 2A [pro] inhibits nuclear import and export of protein cargoes and also disrupts the permeability barrier of the NPC, while having no apparent effect on RNA export. We further show that 2A [pro] is toxic to induced pluripotent stem cell derived motor neurons by demonstrating a rescue of toxicity with 2A [pro] inhibitor telaprevir at concentrations that are insufficient to inhibit viral replication. This study expands our understanding of EV-D68 neuropathogenesis and provides a rationale for targeting the NPC or 2A [pro] therapeutically in AFM.}, } @article {pmid39975323, year = {2025}, author = {Bekier, ME and Pinarbasi, E and Mesojedec, JJ and Ghaffari, L and de Majo, M and Ullian, E and Koontz, M and Coleman, S and Li, X and Tank, EMH and Waksmacki, J and Barmada, S}, title = {Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.27.635090}, pmid = {39975323}, issn = {2692-8205}, abstract = {Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK)-a proline-directed serine/threonine kinase-promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.}, } @article {pmid39975241, year = {2025}, author = {Ghaffari, LT and Welebob, E and Boehringer, A and Cyliax, K and Pasinelli, P and Trotti, D and Haeusler, AR}, title = {Neuronal Activity-Dependent Gene Dysregulation in C9orf72 i [3] Neuronal Models of ALS/FTD Pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.27.632228}, pmid = {39975241}, issn = {2692-8205}, abstract = {The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9orf72 (C9) gene is the most common cause of ALS and FTD. Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE iPSC-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization, or a blockade of K [+] channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared to healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.}, } @article {pmid39973992, year = {2025}, author = {Nassan, M and Ayala, IA and Sloan, J and Bonfitto, A and Stark, B and Song, S and Naymik, M and Geula, C and Gefen, T and Barbieri, E and Piras, IS and Mesulam, MM and Huentelman, MJ}, title = {The genetics of TDP43-Type-C neurodegeneration: a whole genome sequencing study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.25.25320561}, pmid = {39973992}, abstract = {Frontotemporal lobar degeneration-TDP Type C (TDP-C) is a unique neurodegenerative disease that starts by attacking the anterior temporal lobe leading to language and/or behavioral syndromes. Current literature on the genetic associations of TDP-C, which we have reviewed here, is uneven and lacks a discernible corpus of robust findings. In our study, we completed genome wide hypothesis-free analyses utilizing artificial Intelligence (AI) to identify rare and common variants associated with TDP-C. We then investigated ANXA11 and TARDBP in a hypothesis-driven analysis, since it was recently shown that TDP-43 and Annexin A11 co-aggregate in all TDP-C cases. 1) Whole genome sequencing was completed to identify pathogenic rare variants prioritized with Illumina's AI-based Emedgene software on 37 confirmed or probable TDP-C cases from the Northwestern-University Cohort. 2) A genome wide association study was then completed to identify common variants associated with TDP-C cases vs 290 controls. 3) Next, common and rare variants in TARDBP, and ANXA11 were investigated in TDP-C vs controls. These analyses identified novel genetic associations between FIG4 , UBQLN2 , INPP5A , and ANXA11 with TDP-C. Of these FIG4, UBQLN2 and ANXA11 have been associated previously with Amyotrophic lateral sclerosis (ALS). To further assess the observed potential genetic overlap between ALS and TDP-C, we leveraged Mendelian randomization (MR) to assess if the ALS genetic load is associated with TDP-C risk, and found evidence supporting this association. The genetic association of ANXA11 with TDP-C is particularly interesting in view of the recently discovered role of Annexin A11 in forming heterodimers with TDP-43 in all abnormal precipitates, a feature not found in TDP-A or TDP-B, which have no similar predilection for the anterior temporal lobe. In addition to the observed overlap between ALS genetics/ genetic load and TDP-C, it is worth mentioning that FIG4, INPP5A and ANXA11 have been implicated in the inositol metabolism pathway, a feature that remains to be elucidated mechanistically. Our TDP-C genetic literature review identified a surprising paucity of neuropathologically confirmed cases in published investigations. Nonetheless, the literature offers support for some of our findings and reemphasizes the absence of dominant or major pathogenic genes for TDP-C, another feature that sets this neuropathologic entity apart from TDP-A and TDP-B.}, } @article {pmid39973136, year = {2025}, author = {Deng, FY and Zhu, GL and Ou, KL and Zhu, LH and Jia, QQ and Wang, X and Guo, MW and Li, B and Li, SH and Li, XJ and Yin, P}, title = {Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain.}, journal = {Zoological research}, volume = {46}, number = {2}, pages = {263-276}, doi = {10.24272/j.issn.2095-8137.2024.286}, pmid = {39973136}, issn = {2095-8137}, mesh = {Animals ; *RNA, Messenger/metabolism/genetics ; *Brain/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Ribosomes/metabolism/genetics ; *Macaca fascicularis/genetics ; Gene Expression Regulation ; }, abstract = {Cytoplasmic accumulation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. While current studies have primarily focused on gene regulation mediated by full-length nuclear TDP-43, the potential effects of cytoplasmic TDP-43 fragments remain less explored. Our previous findings demonstrated that primate-specific cleavage of TDP-43 contributes to its cytoplasmic localization, prompting further investigation into its pathological effects. In the cynomolgus monkey brain, we observed that mutant or truncated TDP-43 was transported onto the ribosome organelle. Ribosome-associated transcriptomic analysis revealed dysregulation of apoptosis- and lysosome-related genes, indicating that cytoplasmic TDP-43 induces neurotoxicity by binding to ribosomes and disrupting mRNA expression. These findings provide mechanistic insights into the gain-of-function effects of pathological TDP-43.}, } @article {pmid39971904, year = {2025}, author = {Hossain, MA and Brahme, RR and Miller, BC and Amin, J and de Barros, M and Schneider, JL and Auclair, JR and Mattos, C and Wang, Q and Agar, NYR and Greenblatt, DJ and Manetsch, R and Agar, JN}, title = {Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1777}, pmid = {39971904}, issn = {2041-1723}, support = {R01NS065263//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 18-IIA-420//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, mesh = {Humans ; *Drug Development/methods ; *Mass Spectrometry/methods ; *Drug Discovery/methods ; *Decision Trees ; Superoxide Dismutase-1/metabolism/genetics ; Models, Theoretical ; Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors/metabolism ; }, abstract = {Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification; the inherent uncoupling of covalent drug concentration and effect [i.e., uncoupling of pharmacokinetics (PK) and pharmacodynamics (PD)]; and a lack of bioanalytical and modeling methods for determining PK and PD parameters. We present a covalent drug discovery workflow that addresses these limitations. Our bioanalytical methods are based upon a mass spectrometry (MS) assay that can measure the percentage of drug-target protein conjugation (% target engagement) in biological matrices. Further we develop an intact protein PK/PD model (iPK/PD) that outputs PK parameters (absorption and distribution) as well as PD parameters (mechanism of action, protein metabolic half-lives, dose, regimen, effect) based on time-dependent target engagement data. Notably, the iPK/PD model is applicable to any measurement (e.g., bottom-up MS and other drug binding studies) that yields % of target engaged. A Decision Tree is presented to guide researchers through the covalent drug development process. Our bioanalytical methods and the Decision Tree are applied to two approved drugs (ibrutinib and sotorasib); the most common plasma off-target, human serum albumin; three protein targets (KRAS, BTK, SOD1), and to a promising SOD1-targeting ALS drug candidates.}, } @article {pmid39971261, year = {2025}, author = {Álvarez-Aznar, A and Desai, MB and Orlich, MM and Vázquez-Liébanas, E and Adams, RH and Brakebusch, C and Gaengel, K}, title = {Cdc42 is crucial for mural cell migration, proliferation and patterning of the retinal vasculature.}, journal = {Vascular pharmacology}, volume = {}, number = {}, pages = {107472}, doi = {10.1016/j.vph.2025.107472}, pmid = {39971261}, issn = {1879-3649}, abstract = {AIMS: Mural cells constitute the outer lining of blood vessels and are essential for vascular development and function. Mural cell loss or malfunction has been associated with numerous diseases including diabetic retinopathy, stroke and amyotrophic lateral sclerosis. In this work, we investigate the role of CDC42 in mural cells in vivo, using the developing mouse retina as a model.

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

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

CONCLUSIONS: Our findings demonstrate that CDC42 is required for mural cell migration and proliferation and suggest that mural cells are essential for normal morphogenesis and patterning of the developing retinal vasculature.}, } @article {pmid39971210, year = {2025}, author = {Brandstötter, C and Büssing, A and Eham, M and Littger, B and Lorenzl, S and Memmel, M and Paal, P and Bublitz, SK}, title = {Assessment of the spiritual needs of people with Amyotrophic Lateral Sclerosis and their caregivers.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2025.02.012}, pmid = {39971210}, issn = {1873-6513}, abstract = {CONTEXT: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder which poses multidimensional burden to patients and caregivers.

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

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

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

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

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

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

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

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

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

CONCLUSION: Current findings suggest that ALS does not uniformly impact the corticospinal tract and corpus callosum. There is a preferential disease profile of neurodegeneration mainly impacting primary motor fibres. Microstructural white matter abnormality indicated presence of ALS pathology while macrostructural white matter abnormality was associated with severity of functional impairment. Quantification of white matter abnormality in corticospinal tract and callosal subdivisions holds translational potential as an imaging biomarker for neurodegeneration in ALS.}, } @article {pmid39969486, year = {2025}, author = {Alder, J and Chukwuma, C and Farragher, T and Holden Smith, S and Morris, R and Ealing, J and Hamdalla, H and Bentley, A and Bokhari, S and Freeman, D and Al-Chalabi, A and Rog, D and Das, J and Chaouch, A}, title = {Impact of relative deprivation and ethnicity on the incidence rate of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2465609}, pmid = {39969486}, issn = {2167-9223}, abstract = {Objective: This study assessed a sizable cohort of patients with amyotrophic lateral sclerosis (ALS) in a relatively deprived and ethnically diverse area in the northwest of England. We aimed to evaluate the interaction of relative deprivation and ethnicity with the incidence of ALS. Methods: Six hundred and ninety-three adults from Greater Manchester who were diagnosed with ALS between 1 January 2011 and 31 December 2021 were included in this study. Data were collected from electronic patient records. Relative deprivation was estimated using the Index of Multiple Deprivation 2019 and patients were divided into quartiles of deprivation in England. Ethnicity was sub-grouped into White, Southeast Asian, Black, and Other. Poisson's regression analysis was used to calculate the incidence rate and its interactions with deprivation and ethnicity. Results: 55.4% of patients were male, 95.4% were White, 57.4% were in the two most deprived quartiles, and 87.2% had died by the end of the observation period. The crude incidence rate was 2.21 cases per 100,000 (95% CI 2.00-2.40) per year. There was no difference in the adjusted incidence rates among the quartiles of deprivation, even when considering ethnicity as a confounding variable. The risk of ALS in the White population was 2.08 (95% CI 1.47-3.04) times greater than that in the non-White population. Conclusion: In our cohort, relative deprivation was not an independent risk factor for ALS. A stronger association between White ethnicity and ALS was noted. The reason for this association remains unclear, highlighting the need for more research in this field.}, } @article {pmid39967643, year = {2025}, author = {Abdel-Magid, AF}, title = {Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {2}, pages = {204-206}, pmid = {39967643}, issn = {1948-5875}, abstract = {The invention in this patent application relates to 2-amino-[1,2,4]triazolo[1,5-a]pyridin derivatives represented generally herein as formula 1. These compounds have activities as receptor-interacting protein kinase 1 (RIPK1) inhibitors and may potentially provide treatment and/or prophylaxis of inflammatory and neurodegenerative diseases associated with aberrant RIPK1 activity such as ulcerative colitis, Crohn's disease, psoriasis, NASH, heart failure, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.}, } @article {pmid39965449, year = {2025}, author = {Awasthi, S and Tiwari, PC and Awasthi, S and Dwivedi, A and Srivastava, S}, title = {Mechanistic role of proteins and peptides in Management of Neurodegenerative Disorders.}, journal = {Neuropeptides}, volume = {110}, number = {}, pages = {102505}, doi = {10.1016/j.npep.2025.102505}, pmid = {39965449}, issn = {1532-2785}, abstract = {Proteins and peptides have emerged as significant contributors in the management of neurodegenerative disorders due to their diverse biological functions. These biomolecules influence various cellular processes, including cellular repair, inflammation reduction, and neuronal survival, which are crucial for mitigating the effects of diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS). By interacting with specific cellular receptors, proteins and peptides like neurotrophic factors, cytokines, and enzyme inhibitors promote neurogenesis, reduce oxidative stress, and enhance synaptic plasticity. Nevertheless, till certain limitations and challenges do exist to deliver these fragile therapeutic bioactives. Moreover, targeted delivery systems, such as nanoparticles and biomolecular carriers, are being developed to improve the bioavailability and specificity of these protein-based therapeutics, ensuring efficient crossing of the blood-brain barrier. This review explores the mechanistic pathways through which these biomolecules act, emphasizing their potential to modify disease progression and improve the quality of life in patients with neurodegenerative conditions. Overall, proteins and peptides are not only seen as promising therapeutic agents but also as foundational tools in advancing personalized medicine in the field of neurodegenerative disorders.}, } @article {pmid39965330, year = {2025}, author = {Petro, TM and Esmael, A and Pattee, GL and Al-Sarmi, F and Chiodo, F and Agarkova, IV and Dunigan, DD and Van Etten, JL}, title = {Expression of human superoxide dismutase (SOD) 1 G93A and chlorovirus ATCV-1 SOD increases the response of macrophages to inflammatory stimulants, including ATCV-1 major capsid protein glycans.}, journal = {Immunobiology}, volume = {230}, number = {2}, pages = {152881}, doi = {10.1016/j.imbio.2025.152881}, pmid = {39965330}, issn = {1878-3279}, abstract = {One cause of familial Amyotrophic Lateral Sclerosis (ALS) is a mutation in Super Oxide Dismutase 1 (SOD1) whereby amino acid 93 is alanine instead of glycine (SOD1-G93A). Transgenic mice expressing human SOD1-G93A pathogenic variant develop motor neuron disease (MND), similar to ALS. Humans with ALS and SOD1-G93A mice have elevated production of inflammatory cytokines, such as IL-6, which may promote MND. We previously showed that infection with the Chlorovirus Acanthocystis turfacea chlorella virus 1 (ATCV-1), which encodes a SOD1, accelerates onset of MND in these mice and induces macrophages to produce high levels of IL-6. We confirm here that ALS patients compared with healthy controls have significantly elevated levels of plasma IL-6 and Interferon-gamma (IFN-γ), but not IL-17. To determine if expression of ATCV-1 SOD1 or SOD1-G93A in mouse macrophages elevates expression of inflammatory cytokines, we transfected the RAW264.7 mouse macrophage cell line with plasmids encoding ATCV-1 SOD1, wild-type human SOD1, SOD1-G93A, or an empty vector. RAW264.7 cells stably expressing wtSOD1 or G93A-SOD1 were stimulated with poly I:C and Interferon-gamma, alone, or in combination to induce inflammatory factors, such as IL-6 and Nitric Oxide (NO), anti-inflammatory factors, such as IL-10, or activation of Interferon Stimulated Response Elements (ISRE) promoters. After stimulation, production of IL-6 and NO, but not IL-10 or ISRE promoter activity was significantly higher in RAW264.7 cells expressing SOD1-G93A compared with wt SOD1. Moreover, RAW264.7 cells expressing SOD1-G93A compared with wt SOD1 produced higher levels of IL-6 and NO in response to ATCV-1 glycoproteins. Finally, transfection of plasmid encoding ATCV-1 SOD1 into RAW264.7 cells significantly increased expression of inflammatory factors in responses to poly I:C and IFN-γ, primarily in an Interferon regulatory factor 3 (IRF3) dependent fashion. These data clearly show that expression of G93A-SOD1 or ATCV-1 SOD1 in macrophages significantly elevates expression of inflammatory factors following stimulations that mimic virus infection, viral components, or T cell cytokines, thereby suggesting one mechanism by which atypical SOD1 in macrophages can contribute to ALS-MND.}, } @article {pmid39963928, year = {2025}, author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A}, title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.}, journal = {Nanomedicine (London, England)}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/17435889.2025.2461984}, pmid = {39963928}, issn = {1748-6963}, abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.}, } @article {pmid39962920, year = {2025}, author = {}, title = {Correction to "Early Nuclear Phenotypes and Reactive Transformation in Human iPSC-Derived Astrocytes From ALS Patients With SOD1 Mutations".}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.70003}, pmid = {39962920}, issn = {1098-1136}, } @article {pmid39962623, year = {2025}, author = {Caratelli, S and De Paolis, F and Silvestris, DA and Baldari, S and Salvatori, I and Tullo, A and Lanzilli, G and Gurtner, A and Ferri, A and Valle, C and Padovani, S and Cesarini, V and Sconocchia, T and Cifaldi, L and Arriga, R and Spagnoli, GC and Ferrone, S and Venditti, A and Rossi, P and Pesole, G and Toietta, G and Sconocchia, G}, title = {The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody-dependent cytotoxicity.}, journal = {Experimental hematology & oncology}, volume = {14}, number = {1}, pages = {17}, pmid = {39962623}, issn = {2162-3619}, support = {TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; Investigator Grants 2020-24440//Italian Association for Cancer Research (AIRC) Foundation/ ; }, abstract = {BACKGROUND: Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck.

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

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

CONCLUSIONS: CD64/CD28/CD3ζ T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel FcγR ALs in cancer and healthy cells.}, } @article {pmid39961705, year = {2025}, author = {Shah, NM and Kaltsakas, G and Madden-Scott, S and Apps, C and Sheridan, S and Ramsay, M and Srivastava, S and Suh, ES and D'Cruz, R and Mackie, M and Weston, N and Hart, N and Murphy, P}, title = {Mechanical insufflation-exsufflation use in neuromuscular disease: a single centre cohort study.}, journal = {BMJ open respiratory research}, volume = {12}, number = {1}, pages = {}, doi = {10.1136/bmjresp-2024-002651}, pmid = {39961705}, issn = {2052-4439}, mesh = {Humans ; *Insufflation/methods ; *Neuromuscular Diseases/complications ; Middle Aged ; Female ; Retrospective Studies ; Male ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/therapy ; Cohort Studies ; }, abstract = {INTRODUCTION: Mechanical insufflation-exsufflation (MIE) is a commonly used therapy to augment secretion clearance in individuals with neuromuscular disease. There are no clear evidence-based guidelines on the settings that should be used in different diagnostic groups and how they should be titrated. We report on the settings used in the largest cohort of individuals using domiciliary MIE in the literature.

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

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

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

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

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

CONCLUSIONS: We evidenced convergent trajectories of respiratory decline across B-ALS, S-ALS and pLMN, highlighting the utility of multimodal assessments for tracking progressing respiratory disturbances. These findings have potential to accelerate earlier and more tailored respiratory management across diverse MND phenotypes.}, } @article {pmid39960747, year = {2025}, author = {Turnbull, J}, title = {Platform Trials in ALS.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.0100}, pmid = {39960747}, issn = {1538-3598}, } @article {pmid39960672, year = {2025}, author = {Paganoni, S and Fournier, CN and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Ajroud-Driss, S and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Shefner, JM and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and Dagostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Heiman-Patterson, T and Caress, JB and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Harvey, B and Patel, S and Mahoney, P and Duda, PW and Cudkowicz, ME and , }, title = {Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459058}, doi = {10.1001/jamanetworkopen.2024.59058}, pmid = {39960672}, issn = {2574-3805}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; Edaravone/therapeutic use ; }, abstract = {IMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.

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

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

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

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

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

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

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683.}, } @article {pmid39959987, year = {2025}, author = {Lee, D and Shin, Y and Roh, JS and Ahn, J and Jeoong, S and Shin, SS and Yoon, M}, title = {RETRACTED: Lee et al. Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice. Int. J. Mol. Sci. 2020, 21, 4256.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, doi = {10.3390/ijms26041696}, pmid = {39959987}, issn = {1422-0067}, abstract = {The journal retracts the article titled "Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice" [...].}, } @article {pmid39958595, year = {2025}, author = {Arnold, WD and Majithia, K}, title = {Triumphs, Trials, and Future Considerations in Genetic Therapies for Hereditary Neuromuscular Diseases.}, journal = {Missouri medicine}, volume = {122}, number = {1}, pages = {46-52}, pmid = {39958595}, issn = {0026-6620}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neuromuscular Diseases/genetics/therapy ; *Muscular Dystrophy, Duchenne/genetics/therapy ; Amyotrophic Lateral Sclerosis/genetics/therapy ; Muscular Atrophy, Spinal/genetics/therapy ; Precision Medicine/methods/trends ; }, abstract = {Neuromuscular diseases include conditions that affect the spinal motor neurons, peripheral nerves, neuromuscular junctions, and muscles, and they can result from acquired and inherited causes. The number of genetic therapies targeting the inherited causes of neuromuscular diseases has surged in the last decade. This review aims to highlight the current state of genetic therapies within the framework of precision medicine, focusing on the achievements and the gaps that remain. A major emphasis is on spinal muscular atrophy, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis, as these neuromuscular diseases have seen tremendous recent advancements. We will also discuss the future considerations necessary to accelerate the development of next-generation genetic therapies and enhance therapeutic outcomes for patients with neuromuscular diseases.}, } @article {pmid39958549, year = {2025}, author = {Zhang, Y}, title = {Enhancing rectal cancer liver metastasis prediction: Magnetic resonance imaging-based radiomics, bias mitigation, and regulatory considerations.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {2}, pages = {102151}, pmid = {39958549}, issn = {1948-5204}, abstract = {In this article, we comment on the article by Long et al published in the recent issue of the World Journal of Gastrointestinal Oncology. Rectal cancer patients are at risk for developing metachronous liver metastasis (MLM), yet early prediction remains challenging due to variations in tumor heterogeneity and the limitations of traditional diagnostic methods. Therefore, there is an urgent need for non-invasive techniques to improve patient outcomes. Long et al's study introduces an innovative magnetic resonance imaging (MRI)-based radiomics model that integrates high-throughput imaging data with clinical variables to predict MLM. The study employed a 7:3 split to generate training and validation datasets. The MLM prediction model was constructed using the training set and subsequently validated on the validation set using area under the curve (AUC) and dollar-cost averaging metrics to assess performance, robustness, and generalizability. By employing advanced algorithms, the model provides a non-invasive solution to assess tumor heterogeneity for better metastasis prediction, enabling early intervention and personalized treatment planning. However, variations in MRI parameters, such as differences in scanning resolutions and protocols across facilities, patient heterogeneity (e.g., age, comorbidities), and external factors like carcinoembryonic antigen levels introduce biases. Additionally, confounding factors such as diagnostic staging methods and patient comorbidities require further validation and adjustment to ensure accuracy and generalizability. With evolving Food and Drug Administration regulations on machine learning models in healthcare, compliance and careful consideration of these regulatory requirements are essential to ensuring safe and effective implementation of this approach in clinical practice. In the future, clinicians may be able to utilize data-driven, patient-centric artificial intelligence (AI)-enhanced imaging tools integrated with clinical data, which would help improve early detection of MLM and optimize personalized treatment strategies. Combining radiomics, genomics, histological data, and demographic information can significantly enhance the accuracy and precision of predictive models.}, } @article {pmid39958442, year = {2025}, author = {Ozbey, D and Saribas, S and Kocazeybek, B}, title = {Gut microbiota in Crohn's disease pathogenesis.}, journal = {World journal of gastroenterology}, volume = {31}, number = {6}, pages = {101266}, pmid = {39958442}, issn = {2219-2840}, mesh = {Humans ; *Crohn Disease/microbiology/immunology/therapy ; *Gastrointestinal Microbiome ; *Fecal Microbiota Transplantation ; Treatment Outcome ; Intestinal Mucosa/microbiology/immunology/pathology ; Feces/microbiology ; Colon/microbiology/pathology/immunology ; Dysbiosis ; Ileum/microbiology/pathology/immunology ; Animals ; Colitis, Ulcerative/microbiology/therapy/immunology ; }, abstract = {Inflammatory bowel diseases (IBDs) are classified into two distinct types based on the area and severity of inflammation: Crohn's disease (CD) and ulcerative colitis. In CD, gut bacteria can infiltrate mesenteric fat, causing expansion known as creeping fat, which may limit bacterial spread and inflammation but can promote fibrosis. The gut bacteria composition varies depending on whether the colon or ileum is affected. Fecal microbiota transplantation (FMT) transfers feces from a healthy donor to restore gut microbiota balance, often used in IBD patients to reduce inflammation and promote mucosal repair. The use of FMT for CD remains uncertain, with insufficient evidence to fully endorse it as a definitive treatment. While some studies suggest it may improve symptoms, questions about the duration of these improvements and the need for repeated treatments persist. There is a pressing need for methods that provide long-term benefits, as highlighted by Wu et al's research.}, } @article {pmid39957655, year = {2025}, author = {Mombaur, B and Dias, K}, title = {Patient Navigation in Amyotrophic Lateral Sclerosis (ALS): A Potential Approach to Timely Diagnosis.}, journal = {Journal of health care for the poor and underserved}, volume = {36}, number = {1}, pages = {361-374}, doi = {10.1353/hpu.2025.a951602}, pmid = {39957655}, issn = {1548-6869}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Patient Navigation/organization & administration ; Healthcare Disparities ; Delayed Diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) poses challenges for timely diagnosis due to its protean early manifestations and lack of definitive tests. This article explores how patient navigation interventions can expedite diagnosis, particularly for underserved patients who face disproportionately longer delays. Patient navigation has proven effective in reducing disparities in various diseases by providing guidance and support to patients and caregivers. It enhances awareness, facilitates communication with health care providers, and streamlines diagnosis. Drawing from literature on patient navigation in other diseases, this article proposes tailored adaptations for ALS diagnosis and addresses potential implementation barriers and strategies to overcome them. Integrating patient navigation into the ALS diagnostic pathway holds promise for improving efficiency, optimizing outcomes, and reducing health care disparities among underserved populations.}, } @article {pmid39957101, year = {2025}, author = {Kikuchi, K and Yamazaki, Y and Kanekura, K and Hayamizu, Y}, title = {Graphene Biosensor Differentiating Sensitive Interactions between Ribonucleic Acid and Dipeptide Repeats in Liquid-Liquid Phase Separation.}, journal = {ACS applied materials & interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.4c15382}, pmid = {39957101}, issn = {1944-8252}, abstract = {Liquid-Liquid Phase Separation (LLPS) plays a crucial role in cell biology and is closely associated with neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Recent studies connect mutations in the C9ORF72 gene to the production of arginine-rich dipeptide repeat proteins (R-DPRs), such as poly(PR) and poly(GR). These R-DPRs disrupt LLPS in membrane-less organelles (MLOs) and contribute to disease pathology. While traditional analysis techniques like nuclear magnetic resonance (NMR), fluorescence recovery after photobleaching (FRAP), and Förster resonance energy transfer (FRET) provide insights into LLPS's role in these diseases, their ability is limited in detecting weak intermolecular interactions within LLPS droplets. This study employs graphene field-effect transistors (GFETs) for their superior sensitivity in detecting these molecular interactions. We immobilized RNA (poly-A) on GFETs and measured the electrical conductivity of GFETs to characterize shifts in the voltage of the charge neutral point in GFETs, allowing for the detection of dipeptide repeat peptides, such as (PR)12, (GR)12, and R12. Our results show that interactions between peptides and RNA require a specific peptide concentration threshold and vary between peptide types. Notably, the minimal conductivity shift suggests that peptides containing proline residues exhibit a nonuniform spatial distribution during interactions with RNA on graphene surfaces. This finding indicates that peptide rigidity induced by prolines plays a vital role in these molecular interactions and their multivalent contacts with RNA, which agrees with findings reported in other recent works. The capability of GFETs to detect these interactions at nanomolar concentrations marks a significant advancement in sensitivity over existing methods. This research sheds light on the mechanisms of LLPS involving R-DPRs and opens avenues for further understanding of related neurodegenerative diseases.}, } @article {pmid39956874, year = {2025}, author = {Demaegd, KC and Kernan, A and Cooper-Knock, J and van Vugt, JJFA and Harvey, C and Moll, T and O'Brien, D and Gornall, S and Drury, L and Farhan, SMK and Dion, PA and Rouleau, GA and Western, A and Parsons, PJ and Mclean, B and Benatar, M and van den Berg, LH and Van Damme, P and Willem Dankbaar, J and Hendrikse, J and Koole, W and de Bie, C and Hobson, E and Veldink, JH and van de Warrenburg, B and Pasterkamp, RJ and van Rheenen, W and Kirby, J and Shaw, PJ and van Es, MA}, title = {An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {39956874}, issn = {1476-5438}, support = {216596/Z/19/Z//Wellcome Trust (Wellcome)/ ; 899-792//Motor Neurone Disease Association (MNDA)/ ; 974-797//Motor Neurone Disease Association (MNDA)/ ; 972-797//Motor Neurone Disease Association (MNDA)/ ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 and with TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length expansion of 31-33 CAG-repeats is associated with sporadic ALS and a full length expansion of ≥34 CAG-repeats is associated with SCA2. We report the clinical phenotype of ATXN2-positive patients and their relatives, identified in three specialist ALS clinics, which force a reconsideration of this dichotomy. We also report the frequency of ATXN2 expansions in two large cohorts of ALS patients and in a population-matched cohort of controls. We report ten cases of familial ALS in which disease is associated with either an intermediate or a full-length ATXN2 CAG-repeat expansion. Pedigrees and patients feature additional phenotypes including parkinsonism, dementia and essential tremor (ET). We conclude that CAG-repeat expansions in ATXN2 exhibit pleiotropy and are associated with a disease spectrum that includes ALS, SCA2, and parkinsonism; to recognise this complexity we propose the new term 'ATXN2-related neurodegeneration'. We also observed sporadic ALS associated with full-length expansions. We conclude that ATXN2 CAG-repeat expansions, irrespective of length, should be considered a risk factor for ALS. Interrupted CAG-repeats were associated with an ALS phenotype in our data but we also identified ALS cases with uninterrupted expansions. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.}, } @article {pmid39956001, year = {2025}, author = {Romero-Gavilán, F and Cerqueira, A and García-Arnáez, I and Scalschi, L and Vicedo, B and Azkargorta, M and Elortza, F and Izquierdo, R and Gurruchaga, M and Goñi, I and Suay, J}, title = {Proteomic evaluation of borosilicate hybrid sol-gel coatings with osteogenic, immunomodulatory and antibacterial properties.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {250}, number = {}, pages = {114561}, doi = {10.1016/j.colsurfb.2025.114561}, pmid = {39956001}, issn = {1873-4367}, abstract = {Silica hybrid sol-gel coatings represent an interesting approach to bioactivate dental implants. Boron is known for its osteogenic, angiogenic and antibacterial functions in biomedical applications. This study describes the synthesis of a novel borosilicate hybrid sol-gel coating using a mixture of methyltrimethoxysilane, tetraethyl orthosilicate and trimethyl borate (TMB). Coatings with different amounts of boron were obtained, and their physiochemical properties were examined; in vitro tests with human osteoblasts and macrophages (THP-1) were carried out. The effects of these materials on bacteria viability were evaluated using Escherichia coli and Staphylococcus aureus. The human serum proteins adsorbed onto the coatings were analysed employing proteomic techniques. To synthesise the new materials, the appropriate sol-gel reactions were developed; boron was integrated into the silica network, and well-adhering coatings were obtained. These borosilicate coatings were non-cytotoxic, displayed osteogenic potential, and upregulated adsorption of proteins related to bone regeneration (IGF2, ALS and APOE). Boron upregulated the expression of TNF-α, INFg and TGF-β and increased the TNF-α and TGF-β cytokine production in THP-1. Moreover, the addition of boron caused downregulation of NOX2 expression. Proteomic analysis revealed that boron-doping reduced the adsorption of immunoglobulins and complement system proteins. It also caused an increase in the levels of apolipoproteins, antioxidant proteins and serum amyloid A proteins, which was in agreement with in vitro results. The coatings with 10 and 20 % TMB displayed antibacterial effect against S. aureus. The results of this study will enhance our comprehension of interactions between boron-containing biomaterials and biological systems.}, } @article {pmid39955058, year = {2025}, author = {Paul, S and Dansithong, W and Figueroa, KP and Gandelman, M and Hivare, P and Scoles, DR and Pulst, SM}, title = {Staufen2 dysregulation in neurodegenerative disease.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {108316}, doi = {10.1016/j.jbc.2025.108316}, pmid = {39955058}, issn = {1083-351X}, abstract = {Staufen2 (STAU2) is an RNA binding protein that controls mRNA trafficking and expression. Previously, we showed that its paralog Staufen1 (STAU1) was overabundant in cellular and mouse models of neurodegenerative diseases and amyotrophic lateral sclerosis (ALS) patient spinal cord. Here we investigated features of STAU2 that might parallel STAU1. STAU2 protein, but not mRNA, was overabundant in spinocerebellar ataxia type 2 (SCA2), ALS/frontotemporal dementia (FTD) patient fibroblasts, ALS patient spinal cord tissues, and in central nervous system (CNS) tissues from SCA2 and ALS animal models. Exogenous expression of STAU2 in HEK293 cells activated mechanistic target of rapamycin (mTOR) and stress granule formation. Targeting STAU2 by RNAi normalized mTOR in SCA2 and C9ORF72 cellular models. The microRNA miR-217, previously identified as downregulated in SCA2 mice, targets the STAU2 3'-UTR. We now demonstrate that exogenous expression of miR-217 significantly reduced STAU2 and mTOR levels in cellular models of neurodegenerative disease. These results suggest a functional link between STAU2 and mTOR signaling and identify a major role for miR-217 that could be exploited in therapeutic development.}, } @article {pmid39954969, year = {2025}, author = {Utami, KH and Morimoto, S and Mitsukura, Y and Okano, H}, title = {The roles of intrinsically disordered proteins in neurodegeneration.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {}, number = {}, pages = {130772}, doi = {10.1016/j.bbagen.2025.130772}, pmid = {39954969}, issn = {1872-8006}, abstract = {Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.}, } @article {pmid39954940, year = {2025}, author = {Satao, KS and Doshi, GM}, title = {Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders.}, journal = {Life sciences}, volume = {}, number = {}, pages = {123468}, doi = {10.1016/j.lfs.2025.123468}, pmid = {39954940}, issn = {1879-0631}, abstract = {Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.}, } @article {pmid39954710, year = {2025}, author = {Nadeem, ZA and Ahmed, S}, title = {Amyotrophic lateral sclerosis and lovastatin: a promising treatment perspective.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2025.2463943}, pmid = {39954710}, issn = {2167-9223}, } @article {pmid39954573, year = {2025}, author = {Kiernan, MC and Timmins, HC}, title = {Utility of the Gold Coast criteria for amyotrophic lateral sclerosis: Experience with fast progressors.}, journal = {Journal of the neurological sciences}, volume = {470}, number = {}, pages = {123417}, doi = {10.1016/j.jns.2025.123417}, pmid = {39954573}, issn = {1878-5883}, } @article {pmid39894369, year = {2025}, author = {Jairath, N and Manduca, S and Que, SKT}, title = {Response to Wang et al's limitations and risks of custom GPTs in dermatology. Comment on "ReconGPT: A novel artificial intelligence tool and its potential use in post-Mohs reconstructive decision-making".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.072}, pmid = {39894369}, issn = {1097-6787}, } @article {pmid39884579, year = {2025}, author = {Liu, WW and Wei, JC}, title = {Response to Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.12.044}, pmid = {39884579}, issn = {1097-6787}, } @article {pmid39954119, year = {2025}, author = {Jacobsen, AB and Fanella, G and de Carvalho, M and Koltzenburg, M and Oliveira Santos, M and Cengiz, B and Blicher, J and Obál, I and Heintzelmann, MB and Nix, W and Camdessanché, JP and Fuglsang-Frederiksen, A and Tankisi, H}, title = {Variability of the Penn upper motor neuron score in amyotrophic lateral sclerosis: need for a revised score.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {208}, pmid = {39954119}, issn = {1432-1459}, support = {R346-2020-1946//Lundbeck Foundation/ ; R392-2022-699//Lundbeck Foundation/ ; J.nr.23-2B-12533//Aage og Johanne Louis-Hansens Fond/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Aged ; Middle Aged ; Reproducibility of Results ; Aged, 80 and over ; *Severity of Illness Index ; Observer Variation ; Motor Neurons/pathology/physiology ; }, abstract = {There is a need for a consensus on a clinical scale for evaluating upper motor neuron (UMN) burden in amyotrophic lateral sclerosis (ALS) to improve consistency in clinical diagnosis, research and monitoring of disease progression. The Penn upper motor neuron score (PUMNS) is the most commonly published scale, however, the reliability of the scale has only been evaluated in a single study involving two raters. The objective of this study was to evaluate the inter-rater reliability of the PUMNS in ALS patients among multiple raters, and to discuss an updated UMN score including the signs with the highest inter-rater reliability. This study included seven ALS patients (mean age: 71 ± 11.5, six males, one female). Each patient was evaluated with the PUMNS by eight raters from different centers blinded to previous observations. The intra-class correlation coefficient (ICC) was calculated to assess the inter-rater reliability of the total PUMNS. The inter-rater reliability of the binary subscores was assessed with Gwet's AC1 coefficient. The inter-rater agreement for the total PUMNS yielded an ICC of 0.81 (95% CI 0.56;0.96). Items with the highest inter-rater reliability included Hoffman's sign, Babinski's sign, clonus and deep tendon reflexes, while the facial reflex (Gwet's AC1 -0.038 (95% CI -0.25,0.18)) and crossed adduction (0.18 (95% CI (-0.32,0.67)) had the lowest inter-rater reliability. In conclusion, PUMNS demonstrated good inter-rater reliability overall, while some of the subscores had poor inter-rater reliability. Based on this, we call for an updated UMN score to enhance diagnostic accuracy and research consistency in ALS.}, } @article {pmid39954028, year = {2025}, author = {Al Ojaimi, Y and Vallet, N and Dangoumau, A and Lanznaster, D and Bruno, C and Lefevre, A and Osman, S and Dupuy, C and Emond, P and Vourc'h, P and Corcia, P and Krupova, Z and Veyrat-Durebex, C and Blasco, H}, title = {Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {21}, pmid = {39954028}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Male ; Middle Aged ; Female ; Aged ; Biomarkers/blood ; Extracellular Vesicles/metabolism ; Proteome/metabolism ; Metabolome ; Adult ; Proteomics/methods ; Case-Control Studies ; Lipid Metabolism ; Exosomes/metabolism ; }, abstract = {The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage. Serum EVs were obtained from 9 healthy controls and 9 ALS patients. After EV purification, proteomic (LC‒MS/MS followed by TimsTOF Pro Mass Spectrometry) and metabolomic (Q Exactive mass spectrometer) analyses were performed. No differences in the size or concentration of EVs were observed between the controls and ALS patients. Proteomic analysis revealed 45 proteins differentially expressed in the EVs of ALS patients compared with those of controls. Metabolomic analysis revealed several distinctly represented metabolites involved in the citrate cycle and complex lipid metabolism between patients and controls. Interomics correlation analysis revealed 2 modules that were strongly associated with ALS and included several lipid metabolism-related proteins and metabolites. This study is the first to evaluate EVs by integrated proteomics and metabolomics in early-stage ALS patients, highlighting the technological progress in global inter-omics explorations of small biological samples. The differences observed in the levels of several exosomal proteins and metabolites, including phospholipids, could be used to identify serum biomarkers and novel players involved in ALS pathogenesis.}, } @article {pmid39953725, year = {2025}, author = {Nishida, K and Sakashita, K and Futamura, N}, title = {Decision-making trends in therapeutic interventions for multiple system atrophy: a 24-year retrospective study.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.70000}, pmid = {39953725}, issn = {2330-1619}, support = {JPMH23FC1010//the Ministry of Health, Labour and Welfare, Japan/ ; }, abstract = {BACKGROUND: Managing multiple system atrophy (MSA) is challenging. While invasive interventions for amyotrophic lateral sclerosis are well-studied, those for MSA remain less explored.

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

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

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

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

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

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

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

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

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

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

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

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

CONCLUSION: In patients with shockable OHCA who received 5 or more defibrillation attempts, a dose of amiodarone 300 mg was associated with a similar survival compared with a total dose of amiodarone 450 mg. Further study is needed to evaluate the need for a second administration of amiodarone in patients with shockable OHCA.}, } @article {pmid39947099, year = {2025}, author = {Tan, HHG and Nitert, AD and van Veenhuijzen, K and Dukic, S and van Zandvoort, MJE and Hendrikse, J and van Es, MA and Veldink, JH and Westeneng, HJ and van den Berg, LH}, title = {Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103749}, doi = {10.1016/j.nicl.2025.103749}, pmid = {39947099}, issn = {2213-1582}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.

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

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

CONCLUSIONS: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.}, } @article {pmid39946662, year = {2025}, author = {Cordts, I and Fuetterer, C and Wachinger, A and von Heynitz, R and Kessler, T and Freigang, M and Quinten, AL and Bjelica, B and Brakemeier, S and Hobbiebrunken, E and Hagenacker, T and Petri, S and Koch, JC and Hahn, A and Lingor, P and Deschauer, M and Günther, R and Weiler, M and Haller, B and Feneberg, E}, title = {Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen.}, journal = {Neurology}, volume = {104}, number = {5}, pages = {e213371}, doi = {10.1212/WNL.0000000000213371}, pmid = {39946662}, issn = {1526-632X}, mesh = {Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Male ; Female ; Adult ; *Oligonucleotides/therapeutic use ; Retrospective Studies ; Middle Aged ; *Muscular Atrophy, Spinal/drug therapy/blood/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.

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

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

DISCUSSION: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.}, } @article {pmid39946043, year = {2025}, author = {Patnana, DP and Kanikaram, SP and Kumar, P and Cheerala, VSK and Sivaramakrishnan, V and Tripathi, P and Chandra, BP}, title = {Simultaneous determination of polycyclic aromatic hydrocarbons, their derivatives, and phthalic acid esters bound to ambient PM2.5 during pre-summer season in Bengaluru, India, and potential effect on protein aggregation diseases.}, journal = {Environmental science and pollution research international}, volume = {}, number = {}, pages = {}, pmid = {39946043}, issn = {1614-7499}, abstract = {Air pollution pertaining to particulate matter (PM) is a major issue in most of the metropolitan cities across the world. Inhalation exposure to organic species like polycyclic aromatic hydrocarbons (PAHs), derivatives of PAHs (oxygenated and nitrated PAHs), and phthalic acid esters (PAEs) bound to PM is of major concern owing to its carcinogenic, mutagenic, and endocrine disrupting nature. In this study for the first time, we report a total of 22 aromatic organic species which include PAHs, derivatives of PAHs, and PAEs using an optimized high-performance liquid chromatography coupled to the tandem mass spectrometer (HPLC-MS/MS) method. Further, this optimized method was used to carry out the measurements of the 22 targeted organic constituents bound to the ambient fine particulate matter (PM2.5) collected in Bengaluru, a metropolitan city in India as a part of a pilot study during the pre-summer season. Among the reported compounds, benzo[b]fluoranthene (3.82 ng m[-3]), 9-nitroanthracene (10.47 ng m[-3]), and diethyl phthalate (5.38 ng m[-3]) are the most abundant PAHs, the derivatives of PAHs, and PAEs, respectively. Determined diagnostic ratios of PAHs have shown that the sampling site is majorly influenced by traffic emissions. Benzo[a]pyrene, a Group 1 carcinogen has occasionally exceeded the limits set by National Ambient Air Quality Standards (NAAQs), India during the sampling period. Further, a preliminary study was performed using a yeast model of amyotrophic lateral sclerosis (ALS) expressing transactive response DNA binding protein 43 (TDP43) and we demonstrated that commonly reported organics such as PAHs and PAEs bound to PM2.5 have induced significantly elevated aggregation in wild type TDP43. Preliminary results of this study indicate that there is a need for further detailed health risk assessment due to inhalation exposure of organic constituents bound to the ambient PM in Bengaluru.}, } @article {pmid39945358, year = {2025}, author = {Badger, SE and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Moutin, C and Mohd Imran, K and Day, JC and Cooper-Knock, J and Mead, RJ and Alix, JJP}, title = {A bacterial artificial chromosome mouse model of amyotrophic lateral sclerosis manifests 'space cadet syndrome' on two FVB backgrounds.}, journal = {Disease models & mechanisms}, volume = {18}, number = {2}, pages = {}, doi = {10.1242/dmm.052221}, pmid = {39945358}, issn = {1754-8411}, support = {Alix/Apr19/871-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //University of Sheffield/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Disease Models, Animal ; *C9orf72 Protein/genetics ; *Mice, Transgenic ; *Chromosomes, Artificial, Bacterial/genetics ; *Phenotype ; Frontotemporal Dementia/genetics/pathology ; Mice ; Humans ; Syndrome ; }, abstract = {C9orf72-related amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) has proven difficult to model in mice. Liu et al. (2016) reported a bacterial artificial chromosome (BAC) transgenic mouse displaying behavioural, motor and pathological abnormalities. This was followed by multiple laboratories independently refuting and confirming phenotypes. A proposed explanation centred on the use of different FVB background lines (from The Jackson Laboratory and Janvier Labs). We studied C9orf72 BAC mice on both backgrounds and found significantly elevated levels of dipeptide repeat proteins, but no evidence of a transgene-associated phenotype. We observed seizures and a gradual decline in functional performance in transgenic and non-transgenic mice, irrespective of genetic background. The phenotype was in keeping with the so-called 'space cadet syndrome'. Our findings indicate that the differences previously reported are not due to C9orf72 status and highlight the importance of using genetic backgrounds that do not confound interpretation of neurodegenerative phenotypes.}, } @article {pmid39944773, year = {2025}, author = {Cheng, R and Dimitriou, D and Yao, G and Li, X and Lv, X and Yang, Y and Ying, H and Wang, Z and Tsai, TY}, title = {Outperformance of Combined Artificial Anterolateral Ligament and ACL Reconstruction Compared With Isolated Artificial ACL Reconstruction in Knees With Anterolateral Structure and ACL Deficiency: A Biomechanical Analysis.}, journal = {Orthopaedic journal of sports medicine}, volume = {13}, number = {2}, pages = {23259671241309270}, pmid = {39944773}, issn = {2325-9671}, abstract = {BACKGROUND: Despite the promising clinical outcomes of artificial polyethylene terephthalate (PET) ligaments in isolated anterior cruciate ligament reconstruction (ACLR), their biomechanical performance after combined anterolateral ligament reconstruction (ALLR)/ACLR in anterolateral structure (ALS)/anterior cruciate ligament (ACL)-deficient knees has not been investigated.

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

STUDY DESIGN: Controlled laboratory study.

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

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

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

CLINICAL RELEVANCE: The indications of the artificial PET ligament may be expanded to include combined ALLR/ACLR to restore knee stability better than isolated artificial ACLR in ALS/ACL-deficient knees.}, } @article {pmid39944166, year = {2025}, author = {Islam, S and Noorani, A and Sun, Y and Michikawa, M and Zou, K}, title = {Multi-functional role of apolipoprotein E in neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1535280}, pmid = {39944166}, issn = {1663-4365}, abstract = {Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as the major susceptibility genetic risk factor for sporadic Alzheimer's disease (SAD). Specifically, the ApoEε4 allele is a significant risk factor for SAD, while ApoEε2 allele provides protection compared to the more common ApoEε3 allele. This review discusses the role of the ApoE in AD and other neurodegenerative disorders. ApoE, a cholesterol transport protein, influences several pathways involved in neurodegeneration, particularly in AD. Beyond its established role in amyloid β-protein (Aβ) metabolism and deposition, ApoE also impacts tau pathology, neurodegeneration, and the microglial response to AD. The review aims to provide an updated overview of ApoE's diverse roles, emphasizing its involvement in Aβ clearance through ApoE receptors. It also covers ApoE's influence in other neurodegenerative diseases like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington's disease (HD), vascular dementia (VD), and multiple sclerosis (MS). New research highlights the interaction between ApoE and presenilin (PS), suggesting connections between familial AD (FAD) and SAD. The review also explores protective effects of ApoE mutations against AD and ApoE4-induced tauopathy, neurodegeneration, and neuroinflammation. The insights from this comprehensive update could indeed lead to new therapeutic strategies for neurodegenerative diseases.}, } @article {pmid39944085, year = {2025}, author = {Sakurai, H and Suzuki, M and Asakura, A}, title = {Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1556403}, pmid = {39944085}, issn = {2296-634X}, } @article {pmid39942798, year = {2025}, author = {Długosz, A and Błaszak, B and Czarnecki, D and Szulc, J}, title = {Mechanism of Action and Therapeutic Potential of Xanthohumol in Prevention of Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, doi = {10.3390/molecules30030694}, pmid = {39942798}, issn = {1420-3049}, mesh = {*Propiophenones/pharmacology/therapeutic use ; *Flavonoids/pharmacology/chemistry/therapeutic use ; Humans ; *Neurodegenerative Diseases/prevention & control/drug therapy/metabolism ; Animals ; Antioxidants/pharmacology/therapeutic use ; Alzheimer Disease/prevention & control/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism/prevention & control ; Humulus/chemistry ; }, abstract = {Xanthohumol (XN), a bioactive plant flavonoid, is an antioxidant, and as such, it exhibits numerous beneficial properties, including anti-inflammatory, antimicrobial, and antioxidative effects. The main dietary source of XN is beer, where it is introduced through hops. Although the concentration of XN in beer is low, the large quantities of hop-related post-production waste present an opportunity to extract XN residues for technological or pharmaceutical purposes. The presented study focuses on the role of XN in the prevention of neurodegenerative diseases, analyzing its effect at a molecular level and including its signal transduction and metabolism. The paper brings up XN's mechanism of action, potential effects, and experimental and clinical studies on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Additionally, challenges and future research directions on XN, including its bioavailability, safety, and tolerance, have been discussed.}, } @article {pmid39942481, year = {2025}, author = {Kavanaugh, MS and Zawadzki, MJ and Johnson, KT and Boville, MR}, title = {Moments of Care: Perceptions of Young Carers and Day-to-Day Well-Being.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, doi = {10.3390/healthcare13030292}, pmid = {39942481}, issn = {2227-9032}, abstract = {Background/Objectives: Over 5 million youth under the age of 19 provide daily, hands-on care to an ill or injured family member across the United States. Yet how these young carers perceive the care they deliver in the moment, and how these perceptions relate to well-being, is unexplored, particularly in complex neurological conditions. This paper presents initial data on young carers for a family member with amyotrophic lateral sclerosis (ALS). Methods: Ecological momentary assessment (EMA) was used to measure perceptions of care in the moments of care and the cognitive and emotional states of the young carers during those moments. Young carers (n = 15) aged 10-19 were followed for seven days, completing assessments three times per day, which provided 260 total measurements. Young carers reported frequently engaging in caregiving (~39% of assessments). Results: The results indicated that it was not simply performing a caregiving task that related to outcomes, but rather how caregiving moments were perceived that mattered. Caregiving moments perceived as more fulfilling resulted in young carers feeling less discontent and more focused, whereas caregiving moments perceived as lacking resources predicted more discontent and distress. Exploratory analyses highlighted the potential for burden for young carers. They reported high levels of worry when they were not around the care recipient, with this worry predicting feeling more discontent and distressed. Conclusions: Young carers are deeply involved in care and perceive care differently across moments, both positive and negative. These initial data can be used to develop targeting support programs in the moment of care, potentially lessening the negative impacts of care.}, } @article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031333}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/metabolism ; *Vitamins/therapeutic use ; Dietary Supplements ; Animals ; Alzheimer Disease/prevention & control/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, } @article {pmid39941012, year = {2025}, author = {Sonkodi, B}, title = {PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031246}, pmid = {39941012}, issn = {1422-0067}, mesh = {Humans ; *Ion Channels/metabolism ; Animals ; Protons ; Central Nervous System Sensitization ; Pain/metabolism/physiopathology ; Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Pain Threshold ; }, abstract = {The current opinion manuscript posits that not only Piezo2 voltage block, but also proton affinity and availability in relation to Piezo2, a mechanically gated ion channel, may count in the mediation of pain and its sensitivity. Moreover, this paper argues that autonomously acquired Piezo2 channelopathy on somatosensory terminals is likely the initiating peripheral impaired input source that drives the central sensitization of spinal nociceptive neurons on the chronic path as being the autonomous pain generator. In parallel, impaired proprioception and the resultant progressive deficit in neuromuscular junctions of motoneurons might be initiated on the chronic path by the impairment of the proton-based ultrafast proprioceptive feedback to motoneurons due to disconnection through vesicular glutamate transporter 1. The irreversible form of this autonomously acquired Piezo2 ion channel microdamage, in association with genetic predisposition and/or environmental risk factors, is suggested to lead to progressive motoneuron death in addition to loss of pain sensation in amyotrophic lateral sclerosis. Furthermore, the impairment of the proton-based ultrafast long-range oscillatory synchronization to the hippocampus through vesicular glutamate transporter 2 may gain further importance in pain modulation and formation on the chronic path. Overall, this novel, unaccounted Piezo2-initiated protonic extrafast signaling, including both the protonic ultrafast proprioceptive and the rapid nociceptive ones, within the nervous system seems to be essential in order to maintain life. Hence, its microdamage promotes neurodegeneration and accelerates aging, while the complete loss of it is incompatible with life sustainment, as is proposed in amyotrophic lateral sclerosis.}, } @article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26031199}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Protein Multimerization ; alpha-Synuclein/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; Neurodegenerative Diseases/metabolism/diagnosis ; Protein Aggregates ; DNA-Binding Proteins/metabolism/chemistry ; tau Proteins/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, } @article {pmid39940644, year = {2025}, author = {Lee, AJB and Bi, S and Ridgeway, E and Al-Hussaini, I and Deshpande, S and Krueger, A and Khatri, A and Tsui, D and Deng, J and Mitchell, CS}, title = {Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, doi = {10.3390/ijms26030872}, pmid = {39940644}, issn = {1422-0067}, support = {R35GM152245/NH/NIH HHS/United States ; 1944247//National Science Foundation/ ; 253558//Chan Zuckerberg Initiative/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy/pathology ; Animals ; *Homeostasis ; Mice ; *Mice, Transgenic ; *Disease Models, Animal ; Humans ; Disease Progression ; Superoxide Dismutase-1/genetics/metabolism ; Computer Simulation ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.}, } @article {pmid39939579, year = {2025}, author = {Zhou, T and Solis, NV and Marshall, M and Yao, Q and Pearlman, E and Filler, SG and Liu, H}, title = {Fungal Als proteins hijack host death effector domains to promote inflammasome signaling.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1562}, pmid = {39939579}, issn = {2041-1723}, support = {R01GM117111//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01EY036478//U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)/ ; }, mesh = {*Inflammasomes/metabolism ; Humans ; *Caspase 8/metabolism ; *Fas-Associated Death Domain Protein/metabolism/genetics ; Animals ; *Fungal Proteins/metabolism/genetics ; *Signal Transduction ; *Candida albicans/metabolism ; Mice ; *Interleukin-1beta/metabolism ; Jurkat Cells ; Protein Domains ; Apoptosis ; Macrophages/metabolism/microbiology ; CARD Signaling Adaptor Proteins/metabolism/genetics ; }, abstract = {High-damaging Candida albicans strains tend to form hyphae and exacerbate intestinal inflammation in ulcerative colitis patients through IL-1β-dependent mechanisms. Fungal agglutinin-like sequence (Als) proteins worsen DSS-induced colitis in mouse models. FADD and caspase-8 are important regulators of gut homeostasis and inflammation. However, whether they link directly to fungal proteins is not fully understood. Here, we report that Als proteins induce IL-1β release in immune cells. We show that hyphal Als3 is internalized in macrophages and interacts with caspase-8 and the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC). Caspase-8 is essential for Als3-mediated ASC oligomerization and IL-1β processing. In non-immune cells, Als3 is associated with cell death core components FADD and caspase-8. N-terminal Als3 (N-Als3) expressed in Jurkat cells partially inhibits apoptosis. Mechanistically, N-Als3 promotes oligomerization of FADD and caspase-8 through their death effector domains (DEDs). N-Als3 variants with a mutation in the peptide-binding cavity or amyloid-forming region are impaired in DED oligomerization. Together, these results demonstrate that DEDs are intracellular sensors of Als3. This study identifies additional potential targets to control hypha-induced inflammation.}, } @article {pmid39938954, year = {2025}, author = {Flügel, V and Hering, T and Dadaczynski, K}, title = {Development and validation of a questionnaire on parental health literacy in the context of promoting healthy lifestyles during childhood: a study protocol.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e088037}, doi = {10.1136/bmjopen-2024-088037}, pmid = {39938954}, issn = {2044-6055}, mesh = {Humans ; *Health Literacy ; Surveys and Questionnaires ; *Parents ; Child ; *Health Promotion/methods ; *Healthy Lifestyle ; Child, Preschool ; Reproducibility of Results ; Research Design ; Female ; Male ; Factor Analysis, Statistical ; }, abstract = {INTRODUCTION: Becoming a parent presents profound changes and numerous challenges, notably the necessity for reliable information regarding their child's health. Given the overabundance of information available today, it is important for parents to acquire the skills necessary to find, understand, evaluate and apply health information. Research demonstrates that this ability, known as parental health literacy (PHL), is crucial for developing and maintaining a healthy lifestyle during childhood. However, there is currently no reliable instrument for measuring PHL in the field of prevention and health promotion. This paper presents the development and validation of a new questionnaire designed to assess parents' ability to process health-related information to support the healthy development of their children aged 3-6 years.

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

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

TRIAL REGISTRATION NUMBER: DRKS00033482.}, } @article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The Antioxidant Role of Aromatic Plant Extracts in Managing Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Brain research bulletin}, volume = {}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, } @article {pmid39937422, year = {2025}, author = {Grassano, M and Chiò, A}, title = {microRNA in ALS: finally ready for prime time?.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39937422}, issn = {1590-3478}, } @article {pmid39936986, year = {2025}, author = {Ramírez, OA and Hellwig, A and Zhang, Z and Bading, H}, title = {Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage.}, journal = {Cells}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/cells14030195}, pmid = {39936986}, issn = {2073-4409}, mesh = {*Receptors, N-Methyl-D-Aspartate/metabolism ; *Dendrites/drug effects/metabolism ; Animals ; *TRPM Cation Channels/metabolism ; *Mitochondria/metabolism/drug effects ; *Signal Transduction/drug effects ; Endoplasmic Reticulum/metabolism/drug effects ; Humans ; Calcium/metabolism ; Organelles/metabolism/drug effects ; Neurons/drug effects/metabolism/pathology ; Rats ; N-Methylaspartate/pharmacology/toxicity ; Calcium Signaling/drug effects ; }, abstract = {Focal swellings of dendrites ("dendritic blebbing") together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called "overactivation" of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein-protein complex with TRPM4, drives these pathological traits. In contrast, strong activation of synaptic NMDARs fails to induce cell damage despite evoking plateau-type calcium signals that are comparable to those generated by activation of the NMDAR/TRPM4 complex, indicating that high intracellular calcium levels per se are not toxic to neurons. Using confocal laser scanning microscopy and transmission electron microscopy, we show that disrupting the NMDAR/TRPM4 complex using the recently discovered small-molecule TwinF interface inhibitor FP802 inhibits the NMDA-induced neurotoxicity-associated dendritic blebbing and structural damage to mitochondria and the ER. It also prevents, at least in part, the disruption of ER-mitochondria contact sites. These findings establish the NMDAR/TRPM4 complex as the trigger for the structural damage of dendrites and intracellular organelles associated with excitotoxicity. They also suggest that activation of the NMDAR/TRPM4 complex, in addition to inducing high-amplitude, plateau-type calcium signals, generates a second signal required for glutamate neurotoxicity ("two-hit hypothesis"). As structural damage to organelles, particularly mitochondria, is a common feature of many human neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS), TwinF interface inhibitors have the potential to provide neuroprotection across a broad spectrum of these diseases.}, } @article {pmid39936815, year = {2025}, author = {Mendes, RA and Lima, ILB and Dourado Júnior, MET and Gonçalves, MJ}, title = {Is there a decline in speech and swallowing in Amyotrophic Lateral Sclerosis over ten years?.}, journal = {CoDAS}, volume = {37}, number = {2}, pages = {e20240159}, doi = {10.1590/2317-1782/e20240159pt}, pmid = {39936815}, issn = {2317-1782}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Retrospective Studies ; *Deglutition Disorders/physiopathology/etiology ; Middle Aged ; Longitudinal Studies ; *Disease Progression ; Aged ; Speech Disorders/etiology/physiopathology ; Adult ; Dysarthria/etiology/physiopathology ; Deglutition/physiology ; Time Factors ; Cohort Studies ; }, abstract = {PURPOSE: To analyze the evolution of speech and swallowing decline in patients with amyotrophic lateral sclerosis (ALS) over a ten-year period.

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

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

CONCLUSION: There is a decline in speech and swallowing over ten years in ALS. The bulbar type leads to a faster decline in the studied functions than the spinal type.}, } @article {pmid39936380, year = {2025}, author = {Lero, CM and Yang, A and Everett, E and Pitzer, KA and McCoy Gross, K and Washington, KT}, title = {Associations Between End-Stage ALS Care and Specialty Palliative Care: A Hypothesis-Generating Study.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28370}, pmid = {39936380}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) care is typically delivered via a multidisciplinary approach that may include specialty palliative care (SPC). Opportunities for SPC to enhance ALS care have been identified; however, investigation of these proposed benefits is scant. In this exploratory study, investigators examined associations between receipt of SPC and variables particularly relevant to end-stage ALS.

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

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

DISCUSSION: Clinical characteristics and end-of-life outcome differences between groups support further investigation of the proposed benefits of SPC regarding hospice enrollment, report of healthcare proxies, and documented goals of care conversations.}, } @article {pmid39936266, year = {2025}, author = {Denton, TT and Carter, GT and Goddard, M and Weiss, J and Weeks, DL and Weydt, P and Russo, EB and Weiss, MD}, title = {Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28359}, pmid = {39936266}, issn = {1097-4598}, abstract = {A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1[G93A] mouse model of ALS. The use of CEs in SOD1[G93A] murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.}, } @article {pmid39936211, year = {2025}, author = {Naveed, A and Usmani, WA and Vandara, MP and Karmani, VK}, title = {Tofersen for Amyotrophic Lateral Sclerosis: A Step Forward or Another False Hope?.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {35}, number = {2}, pages = {259-260}, doi = {10.29271/jcpsp.2025.02.259}, pmid = {39936211}, issn = {1681-7168}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Treatment Outcome ; }, abstract = {Null.}, } @article {pmid39936179, year = {2025}, author = {Morrison, AH and Jimenez, JV and Hsu, JY and Elman, L and Choi, PJ and Ackrivo, J}, title = {Identifying Daytime Hypercapnia Using Transcutaneous Carbon Dioxide Monitoring in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28366}, pmid = {39936179}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Respiratory failure from hypoventilation is the most common cause of death in amyotrophic lateral sclerosis (ALS). However, ALS care rarely assesses hypercapnia, a physiologic measure of hypoventilation. We investigated the prevalence and clinical significance of daytime hypercapnia measured by transcutaneous carbon dioxide (tcCO2) monitoring in patients with ALS.

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

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

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

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

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

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

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

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

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

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

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

CONCLUSION: Evidence of tissue damage that extended beyond that visualised under white light was noted with ALS. Usefulness of ultrasound was limited over bony prominences where there was too little subcutaneous tissue. Further research is warranted to investigate the potential application of ALS for the early detection of PIs.}, } @article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; *Biological Products/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Liposomes ; Anti-Inflammatory Agents/administration & dosage ; Nanoparticles/chemistry ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, } @article {pmid39927436, year = {2025}, author = {}, title = {Novel Biomarkers of FTD-ALS.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {31}, number = {1}, pages = {6}, doi = {10.1177/10738584241308752}, pmid = {39927436}, issn = {1089-4098}, } @article {pmid39926223, year = {2025}, author = {Moore, S and Donlon, NE}, title = {Improving gastrointestinal scoring systems for predicting short-term mortality in critically ill patients.}, journal = {World journal of gastroenterology}, volume = {31}, number = {5}, pages = {102622}, pmid = {39926223}, issn = {2219-2840}, mesh = {Humans ; *Critical Illness/mortality ; *Intensive Care Units/statistics & numerical data ; *Gastrointestinal Diseases/mortality/diagnosis ; Retrospective Studies ; *Severity of Illness Index ; Prognosis ; Hospital Mortality ; Predictive Value of Tests ; }, abstract = {Shen et al's retrospective study aims to compare the utility of two separate scoring systems for predicting mortality attributable to gastrointestinal (GI) injury in critically ill patients [the GI Dysfunction Score (GIDS) and the Acute Gastrointestinal Injury (AGI) grade]. The authors note that this study is the first proposal that suggests an equivalence between the ability of both scores to predict mortality at 28 days from intensive care unit (ICU) admission. Shen et al retrospectively analysed an ICU cohort of patients utilising two physicians administering both the AGI grade and GIDS score, using electronic healthcare records and ICU flowsheets. Where these physicians disagreed about the scores, the final decision as to the scores was made by an associate chief physician, or chief physician. We note that the primary reason for the development of GIDS was to create a clear score for GI dysfunction, with minimal subjectivity or inter-operator variability. The subjectivity inherent to the older AGI grading system is what ultimately led to the development of GIDS in 2021. By ensuring consensus between physicians administering the AGI, Shen et al have controlled for one of this grading systems biggest issues. We have concerns, however, that this does not represent the real-world challenges associated with applying the AGI compared to the newer GIDS, and wonder if this arbitration process had not been instituted, would the two scoring systems remain equivalent in terms of predicted mortality?}, } @article {pmid39924298, year = {2025}, author = {Malouin-Lachance, A and Capolupo, J and Laplante, C and Hudon, A}, title = {Does the Digital Therapeutic Alliance Exist? Integrative Review.}, journal = {JMIR mental health}, volume = {12}, number = {}, pages = {e69294}, doi = {10.2196/69294}, pmid = {39924298}, issn = {2368-7959}, mesh = {Humans ; *Therapeutic Alliance ; *Artificial Intelligence ; *Mental Disorders/therapy ; Telemedicine ; Psychotherapy/methods ; }, abstract = {BACKGROUND: Mental health disorders significantly impact global populations, prompting the rise of digital mental health interventions, such as artificial intelligence (AI)-powered chatbots, to address gaps in access to care. This review explores the potential for a "digital therapeutic alliance (DTA)," emphasizing empathy, engagement, and alignment with traditional therapeutic principles to enhance user outcomes.

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

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

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

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

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

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

CONCLUSIONS: Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.}, } @article {pmid39922547, year = {2025}, author = {Rossi, S and Milani, M and Valle, ID and Apolloni, S}, title = {Transcriptomic profiling of symptomatic and end-stage SOD1-G93A transgenic mice reveals extracellular matrix components as key players in ALS pathogenesis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {}, number = {}, pages = {167707}, doi = {10.1016/j.bbadis.2025.167707}, pmid = {39922547}, issn = {1879-260X}, } @article {pmid39922366, year = {2025}, author = {Kopalli, SR and Behl, T and Kyada, A and Rekha, MM and Kundlas, M and Rani, P and Nathiya, D and Satyam Naidu, K and Gulati, M and Bhise, M and Gupta, P and Wal, P and Fareed, M and Ramniwas, S and Koppula, S and Gasmi, A}, title = {Synaptic plasticity and neuroprotection: The molecular impact of flavonoids on neurodegenerative disease progression.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2025.02.007}, pmid = {39922366}, issn = {1873-7544}, abstract = {Flavonoids are a broad family of polyphenolic chemicals that are present in a wide variety of fruits, vegetables, and medicinal plants. Because of their neuroprotective qualities, flavonoids have attracted a lot of interest. The potential of flavonoids to control synaptic plasticity-a crucial process underlying memory, learning, and cognitive function-is becoming more and more clear. Dysregulation of synaptic plasticity is a feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (0.4 %), Parkinson's (1-2 %), Alzheimer's (5-7 %), and Huntington's ((0.2 %)). This review discusses the molecular mechanisms via which flavonoids influence synaptic plasticity as well as their therapeutic potential in neurodegenerative diseases. Flavonoids modulate key signaling pathways such as MAPK/ERK and PI3K/Akt/mTOR to support neuroprotection, synaptic plasticity, and neuronal health, while also influencing neurotrophic factors (BDNF, NGF) and their receptors (TrkB, TrkA). They regulate neurotransmitter receptors like GABA, AMPA, and NMDA to balance excitatory and inhibitory transmission, and exert antioxidant effects via the Nrf2-ARE pathway and anti-inflammatory actions by inhibiting NF-κB signaling, highlighting their potential for treating neurodegenerative diseases. These varied reactions support the preservation of synapse function and neuronal integrity in the face of neurodegenerative insults. Flavonoids can reduce the symptoms of neurodegeneration, prevent synaptic loss, and enhance cognitive function, according to experimental studies. However, there are still obstacles to using these findings in clinical settings, such as limited bioavailability and the need for consistent dose. The focus of future research should be on improving flavonoid delivery systems and combining them with conventional medications.}, } @article {pmid39863163, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Gutierrez, D and Lo Sicco, KI}, title = {Response to Sood et al's "Systemic Janus kinase inhibitor treatment for vitiligo: An evidence-based review".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.059}, pmid = {39863163}, issn = {1097-6787}, } @article {pmid39921200, year = {2025}, author = {Shiozumi, T and Matsuyama, T and Nishioka, N and Kiguchi, T and Kitamura, T and Ohta, B and Iwami, T}, title = {Evaluation of Interventions in Prehospital and In-hospital Settings and Outcomes for Out-of-Hospital Cardiac Arrest Patients Meeting the Termination of Resuscitation Rule in Japan: A Nationwide Database Study (The JAAM-OHCA Registry).}, journal = {Resuscitation}, volume = {}, number = {}, pages = {110530}, doi = {10.1016/j.resuscitation.2025.110530}, pmid = {39921200}, issn = {1873-1570}, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a global health burden with low survival rates. The termination of resuscitation (TOR) rule, widely adopted internationally, aims to preserve dignity, optimize resources, and protect healthcare providers. However, prehospital TOR is not implemented in Japan, presenting legal and practical challenges. This study analyzes temporal trends in prehospital and in-hospital interventions for OHCA patients with poor predicted outcomes.

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

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

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

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

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

CONCLUSIONS: Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.}, } @article {pmid39920055, year = {2025}, author = {Ramsden, V and McInnes, E and Wilson, P and Babl, FE and Kuhn, L and Cowie, J and Campbell, P and Middleton, S and Wilson, C and Straiton, N and Tavender, E}, title = {Sustainability of healthcare system improvements, programmes and interventions in acute care settings: protocol for a mixed methods systematic review.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e094174}, doi = {10.1136/bmjopen-2024-094174}, pmid = {39920055}, issn = {2044-6055}, mesh = {Humans ; *Systematic Reviews as Topic ; *Delivery of Health Care/organization & administration ; Research Design ; Quality Improvement/organization & administration ; }, abstract = {INTRODUCTION: Sustaining evidence-based care is challenging in all clinical settings. Acute care settings have a unique set of contextual factors that may impact sustainability (eg, fast-paced, regular staff turnover). Much of the previous research explores sustainability across undifferentiated healthcare settings making it difficult to determine factors that influence sustainability in acute care settings. The aim of this review is to identify facilitators and barriers that influence the delivery of sustained healthcare interventions (eg, integration of clinical guidelines) within adult and paediatric hospital-based acute care settings.

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

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

PROSPERO REGISTRATION NUMBER: PROSPERO CRD42024547535.}, } @article {pmid39918735, year = {2025}, author = {Wentzel, A and Smith, W and Jansen van Vuren, E and Kruger, R and Breet, Y and Wonkamtinitang, E and Hanchard, NA and Chung, ST}, title = {Allostatic load and cardiometabolic health in a young adult South African population: The African-PREDICT study.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajpheart.00845.2024}, pmid = {39918735}, issn = {1522-1539}, support = {//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; //South African Medical Research Council (SAMRC)/ ; //South African National Research Foundation (SA-NRF)/ ; //Newton Fund (NF)/ ; //Pfizer (South Africa)/ ; //Boeringer-Ingelheim (South Africa)/ ; //Norvatis (South Africa)/ ; //MediClinic Hospital Group (South Africa)/ ; //Roche Holding | Roche Diagnostics (Roche Diagnostics Corporation)/ ; }, abstract = {Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile using a tiered approach stratified by age (emerging adults 20-24y, EA vs. young adults 25-30y, YA) and ALS (high vs. low). In 1054 healthy African-PREDICT participants, we determined: 1) ALS in EA vs. YA; 2) the relationship between ALS with cardiovascular health; and 3) the odds of high ALS>4 to identify masked hypertension and prediabetes as cardiometabolic outcomes. A 9-component four-domain ALS was compiled: neuro-endocrine (dehydroepiandrosterone, cortisol), inflammatory (interleukin-6, C-reactive protein), cardiovascular (systolic and diastolic-blood pressure), and metabolic (total cholesterol, HDL-cholesterol, body mass index). Retinal vessel caliber, pulse wave velocity (PWV), cardiac structure and function were assessed. Median ALS was 3 (range:1-9). A high-ALS>4 was more common in YA vs. EA (47%vs.35%, P=0.032). Higher ALS associated with narrower retinal arteries (P<0.01), greater PWV (P=<0.01), lower diastolic (P<0.01) and left ventricular function (P<0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular function (all P≤0.01) in EA and YA independent of traditional CVD risk factors. The composite ALS identified early stress dysregulation in cardiometabolic health and higher odds for prediabetes and masked hypertension in young adults. Cumulative stress may be a modifiable independent cardiometabolic risk factor in younger populations that needs further investigation.}, } @article {pmid39917359, year = {2025}, author = {Ahmadi Marzaleh, M and Bastani, P and Raeyat Mohtashami, A and Farhadi, P and Ghanbari, S and Ravangard, R}, title = {Predicting Factors Affecting the Behavior of Healthcare Employees in the Use of Personal Protective Equipment During Epidemics Based on Godin et al's Model: A Study in Iran.}, journal = {Health services insights}, volume = {18}, number = {}, pages = {11786329251316668}, pmid = {39917359}, issn = {1178-6329}, abstract = {BACKGROUND: Protecting healthcare employees and preventing infection transmission are paramount concerns during epidemics. Predicting healthcare employees' behavior regarding the use of personal protective equipment (PPE) and identifying the related effective factors can guide educational and administrative strategies and enable timely interventions during outbreaks. This study aimed to predict factors affecting the healthcare employees' behavior in the use of PPE at Shiraz University of Medical Sciences in Iran, based on Godin et al's model.

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

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

CONCLUSION: The results emphasized the necessity of targeted interventions based on the studied model constructs within healthcare organizations. By promoting positive beliefs about PPE effectiveness and encouraging appropriate intentions and behaviors, healthcare organizations can significantly improve employee's adherence to PPE use during pandemics.}, } @article {pmid39916983, year = {2024}, author = {González Bolívar, S and Ayoubi, R and Alende, C and Fothouhi, M and Shlaifer, I and McPherson, PS and Laflamme, C and , and , }, title = {A guide to selecting high-performing antibodies for VAPB (UniProt ID: O95292) for use in western blot, immunoprecipitation, and immunofluorescence.}, journal = {F1000Research}, volume = {13}, number = {}, pages = {1559}, pmid = {39916983}, issn = {2046-1402}, mesh = {Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western ; *Antibodies/immunology ; HEK293 Cells ; Vesicular Transport Proteins ; }, abstract = {VAPB is an adaptor protein known for its role as an anchor for other proteins at the endoplasmic reticulum. A mutant form of VAPB has been linked to amyotrophic lateral sclerosis and the underlying mechanisms resulting from this defect are studied by researchers in this area to uncover its implication in the disease. Here we have characterized six VAPB commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.}, } @article {pmid39916853, year = {2025}, author = {Rosina, M and Scaricamazza, S and Riggio, F and Fenili, G and Giannessi, F and Matteocci, A and Nesci, V and Salvatori, I and Angelini, DF and Aquilano, K and Chiurchiù, V and Barbato, DL and Mercuri, NB and Valle, C and Ferri, A}, title = {Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e41801}, pmid = {39916853}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. The contribution of peripheral organs remains incompletely understood. We focused our attention on brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) given their role in regulating systemic energy balance. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed consistent changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting alterations such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content. In parallel, such EVs negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS mouse model and could impact on skeletal muscle homeostasis through the secretion of dysfunctional EVs.}, } @article {pmid39916336, year = {2025}, author = {Calvi, F and Fortuna, A and Bello, L and Anglani, M and Cecchin, D and Sabbatini, D and Andrigo, C and Ferullo, M and Ruggero, S and Falda, M and Pegoraro, E and Sorarù, G}, title = {MEPs and MRI Motor Band Sign as Potential Complementary Markers of Upper Motor Neuron Involvement in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {2}, pages = {e70055}, doi = {10.1111/ene.70055}, pmid = {39916336}, issn = {1468-1331}, support = {//EuroBiobank/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging ; Aged ; *Motor Neurons/pathology ; Retrospective Studies ; *Evoked Potentials, Motor/physiology ; Adult ; Positron-Emission Tomography ; Biomarkers ; Neural Conduction/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of both upper and lower motor neurons (UMNs and LMNs). Recognizing the involvement of UMNs is challenging because of the absence of reliable biomarkers beyond clinical evaluation.

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

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

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

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

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

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

CONCLUSIONS: Plasma miRNA-214 could serve as a novel biomarker for predicting the progression and prognosis of ALS.}, } @article {pmid39914774, year = {2025}, author = {Zamani, A and Walker, AK and Wright, DK}, title = {Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106832}, doi = {10.1016/j.nbd.2025.106832}, pmid = {39914774}, issn = {1095-953X}, abstract = {Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43. This study extends this work to investigate how glymphatic function changes over time in the rNLS8 doxycycline (Dox)-dependent TDP-43 mouse model of ALS. Motor function, advanced MRI biomarkers of neurodegeneration, and cortical glymphatic pathway gene expression were assessed together with dynamic contrast-enhanced MRI (DCE-MRI) assessment of glymphatic function at 0-, 3-, 7-, and 21-days after removing mice from Dox feed to initiate cytoplasmic human TDP-43 expression. A trend toward increased glymphatic influx was observed at 3-days post-Dox, together with MRI evidence of brain changes that occurred in the absence of hind-limb clasping and motor impairment. Glymphatic flow is facilitated by aquaporin-4 (AQP4) water channels polarized to astrocytic end feet. We found that while glymphatic function normalized to control levels at 7-days post-Dox, AQP4 expression in the cortex was significantly decreased. After 3-weeks of human TDP-43 expression, glymphatic dysfunction, weight loss, neurodegeneration, motor impairments and astrogliosis were observed. Our findings highlight early glymphatic dysfunction in ALS, suggesting its potential as a therapeutic target.}, } @article {pmid39914266, year = {2025}, author = {Wei, D and Freydenzon, A and Guinebretiere, O and Zaidi, K and Yang, F and Ye, W and Hammar, N and Modig, K and Wray, NR and Feychting, M and Hamieh, N and Ventelou, B and Lekens, B and Gantzer, L and Durrleman, S and McRae, A and Couvy-Duchesne, B and Fang, F and Nedelec, T and , }, title = {Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {113}, number = {}, pages = {105585}, doi = {10.1016/j.ebiom.2025.105585}, pmid = {39914266}, issn = {2352-3964}, abstract = {BACKGROUND: Many studies have investigated early predictors for Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, evidence is sparse regarding specific and common predictors for these diseases. We aimed to identify medication use, health conditions, and blood biomarkers that might be associated with the risk of AD, PD, and ALS ten years later.

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

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

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

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

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

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

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

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

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

CONCLUSIONS: This study underscored the relevance of information about NfL and ALSFRS-R from the patient's perspective. Furthermore, patients proved to appreciate the relevance of this data for ALS research. Sharing information about NfL or ALSFRS-R was rarely perceived as burdensome even in a remote setting using the ALS app. These findings pave the way for further development of the patient-centered approach to sharing prognostic information in ALS.}, } @article {pmid39910617, year = {2025}, author = {Mai, YD and Zhang, Q and Fung, CL and Leung, SO and Chong, CH}, title = {CD22 modulation alleviates amyloid β-induced neuroinflammation.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {32}, pmid = {39910617}, issn = {1742-2094}, mesh = {Animals ; Mice ; Humans ; *Sialic Acid Binding Ig-like Lectin 2/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; *Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism ; Microglia/metabolism/drug effects ; Mice, Inbred C57BL ; Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; Male ; }, abstract = {Neuroinflammation is a crucial driver of multiple neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Yet, therapeutic targets for neurodegenerative diseases based on neuroinflammation still warrant investigation. CD22 has been implicated in neuroinflammatory diseases, namely AD. Specifically, plasma soluble CD22 (sCD22) level is upregulated in patients with AD. Direct experimental evidence for the role of CD22 in neuroinflammation is needed, as is a better understanding of its impact on microglia activation and therapeutic potential. Here we reported that sCD22 promotes neuroinflammation both in vivo and in vitro. sCD22 activated microglia via both p38 and ERK1/2 signaling pathway for the secretion of TNFα, IL-6 and CCL3. Moreover, sCD22 activated microglia via sialic acid binding domain and 2,6 linked sialic acid glycan on sCD22. The pivotal therapeutic potential of targeting CD22 was demonstrated in Amyloid β (Aβ) induced-neuroinflammation in hCD22 transgenic mice. Suciraslimab improved working memory and resolved neuroinflammation in vivo. Further, membrane CD22 inhibited Amyloid β (Aβ) induced-NFκB signaling pathway and mechanistic study delineated that suciraslimab suppressed Aβ-induced IL-1β secretion in human microglia and PBMC. Suciraslimab also suppressed IL-12 and IL-23 secretion in human PBMC. Moreover, suciraslimab reduced the surface expression of α4 integrin on B cells. Intriguingly, we discovered that CD22 interact with Aβ and suciraslimab enhanced internalization of CD22-Aβ complex in microglia. Our data highlights the importance of sCD22 in driving neuroinflammation and the dual mechanism of targeting CD22 to resolve Aβ-induced inflammation and promote Aβ phagocytosis.}, } @article {pmid39910275, year = {2025}, author = {Peters, TL and Qiu, W and Yang, H and Huang, W and Hu, Y and Zou, Z and Ye, W}, title = {Associations of cachexia and frailty with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4437}, pmid = {39910275}, issn = {2045-2322}, support = {2024XH028//Postdoctoral Fund project of Fujian Medical University Union Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Cachexia/etiology ; Female ; Male ; *Frailty/complications ; Middle Aged ; Aged ; Prospective Studies ; Risk Factors ; Hand Strength ; United Kingdom/epidemiology ; Body Mass Index ; }, abstract = {In the present study, we investigated the associations of cachexia (loss of muscle, weight and fat) and frailty (loss of weight and muscle) status with the risk of developing amyotrophic lateral sclerosis, because these specific terms are rarely used in this research area. In this prospective study, we extracted cachexia and frailty status from the UK Biobank cohort to study the associations of these conditions (as determined via international classification of disease-10 codes) with amyotrophic lateral sclerosis. There was a greater risk of developing amyotrophic lateral sclerosis among individuals with cachexia and frailty status after adjusting for age, sex, income (pounds), body mass index, UK Biobank centers and smoking status. Among individuals with frailty status: a grip strength of < 21 kg, a slow walking speed, and exhaustion (more than half the days or nearly every day) increase the risk of developing amyotrophic lateral sclerosis. We believe that studying cachexia and frailty status can be used to help define and treat amyotrophic lateral sclerosis.}, } @article {pmid39908935, year = {2025}, author = {Lu, T and Li, J and Xiao, E and Zhong, H and Deng, J and Ma, L and Ning, Z and Xiao, T}, title = {Assemblage of root-associated microbiome contributes to disparate performance of two rice genotypes under aluminum stress.}, journal = {Plant physiology and biochemistry : PPB}, volume = {220}, number = {}, pages = {109539}, doi = {10.1016/j.plaphy.2025.109539}, pmid = {39908935}, issn = {1873-2690}, abstract = {Aluminum (Al) toxicity severely inhibits rice growth under acidic soils, posing a significant threat to food security. The assemblies of root-associated microbiomes throughout the lifecycle of rice are hypothesized to furnish a resilient reservoir of ecological functions for rice growth performance under Al stresses. However, the mechanisms that drive the assembly of root-associated microbiomes of rice are largely unknown. In this study, we chose two rice genotypes (including aluminum-tolerant (Al-T) and aluminum-sensitive (Al-S)) as model plants to investigate the microbial assemblage of root-associated microbiome and their potential roles on the plant growth performance under Al stress. The microbial community diversity (Shannon) and evenness (Chao1) in the endosphere of the Al-T genotype gradually decreased, converging towards levels observed in the Al-S genotype. In addition, the rhizosphere and endosphere microbiomes of Al-T genotype are primarily influenced by deterministic processes, while those of Al-S genotype are more influenced by stochastic processes. Compared to Al-S genotype, Al-T genotype exhibited higher complexity and stability in its rhizosphere and endosphere microbiomes, while the rhizoplane microbiome showed the opposite trend. In the rhizosphere microbiome of the Al-T genotype, we identified Gallionellales, Rhodobacterales, and Rhizobiales as keystone taxa. Their abundance was closely associated with microbial functions, including indole-3-acetic acid (IAA) synthesis, phosphorus solubilization, glutathione (GSH) metabolism, and 1-aminocyclopropane-1-carboxylate (ACC) metabolism. In the Al-S genotype, the keystone taxa included Actinomycetales and Burkholderiales. This study offers new insights into plant adaptation to abiotic stress and underscores the significance of the assemblage of root-associated microbiome in this process.}, } @article {pmid39908735, year = {2025}, author = {Ghannam, IAY and Hassan, RM and Abdel-Maksoud, MS}, title = {Peroxisome proliferator-activated receptors (PPARs) agonists as promising neurotherapeutics.}, journal = {Bioorganic chemistry}, volume = {156}, number = {}, pages = {108226}, doi = {10.1016/j.bioorg.2025.108226}, pmid = {39908735}, issn = {1090-2120}, abstract = {Neurodegenerative disorders are characterized by a continuous neurons loss resulting in a wide range of pathogenesis affecting the motor impairment. Several strategies are outlined for therapeutics of synthetic and natural PPARs agonists in some neurological disorders; Parkinson's disease (PD), Alzheimer's disease (AD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The aim of this review is to provide a recent update of the previously reported studies, and reviews dealing with the medicinal chemistry of PPARs and their agonists, and to highlight the outstanding advances in the development of both synthetic compounds including; PPARα agonists (fibrates), PPARγ agonists (thiazolidindiones), and PPARβ/δ agonists either as sole or dual acting PPAR full or pan agonists, in addition to the natural phytochemicals; acids, cannabinoids, and flavonoids for their different neuroprotection effects in the previously mentioned neurodegenerative disorders (PD, AD, MS, ALS, and HD). Moreover, this review reports the diverse pre-clinical and clinical studies of PPARs agonists in the neurodegenerative diseases via cellular, and animal models and human.}, } @article {pmid39908264, year = {2025}, author = {Hobert, MA and Helle, N and Siebert, C and Eisenhauer, A and Gledhill, M and Maetzler, W}, title = {Exploiting the Fractionation of Stable Isotopes in Biochemical Processes for Medical Diagnosis: A Narrative Review.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1577}, pmid = {39908264}, issn = {2152-5250}, abstract = {Analysis of isotope distributions plays a crucial role in medical diagnostics. While radioactive and radiogenic isotopes - those that undergo or result from radioactive decay - are widely used, stable isotopes are less commonly applied despite their significant diagnostic potential. For example, calcium isotope ratio analysis is already commercially utilized for calcium loss and the early diagnosis of osteoporosis. Additionally, analyses of iron, copper, and zinc isotope ratios have been explored in various conditions, including hemochromatosis, Wilson's disease, cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. Altered isotope ratios in these diseases are thought to reflect pathophysiologically relevant processes, making them promising biomarkers. This review provides a comprehensive overview of the current and potential applications of stable isotope analysis in medicine.}, } @article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, doi = {10.5644/ama2006-124.463}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; *Translational Research, Biomedical ; Scoping Review as Topic ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.

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

CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, } @article {pmid39907139, year = {2025}, author = {Matera, AG}, title = {Chaperone dysfunction in motor neuron disease: new insights from studies of the SMN complex.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyae223}, pmid = {39907139}, issn = {1943-2631}, support = {//USA National Institutes of Health/ ; }, abstract = {Spinal muscular atrophy and amyotrophic lateral sclerosis are devastating neurodegenerative diseases characterized by motor neuron loss. Although these 2 disorders have distinct genetic origins, recent studies suggest that they share common etiological mechanisms rooted in proteostatic dysfunction. At the heart of this emerging understanding is the survival motor neuron (SMN) complex.}, } @article {pmid39906330, year = {2024}, author = {Hruška, J and Bachmann, P and Odei, SA}, title = {Enhancing ALS disease management: exploring integrated user value through online communities evidence.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1393261}, pmid = {39906330}, issn = {1664-2295}, abstract = {INTRODUCTION: Assistive technologies (ATs) offer significant potential to improve the quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). This study explores the concept of integrated user value (IUV), focusing on five key aspects: quality, user experience, cost-effectiveness, safety, and accessibility. Understanding IUV is crucial for enhancing the development and deployment of ATs in ALS disease management.

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

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

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

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

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

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

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

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

DISCUSSION: SYNGR4 overexpression can affect the prognosis of breast cancer patients by promoting M2 polarization of tumor-associated macrophages in breast cancer, and this molecule may be a novel target for breast cancer immunotherapy.}, } @article {pmid39901730, year = {2025}, author = {Wu, W and Wang, X and Xu, Y and Ma, C and Qian, X and Qiu, W}, title = {Neuropathological comorbidity, genetics and cognition in a Chinese community-based autopsy cohort.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf039}, pmid = {39901730}, issn = {1460-2156}, abstract = {Neurodegenerative comorbidities are common and critical, yet data specific to the Chinese population remains limited. The study aims to investigate the prevalence and associations of neuropathologic changes and comorbidities, and their correlation with genetics and cognition in a community-dwelling autopsy cohort in China. Datasets of 610 participants were obtained from the National Human Brain Bank for Development and Function at the Chinese Academy of Medical Sciences/Peking Union Medical College. Neuropathological changes analysed included Alzheimer's disease neuropathological change (ADNC) (n = 331); α-synucleinopathies (n = 124) with 120 Lewy body disease (LBD) and 4 multiple system atrophy; limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) (n = 341); primary age-related tauopathy (PART) (n = 231); argyrophilic grain disease (AGD) (n = 107); age-related tau astrogliopathy (ARTAG) (n = 144); cerebral amyloid angiopathy (CAA) (n = 183); hippocampus sclerosis (HS) (n = 46). Frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and amygdala-predominant LBD are rare. Descriptive statistics and logistic regression models were used to assess the neuropathological associations. Increased age at death was correlated with increased severity in ADNC, LBD, and LATE-NC, as well as with a higher number of comorbidities. APOE ε4 allele frequency in the present autopsy cohort was 13.63%. The presence of the APOE ε4 allele was linked to an advanced ADNC stage and increased comorbidities. The co-pathology prevalence varied by pathologies, with notable increases in specific subgroups: within the ADNC subgroups, LBD, LATE-NC, CAA, and HS were more frequent in advanced stages; in the LATE-NC subgroups, ADNC, CAA, and ARTAG increased, while PART decreased in higher LATE-NC stages. PART cases presented the highest proportion of pure pathology (37.2%) compared to other groups. Advanced ADNC stages were significantly associated with higher LATE-NC stages, and vice versa. Neocortical LBD was correlated with elevated ADNC levels, and higher LATE-NC stages were associated with worsening LBD pathology. High level ADNC, neocortical LBD, and stage 3 of LATE-NC were identified as independent predictors of severe cognition status. Our study suggests that older age at death and APOE ε4 presence are the risk factors for neuropathologic comorbidities in Chinese people. The findings underscore the importance of considering comorbid neurologic diagnoses and therapies in clinical practice.}, } @article {pmid39901566, year = {2025}, author = {Park, NY and Heo, Y and Yang, JW and Yoo, JM and Jang, HJ and Jo, JH and Park, SJ and Lin, Y and Choi, J and Jeon, H and Cha, SJ and Bae, G and Kim, D and Kim, J and Zeno, W and Park, JB and Isozumi, N and Saio, T and Kim, SH and Lee, H and Hong, BH and Nahm, M and Lee, YH and Hong, YB}, title = {Graphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis.}, journal = {ACS nano}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsnano.4c15283}, pmid = {39901566}, issn = {1936-086X}, abstract = {Aberrant phase separation- and stress granule (SG)-mediated cytosolic aggregation of TDP-43 in motor neurons is the hallmark of amyotrophic lateral sclerosis (ALS). In this study, we found that graphene quantum dots (GQDs) potentially modulate TDP-43 aggregation during SG dynamics and phase separation. The intrinsically disordered region in the C-terminus of TDP-43 exhibited amyloid fibril formation; however, GQDs inhibited the formation of amyloid fibrils through direct intermolecular interactions with TDP-43. These effects were accompanied by attenuation of the ALS phenotype in animal models. Additionally, GQDs delayed the onset and survival of TDP-43 transgenic mouse models by enhancing motor neuron survival, reducing glial activation, and reducing the cytosolic aggregation of TDP-43 in motor neurons. In this research, we demonstrated the efficacy of GQDs on the SG-mediated aggregation of TDP-43 and the binding property of GQDs with TDP-43. Additionally, we demonstrated the clinical feasibility of GQDs using several animal models and other types of ALS caused by FUS and C9orf72. Therefore, GQDs could offer a new therapeutic approach for proteinopathy-associated ALS.}, } @article {pmid39901378, year = {2025}, author = {San Gil, R and Walker, AK}, title = {Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {}, number = {}, pages = {e202400257}, doi = {10.1002/bies.202400257}, pmid = {39901378}, issn = {1521-1878}, abstract = {Neurons degenerate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing progressive and inevitably fatal neurological decline. The best therapeutic strategies target underlying disease mediators, but after decades of intensive research, the causes of these neurodegenerative diseases remain elusive. Recently, coordinated activities of large consortia, increasing open access to large datasets, new methods such as cryo-transmission electron microscopy, and advancements in high-resolution omics technologies have offered new insights into the biology of disease that bring us closer to understanding mechanisms of neurodegeneration. In particular, improved understanding of the roles of the key pathological protein TAR DNA binding protein 43 (TDP-43) in disease has revealed intriguing new opportunities that provide hope for better diagnostic tools and effective treatments for ALS and FTD.}, } @article {pmid39900510, year = {2025}, author = {van Altena, EJE and Jansen, BHE and Vis, AN}, title = {Reply to Ignacio Puche-Sanz, Ugo Giovanni Falagario, Giorgio Gandaglia, et al's Letter to the Editor re: Evelien J.E. van Altena, Bernard H.E. Jansen, Marieke L. Korbee, et al. Prostate-specific Membrane Antigen Positron Emission Tomography Before Reaching the Phoenix Criteria for Biochemical Recurrence of Prostate Cancer After Radiotherapy: Earlier Detection of Recurrences. Eur Urol Oncol. In press. https://doi.org/10.1016/j.euo.2024.09.015.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.01.011}, pmid = {39900510}, issn = {2588-9311}, } @article {pmid39899435, year = {2025}, author = {Blake, J and Peryer, G and Dance, R and Parke, S and Aryankhesal, A and Farquhar, M}, title = {How can healthcare professionals work with families to address misaligned expectations of recovery in brain injury rehabilitation? A scoping review.}, journal = {Brain injury}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/02699052.2025.2450603}, pmid = {39899435}, issn = {1362-301X}, abstract = {INTRODUCTION: Most survivors of severe acquired brain injuries will have significant long-term disability. During inpatient rehabilitation, families often have expectations of recovery that do not match healthcare professional opinion. This impacts on patient care, service processes, professional-family relations, and wellbeing. This review aimed to understand how family expectations are managed in this setting, and to explore potential areas of improvement.

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

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

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

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

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

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

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

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

INTERPRETATION: Approximately 30% of ALS patients experienced cognitive/behavioral decline within the first year after diagnosis. FAS and ECAS verbal fluency were predictive of cognitive phenoconversion. Our findings highlight the importance of early detection of at-risk individuals and the need for longitudinal cognitive assessments to monitor disease progression. ANN NEUROL 2025.}, } @article {pmid39891383, year = {2025}, author = {Chen, M and Cui, H and Zhang, X and Ma, S and Guo, J and Liu, Z and Gu, D and Fan, Y}, title = {Super-Enhancer Protects Cells From Toxicity of C9orf72 Poly(proline-arginine) by Inducing the Expression of KPNA2/KPNB1.}, journal = {Cell biochemistry and function}, volume = {43}, number = {2}, pages = {e70053}, doi = {10.1002/cbf.70053}, pmid = {39891383}, issn = {1099-0844}, support = {//This work was supported by the National Natural Science Foundation of China (31970616, 82070505) and Jiangsu Provincial Natural Science Foundation (BK20211330)./ ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; beta Karyopherins/metabolism ; alpha Karyopherins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR) generated from G4C2 repeat expansions, have been shown to be highly toxic. In this study, PR20 was labeled with fluorescein isothiocyanate (FITC) to track its cellular localization. Several cell lines demonstrated survival under PR20 treatment by sequestering PR20 in the cytoplasm. Treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death. Mechanistically, KPNA2/KPNB1 interacted with PR20 in the cytoplasm and hindered PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Treatment with JQ1 significantly reduced the protein levels of KPNA2/KPNB1, allowing PR20 to enter the nucleus. Overexpression of KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. Our results indicate that super-enhancers shield cells from PR20 toxicity by upregulating the expression of KPNA2/KPNB1.}, } @article {pmid39891231, year = {2025}, author = {Rakab, MS and Zaid, AB and Hamadein, MA and Hamadein, SA and Ashour, MAE and El-Shamia, AS and Mostafa, DA and Rateb, RM and Elashry, MA and El-Badawy, MM and Shaheen, RSB}, title = {Assessment of ABCDE approach knowledge among residents and interns in multiple Egyptian hospitals, a cross-sectional study.}, journal = {BMC medical education}, volume = {25}, number = {1}, pages = {164}, doi = {10.1186/s12909-025-06668-z}, pmid = {39891231}, issn = {1472-6920}, mesh = {Humans ; Egypt ; *Internship and Residency ; Cross-Sectional Studies ; Male ; Female ; Adult ; *Clinical Competence ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach is crucial in emergency care, but there may be variability in adherence among healthcare professionals. Inconsistent application of this approach may lead to variations in patient care quality and outcomes. Identifying the factors influencing adherence can help improve training to ensure more effective application across emergency settings. This study explores the theoretical knowledge of the ABCDE approach among Egyptian resident doctors and medical interns.

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

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

CONCLUSION: This study addresses a critical gap in ABCDE approach knowledge among Egyptian resident doctors and medical interns. The study points to the need for focused education, especially for surgeons, to improve emergency care skills and patient outcomes through continued training.}, } @article {pmid39889925, year = {2025}, author = {Bian, Y and Fukui, Y and Ota-Elliott, RS and Hu, X and Sun, H and Bian, Z and Zhai, Y and Yu, H and Hu, X and An, H and Liu, H and Morihara, R and Ishiura, H and Yamashita, T}, title = {The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model.}, journal = {Neuroscience research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neures.2025.01.006}, pmid = {39889925}, issn = {1872-8111}, abstract = {The disruption of transactive response DNA binding protein 43 kDa (TDP-43) shuttling leads to the depletion of nuclear localization and the cytoplasmic accumulation of TDP-43. We aimed to evaluate the mechanism underlying the behavior of TDP-43 in ischemic stroke. Adult male C57BL/6 J mice were subjected to 30 or 60 min of transient middle cerebral artery occlusion (tMCAO), and examined at 1, 6, and 24 h post reperfusion. Immunostaining was used to evaluate the expression of TDP-43, G3BP1, HDAC6, and RAD23B. The total and cytoplasmic number of TDP-43-positive cells increased compared with sham operation group and peaked at 6 h post reperfusion after tMCAO. The elevated expression of G3BP1 protein peaked at 6 h after reperfusion and decreased at 24 h after reperfusion in ischemic mice brains. We also observed an increase of expression level of HDAC6 and the number of RAD23B-positive cells increased after tMCAO. RAD23B was colocalized with TDP-43 24 h after tMCAO. We proposed that the formation of stress granules might be involved in the mislocalization of TDP-43, based on an evaluation of G3BP1 and HDAC6. Subsequently, RAD23B, may also contribute to the downstream degradation of mislocalized TDP-43 in mice tMCAO model.}, } @article {pmid39889542, year = {2025}, author = {Albrecht, F and Kvist, A and Franzén, E}, title = {Resting-state functional near-infrared spectroscopy in neurodegenerative diseases - A systematic review.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103733}, doi = {10.1016/j.nicl.2025.103733}, pmid = {39889542}, issn = {2213-1582}, abstract = {OBJECTIVE: To systematically review and summarize alterations found in resting-state activity as measured via functional near-infrared spectroscopy (fNIRS) in neurodegenerative diseases.

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

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

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

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

CONCLUSION: rsfNIRS shows promise in neurodegenerative disease, as most studies have observed resting-state alterations when compared to healthy controls. However, inconsistencies across studies limit data comparison and meta-analysis. Hence, we strongly advocate the application of fNIRS reporting guidelines and the establishment of rsfNIRS-specific guidelines. This will ensure reliable and comparable results in future research.}, } @article {pmid39889424, year = {2025}, author = {Pascual, A and May, PB and Cárdenas-Martínez, A and Guerra-Hernández, J and Hunka, N and Bruening, JM and Healey, SP and Armston, JD and Dubayah, RO}, title = {Calibration of GEDI footprint aboveground biomass models in Mediterranean forests with NFI plots: A comparison of approaches.}, journal = {Journal of environmental management}, volume = {375}, number = {}, pages = {124313}, doi = {10.1016/j.jenvman.2025.124313}, pmid = {39889424}, issn = {1095-8630}, abstract = {Observations from the NASA Global Ecosystem Dynamics Investigation (GEDI) provide global information on forest structure and biomass. Footprint-level predictions of aboveground biomass density (AGBD) in the GEDI mission are based on training data sourced from sparsely distributed field plots coincident with airborne laser scanning surveys. National Forest Inventories (NFI) are rarely used to calibrate GEDI footprint biomass models because their sampling and positional accuracy prevent accurate colocation with GEDI or ALS. This omission can limit the harmonization of jurisdictional biomass estimates from NFI's and GEDI; however, there are methods available to improve the colocation of NFI plots with GEDI footprints. Focusing on Mediterranean forests in Spain, we compared different approaches to the collocation of NFI and GEDI data: (i) simulated waveforms from ALS; (ii) nearest-neighbor on-orbit GEDI waveforms; and (iii) imputed GEDI waveforms imputed to NFI plot locations using a novel geostatistical method. These methods are potential solutions to improve the local performance of biomass models and address potential local systematic deviations between GEDI and NFI estimates. We assess the advantages and limitations of these methods to locally calibrate GEDI biomass models and quantify the impact of geolocation errors in reference NFI plot data. The new biomass models from each method were used to predict footprint level AGBD, which were then gridded for a province in the North-West of Spain. It was found that the imputation approach is not sensitive to common errors in NFI plot geolocation, but it can outperform ALS-based simulation in some cases, highlighting the benefit of information from multiple GEDI footprints proximate to NFI plots for improving biomass predictions. This research provides users with benchmark of available techniques to locally-calibrate GEDI footprint biomass models.}, } @article {pmid39887552, year = {2025}, author = {Dopler, MB and Abeer, MI and Arezoumandan, S and Cox, K and Petersen, TL and Daniel, EH and Cannon, CL and Bautista, A and Blancher, KD and Bland, AM and Bond, KJ and Davis, DA and Francois, JM and McCray, EJ and Morgan, JM and Pulliam, JL and Robinson, ZA and Taylor, MJ and Dowell, JA and Cairns, NJ and Gitcho, MA}, title = {A cellular model of TDP-43 induces phosphorylated TDP-43 aggregation with distinct changes in solubility and autophagy dysregulation.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.17413}, pmid = {39887552}, issn = {1742-4658}, support = {0823//The Paul H. Boerger Fund of the Delaware Community Foundation/ ; P20GM103446/GM/NIGMS NIH HHS/United States ; P20GM103653/GM/NIGMS NIH HHS/United States ; T32GM144895-03/GM/NIGMS NIH HHS/United States ; 2023004//National Science Foundation/ ; 52008702//HHMI/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control, and eventually leads to death. Phosphorylated transactive response DNA binding protein-43 (TDP-43) is the major pathological protein in both sporadic and familial ALS, forming cytoplasmic aggregates in over 95% of cases. Of the 10-15% of ALS cases that are familial, mutations in TDP-43 represent about 5% of those with a family history. We have developed an in vitro overexpression model by introducing three familial ALS mutations (A315T, M337V, and S379P) in the TDP-43 (TARDBP) gene which we define as 3X-TDP-43. This overexpression model TDP-43 shows deficits in autophagy flux and colocalization of TDP-43 with stress granules. We also observe a progressive shift of TDP-43 to the cytoplasm in this model. This overexpression model shows a reduction in solubility of phosphorylated TDP-43 from RIPA to urea soluble. Four glycolytic enzymes, phosphoglycerate kinase one (PGK1), aldolase A (ALDOA), enolase 1 (ENO1), and pyruvate dehydrogenase kinase 1 (PDK1) show significant time-dependent decreases in 3X-TDP-43 expressing cells. Shotgun proteomic analysis shows global changes in the importin subunit alpha-1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), and protein disulfide-isomerase A3 (PDIA3) expression levels and coimmunoprecipitation reveals that these proteins complex with TDP-43. Overall, these results suggest that the 3X-TDP-43 model may provide new insights into pathophysiology and an avenue for drug screening in vitro for those suffering from ALS and related TDP-43 proteinopathies.}, } @article {pmid39886876, year = {2025}, author = {Kintner, J and Callaghan, M and Bulawa, L and Chu, A and Ma, Z and Williams, DL and Schoborg, RV and Kruppa, MD and Hall, JV}, title = {Dectin-1 stimulating β-glucans inhibit Chlamydia infections both in vitro and in vivo.}, journal = {Pathogens and disease}, volume = {}, number = {}, pages = {}, doi = {10.1093/femspd/ftaf002}, pmid = {39886876}, issn = {2049-632X}, abstract = {Chlamydia trachomatis and Candida albicans are common inhabitants of the female genital tract. C. albicans can impact viability and pathogenesis of some bacteria. Previously, we investigated physical interactions between C. trachomatis elementary bodies (EB) and C. albicans. This work indicated that EB bind to C. albicans and become noninfectious by 24 hours post binding. Here, we continue our investigation of these interkingdom, polymicrobial interactions. C. albicans adheres to bacteria or host surfaces via agglutinin-like sequence (Als) or heat shock 70 (Ssa) proteins. C. trachomatis EB did not bind C. albicans Ssa2 deficient strains as efficiently as wild type or complemented strains, indicating a role for this protein in chlamydial adherence to Candida. Additionally, C. albicans β-glucans inhibit chlamydial infection when exposure occurs during EB adsorption onto cervical cells. Laminarin (Lam), a β-glucan agonist of the C-type lectin receptor Dectin-1, inhibited chlamydial infection both cervical epithelial cells and mice when exposure occurred prior to, during, or immediately following EB inoculation. Conversely, a Dectin-1 antagonist laminarin (Lam-Ant) did not inhibit infection in vitro, suggesting β-glucan inhibition of C. trachomatis requires CTLR signaling. Overall, our data demonstrate that β-glucans from multiple species, including Candida albicans, inhibits Chlamydia via stimulation of host signaling pathways.}, } @article {pmid39886777, year = {2025}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Ganjali, R and Tavakol-Afshari, J}, title = {Evaluation of Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantation in Patients with Amyotrophic Lateral Sclerosis (ALS) by Investigating Patient's Specific microRNAs as Novel Biomarkers: A Clinical Trial Study.}, journal = {Current stem cell research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/011574888X330199250106081717}, pmid = {39886777}, issn = {2212-3946}, abstract = {BACKGROUND: Since there is currently no cure for amyotrophic lateral sclerosis (ALS), it is essential to search for diagnostic biomarkers and novel treatments to reduce the severity of this disease. One of these treatment approaches is stem cell transplantation.

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

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

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

CONCLUSION: Our results demonstrated that repeated transplantation of BM-MSCs was a safe procedure in ALS patients, leading to delay in disease progression and improvement in clinical symptoms. Future studies are needed to confirm these results.}, } @article {pmid39885830, year = {2025}, author = {Marthinsen, A and Gaweł, BA and Warden, GK and Górska-Ratusznik, A and Gaweł, K and Di Sabatino, M and Hallam, B}, title = {Al doped silica glass: investigation of structural response and defect interactions based on crystalline models.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {}, number = {}, pages = {}, doi = {10.1039/d4cp04581e}, pmid = {39885830}, issn = {1463-9084}, abstract = {High purity quartz glass is an important material in high-tech industries like semiconductors and photovoltaics due to, among other properties, its good mechanical performance at high temperatures. Small amounts of Al in silica glass (in the range between 20 ppm and 100 ppm) have previously been shown to increase the viscosity of the SiO2 glass. The underlying mechanism for this increase is, however, not well understood. In this paper we report on the local structural and electronic effects of the presence of Al in the SiO2 structure by density functional theory (DFT). Comparing the quartz and cristobalite polymorphs, we found that the driving force for Al substitution is larger in the denser quartz structure compared to cristobalite, and that oxygen vacancy (Vo) formation is most stabilized in the nearest neighbour position relative to Al in both polymorphs. Al was not found to inherently strengthen the SiO2 network in the two crystalline polymorphs considered. However, our results suggest that Al preferentially substitutes Si in denser ring configurations, which combined with local Vo formation could lead to locally favourable SiO2 network reconstructions in SiO2 glasses (likely towards 6-membered rings), which could propagate causing an increase in the viscosity. Furthermore, we show that the presence of Al can lower the stability of OH groups due to increased electrostatic interactions between the substitutional Al and H2O which may also be a contributing factor in the increased viscosity of Al doped SiO2 glass. The modelling results are in line with the experimental fluorescence and FT-IR spectroscopy data confirming that the presence of Al in the glass causes formation of oxygen vacancies and correlates with a lower fictive temperature which typically corresponds to a larger average Si-O-Si angle in the glass structure. Our results suggest that Al's contribution to high glass viscosity is not solely due to the substitution of Si atoms by Al atoms in the glass structure but rather due to structural changes of the silica network the substitution causes.}, } @article {pmid39885728, year = {2025}, author = {Gondim, F and Fernandes, JMA}, title = {Another family with ALS and homozygosity for p.Val120Leu (c.358G > C) mutation of SOD1.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2025.2457973}, pmid = {39885728}, issn = {2167-9223}, } @article {pmid39884586, year = {2025}, author = {Ye, L and Dittlau, KS and Sicart, A and Janky, R and Van Damme, P and Van Den Bosch, L}, title = {Sporadic ALS iPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106815}, doi = {10.1016/j.nbd.2025.106815}, pmid = {39884586}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.}, } @article {pmid39883905, year = {2025}, author = {Hollin, IL and Giler, G and Heiman-Patterson, TD and , }, title = {Health Care Delivery and Financial Considerations in Amyotrophic Lateral Sclerosis Clinics: A Survey of Clinic Directors.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e210015}, doi = {10.1212/WNL.0000000000210015}, pmid = {39883905}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Humans ; *Delivery of Health Care/economics ; Ambulatory Care Facilities/economics ; Surveys and Questionnaires ; Patient Care Team/economics ; United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical care for people living with amyotrophic lateral sclerosis (PLWALS) is directed at slowing disease progression and symptom management. The American Academy of Neurology recommends a multidisciplinary approach to providing ALS health care because observational studies show that multidisciplinary clinics (MDCs) extend survival and improve quality of life. However, providing multidisciplinary care is a challenging financial proposition. To understand how MDCs are financed, we surveyed ALS MDCs across the Northeast ALS Consortium network in the United States.

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

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

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

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

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

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

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

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

CONCLUSION: Survival times for different diagnostic groups have changed little over several decades.}, } @article {pmid39880678, year = {2025}, author = {Kozlowski, MM and Strickland, A and Morales Benitez, A and Schmidt, RE and Bloom, AJ and Milbrandt, J and DiAntonio, A}, title = {PMP2+ Schwann cells maintain the survival of large-caliber motor axons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1523/JNEUROSCI.1362-24.2025}, pmid = {39880678}, issn = {1529-2401}, abstract = {Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1, Cldn14, and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor axons. PMP2+ SCs are decreased in both ALS model mice and ALS patient nerves. Thus, PMP2+ SC dysfunction could contribute to motor-selective neuropathies. We engineered a tamoxifen-inducible Pmp2-CreERT2 mouse and expressed diphtheria toxin in PMP2+ SCs to assess the consequences of ablating this SC subtype in male and female mice. Loss of PMP2+ SCs led to significant loss of large-caliber motor axons with concomitant behavioral, electrophysiological, and ultrastructural defects. Subsequent withdrawal of tamoxifen restored both PMP2+ SCs and large-caliber motor axons and improved behavioral and electrophysiological readouts. Together, our findings highlight that the survival of large-caliber motor axons relies on PMP2+ SCs, demonstrating that malfunction of a specific SC subtype can lead to selective neuronal vulnerability.Significance Statement A hallmark of neurodegenerative disease is the differential vulnerability of neuron subtypes. While differences between neurons explain some differential sensitivity of neuronal subtypes, neuron-extrinsic mechanisms likely also contribute to selective neuronal vulnerability. Building on the recent identification of genetically distinct subtypes of myelinating Schwann cells, we test the hypothesis that Schwann cell subtypes support distinct classes of peripheral axons. To examine this, we ablated the PMP2+ subclass of myelinating Schwann cells and found preferential loss of large-caliber motor axons. These findings demonstrate that disrupting a specific SC subtype results in selective axonal vulnerability, highlighting the importance of considering neuron-extrinsic mechanisms when dissecting selective neuronal vulnerability in neurodegenerative disorders.}, } @article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, } @article {pmid39880289, year = {2025}, author = {Chen, SJ and Li, QY and Zhou, J and Wu, Q and Zhang, Y and Zhang, QQ and Hu, H and Xu, XQ and Wu, FY and Niu, Q}, title = {KDiffered brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis patients.}, journal = {Brain research bulletin}, volume = {}, number = {}, pages = {111229}, doi = {10.1016/j.brainresbull.2025.111229}, pmid = {39880289}, issn = {1873-2747}, abstract = {PURPOSE: To investigate the differences in brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis (ALS-L and ALS-B, respectively) patients using resting-state functional MRI (rs-fMRI) with amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo).

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

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

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

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

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

CONCLUSION: The study highlights the protective association of cooked vegetables and fresh fruit intake with ALS risk reduction. Additionally, an intriguing association between water intake and ALS was observed, warranting further investigation to elucidate the underlying mechanisms.}, } @article {pmid39879721, year = {2025}, author = {Derevyanko, A and Tao, T and Allen, NJ}, title = {Common alterations to astrocytes across neurodegenerative disorders.}, journal = {Current opinion in neurobiology}, volume = {90}, number = {}, pages = {102970}, doi = {10.1016/j.conb.2025.102970}, pmid = {39879721}, issn = {1873-6882}, abstract = {Astrocytes perform multiple functions in the nervous system, many of which are altered in neurodegenerative disorders. In this review, we explore shared astrocytic alterations across neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobe degeneration. Assessing recent datasets of single-nucleus RNA-sequencing of human brains, a theme emerges of common alterations in astrocyte state across disorders including in neuroinflammation, synaptic organization, metabolic support, and the cellular stress response. Immune pathways are upregulated by astrocytes across disorders and may exacerbate neurodegeneration. Dysregulated expression of synaptogenic factors could contribute to synaptic loss, while compromised metabolic support affects neuronal homeostasis. On the other hand, upregulated responses to cellular stress may represent a protective response of astrocytes and thus mitigate pathology. Understanding these shared responses offers insights into disease progression and provides potential therapeutic targets for various neurodegenerative disorders.}, } @article {pmid39879575, year = {2025}, author = {Jang, DG and Kind, AJ and Patterson, A and Pedde, M and Powell, WR and Feldman, EL and Goutman, SA}, title = {Impact of the Adverse Social Exposome on Survival in Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e213362}, doi = {10.1212/WNL.0000000000213362}, pmid = {39879575}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; *Exposome ; Aged, 80 and over ; Survival Analysis ; }, abstract = {BACKGROUND AND OBJECTIVES: An adverse social exposome negatively affects many diseases, but its association with amyotrophic lateral sclerosis (ALS) survival is unknown. This study examined the association between the social exposome measure Area Deprivation Index (ADI) and ALS survival.

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

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

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

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

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

DISCUSSION: The ALS MOTOR is a novel, accessible tool for remotely and objectively tracking ALS progression for both clinical care and research studies. Use of Rasch methodology for scale validation allowed for optimization of scale psychometric properties, which is particularly important when using the sum score as an overall outcome measure. Longitudinal and external validation studies are ongoing.}, } @article {pmid39877010, year = {2024}, author = {Stavrovskaya, AV and Voronkov, DN and Pavlova, AK and Olshanskiy, AS and Belugin, BV and Ivanova, MV and Zakharova, MN and Illarioshkin, SN}, title = {Intraventricular Administration of Exosomes from Patients with Amyotrophic Lateral Sclerosis Provokes Motor Neuron Disease in Mice.}, journal = {Acta naturae}, volume = {16}, number = {4}, pages = {73-80}, pmid = {39877010}, issn = {2075-8251}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe disease of the central nervous system (CNS) characterized by motor neuron damage leading to death from respiratory failure. The neurodegenerative process in ALS is characterized by an accumulation of aberrant proteins (TDP-43, SOD1, etc.) in CNS cells. The trans-synaptic transmission of these proteins via exosomes may be one of the mechanisms through which the pathology progresses. The aim of this work was to study the effect of an intraventricular injection of exosomes obtained from the cerebrospinal fluid (CSF) of ALS patients on the motor activity and CNS pathomorphology of mice. The exosomes were obtained from two ALS patients and a healthy donor. Exosome suspensions at high and low concentrations were injected into the lateral brain ventricles of male BALB/c mice (n = 45). Motor activity and physiological parameters were evaluated twice a month; morphological examination of the spinal cord was performed 14 months after the start of the experiment. Nine months after administration of exosomes from the ALS patients, the animals started exhibiting a pathological motor phenotype; i.e., altered locomotion with paresis of hind limbs, coordination impairment, and increasing episodes of immobility. The motor symptoms accelerated after administration of a higher concentration of exosomes. The experimental group showed a significant decrease in motor neuron density in the ventral horns of the spinal cord, a significant increase in the number of microglial cells, and microglia activation. The TDP43 protein in the control animals was localized in the nuclei of motor neurons. TDP43 mislocation with its accumulation in the cytoplasm was observed in the experimental group. Thus, the triggering effect of the exosomal proteins derived from the CSF of ALS patients in the development of a motor neuron pathology in the experimental animals was established. This confirms the pathogenetic role of exosomes in neurodegenerative progression and makes it possible to identify a new target for ALS therapy.}, } @article {pmid39876814, year = {2025}, author = {Papadopoulou, M and Stefanou, MI and Fanouraki, S and Moschovos, C and Bakola, E and Salakou, S and Zouvelou, V and Papadimas, GK and Tsivgoulis, G}, title = {Motor neuron diseases are not exclusively motor; the SSR paradigm.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2458694}, pmid = {39876814}, issn = {2167-9223}, abstract = {Motor Neuron Diseases (MNDs), familial and sporadic, are progressive neurodegenerative disorders that, for an extended period in the past, were considered purely motor disorders. During the course of the disease, however, some patients exhibit concomitant non-motor signs; thus, MNDs are currently perceived as multisystem disorders. Assessment of non-motor symptoms is usually performed clinically, although laboratory tests can also be routinely used to objectively evaluate these symptoms. Sympathetic Skin Response (SSR) is an example of a neurophysiological test that has been used in cases of Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, and Monomelic Atrophy, mostly to assess Autonomic Nervous System (ANS) disorders. Dysautonomia affects quality of life and life expectancy, as it is involved in cardiovascular events and incidents of sudden death. SSR abnormalities are present even in subclinical involvement of the ANS in MNDs. In this review, we present published research examining SSR findings in various MNDs, and discuss the correlation of SSR findings with clinical symptoms and disease severity, as well as the potential sources of abnormal findings. The aim of this study is to raise clinician awareness of autonomic dysfunction in MNDs and present the benefits of SSR examination in patient care.}, } @article {pmid39875596, year = {2025}, author = {Tomar, VR and Sharma, S and Siddhanta, S and Deep, S}, title = {Biophysical and spectroscopical insights into structural modulation of species in the aggregation pathway of superoxide dismutase 1.}, journal = {Communications chemistry}, volume = {8}, number = {1}, pages = {22}, pmid = {39875596}, issn = {2399-3669}, support = {CRG/2020/002091//DST | Science and Engineering Research Board (SERB)/ ; }, abstract = {Superoxide dismutase 1 (SOD1) aggregation is implicated in the development of Amyotrophic Lateral Sclerosis (ALS). Despite knowledge of the role of SOD1 aggregation, the mechanistic understanding remains elusive. Our investigation aimed to unravel the complex steps involved in SOD1 aggregation associated with ALS. Therefore, we probed the aggregation using ThT fluorescence, size-exclusion chromatography, and surface-enhanced Raman spectroscopy (SERS). The removal of metal ions and disulfide bonds resulted in the dimers rapidly first converting to an extended monomers then coming together slowly to form non-native dimers. The rapid onset of oligomerization happens above critical non-native dimer concentration. Structural features of oligomer was obtained through SERS. The kinetic data supported a fragmentation-dominant mechanism for the fibril formation. Quercetin acts as inhibitor by delaying the formation of non-native dimer and soluble oligomers by decreasing the elongation rate. Thus, results provide significant insights into the critical steps in oligomer formation and their structure.}, } @article {pmid39875548, year = {2025}, author = {Rabhi, C and Babault, N and Martin, C and Desforges, B and Maucuer, A and Joshi, V and Pankivskyi, S and Feng, Y and Bollot, G and Rattenbach, R and Pastré, D and Bouhss, A}, title = {TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {136}, pmid = {39875548}, issn = {2399-3642}, support = {ANR-24-CE44-3867-01-SUFATOP//Agence Nationale de la Recherche (French National Research Agency)/ ; CIFRE Grant//Association Nationale de la Recherche et de la Technologie (National Association for Research and Technology)/ ; }, mesh = {Phosphorylation ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Cytoplasm/metabolism ; *Cell Nucleus/metabolism ; RNA, Messenger/metabolism/genetics ; }, abstract = {Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, a nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations. We show that C-terminus phosphorylation prevents the recruitment of TDP-43 in mRNA-rich stress granules only under acute stress conditions because of a low affinity for mRNA but not under mild stress conditions. In addition, the self-assembly of the C-terminus is negatively regulated by phosphorylation in the cytoplasm which in turn promotes TDP-43 nuclear import. We anticipate that reducing TDP-43 C-terminus self-assembly in the cytoplasm may be an interesting strategy to reverse TDP-43 nuclear depletion in neurodegenerative diseases.}, } @article {pmid39874287, year = {2025}, author = {Baek, Y and Kim, H and Lee, D and Kim, D and Jo, E and Roh, SH and Ha, NC}, title = {Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {5}, pages = {e2408582122}, doi = {10.1073/pnas.2408582122}, pmid = {39874287}, issn = {1091-6490}, support = {RS-2021-IP321036//Ministry of Agriculture, Food and Rural Affairs (MAFRA)/ ; RS-2024-00344154//Ministry of Science and ICT, South Korea (MSIT)/ ; RS-2023-00245941//National Research Foundation of Korea (NRF)/ ; 2021M3A9I4021220//Ministry of Science and ICT, South Korea (MSIT)/ ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics/chemistry ; *Cysteine/metabolism/chemistry ; Humans ; *Amyloid/metabolism/chemistry ; *Cryoelectron Microscopy ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mutation ; Models, Molecular ; }, abstract = {The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.}, } @article {pmid39872677, year = {2025}, author = {Pulst, SM}, title = {Spinocerebellar Ataxia Type 2: A Review and Personal Perspective.}, journal = {Neurology. Genetics}, volume = {11}, number = {1}, pages = {e200225}, pmid = {39872677}, issn = {2376-7839}, abstract = {Spinocerebellar ataxias (SCAs) are dominantly inherited diseases that lead to neurodegeneration in the cerebellum and other parts of the nervous system. This review examines the progress that has been made in SCA2 from its initial clinical description to discovery of DNA CAG-repeat expansions in the ATXN2 gene. ATXN2 repeat alleles cover the range from recessive and dominant mendelian alleles to risk alleles for amyotrophic lateral sclerosis. We review studies aimed at defining the normal function of ATXN2 and mutant ATXN2 using cellular and mouse models. Progress in testing small compounds and antisense oligonucleotides in preclinical studies is described as well including our recent focus on staufen-1 (STAU1) and mRNA metabolism and control of autophagy.}, } @article {pmid39871987, year = {2024}, author = {Ribichini, E and Pallotta, N and Badiali, D and Carlucci, M and Ceccanti, M and Cambieri, C and Libonati, L and Corazziari, ES and Ruoppolo, G and Inghilleri, M}, title = {Assessment of upper GI motor activity and GI symptoms in patients with amyotrophic lateral sclerosis: an observational study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1509917}, pmid = {39871987}, issn = {1664-2295}, abstract = {BACKGROUND/AIMS: Oro-pharyngeal dysfunction has been reported in Amyotrophic Lateral Sclerosis (ALS). We aimed to assess ALS patients upper gastrointestinal (GI) motor activity and GI symptoms according to bulbar and spinal onset and severity of ALS.

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

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

CONCLUSIONS: The presence of UES spasm and the delayed gastric emptying in a subgroup of ALS patients may suggest the role of ANS dysfunction in ALS.}, } @article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266357822250119172351}, pmid = {39871563}, issn = {1873-4294}, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, } @article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037338028241230092414}, pmid = {39871559}, issn = {1875-5550}, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, } @article {pmid39870504, year = {2025}, author = {Wilson, C and Giaquinto, L and Santoro, M and Di Tullio, G and Morra, V and Kukulski, W and Venditti, R and Navone, F and Borgese, N and De Matteis, MA}, title = {A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.}, journal = {Life science alliance}, volume = {8}, number = {4}, pages = {}, doi = {10.26508/lsa.202402907}, pmid = {39870504}, issn = {2575-1077}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Mitochondria/metabolism/genetics ; Humans ; *Endoplasmic Reticulum/metabolism ; *Motor Neurons/metabolism/pathology ; *Mutation ; *Vesicular Transport Proteins/metabolism/genetics ; Animals ; Saccharomyces cerevisiae/metabolism/genetics ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Aggregates ; }, abstract = {Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear. A yeast model, expressing human mutant and WT-VAPB under the control of the orthologous yeast promoter in haploid and diploid cells, was developed to mimic the disease situation. Inclusion formation was found to be a developmentally regulated process linked to mitochondrial damage that could be attenuated by reducing ER-mitochondrial contacts. The co-expression of the WT protein retarded P56S-VAPB inclusion formation. Importantly, we validated these results in mammalian motoneuron cells. Our findings indicate that (age-related) damage to mitochondria influences the propensity of the mutant VAPB to form aggregates via ER-mitochondrial contacts, initiating a series of events leading to disease progression.}, } @article {pmid39870443, year = {2025}, author = {Zhang, Q and Walkley, CR}, title = {Mouse models for understanding physiological functions of ADARs.}, journal = {Methods in enzymology}, volume = {710}, number = {}, pages = {153-185}, doi = {10.1016/bs.mie.2024.11.024}, pmid = {39870443}, issn = {1557-7988}, mesh = {Animals ; *Adenosine Deaminase/metabolism/genetics ; Mice ; Humans ; *RNA Editing ; *Disease Models, Animal ; *RNA-Binding Proteins/metabolism/genetics ; Adenosine/metabolism/genetics ; Mutation ; Inosine/metabolism/genetics ; Autoimmune Diseases of the Nervous System/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Nervous System Malformations/genetics/metabolism ; Mice, Knockout ; }, abstract = {Adenosine-to-inosine (A-to-I) editing, is a highly prevalent posttranscriptional modification of RNA, mediated by the adenosine deaminases acting on RNA (ADAR) proteins. Mammalian transcriptomes contain tens of thousands to millions of A-to-I editing events. Mutations in ADAR can result in rare autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) through to irreversible conditions such as motor neuron disease, amyotrophic lateral sclerosis (ALS). Mouse models have played an important role in our current understanding of the physiology of ADAR proteins. With the advancement of genetic engineering technologies, a number of new mouse models have been recently generated, each providing additional insight into ADAR function. This review highlights both past and current mouse models, exploring the methodologies used in their generation, their respective discoveries, and the significance of these findings in relation to human ADAR physiology.}, } @article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {e14548}, doi = {10.1002/alz.14548}, pmid = {39868844}, issn = {1552-5279}, support = {AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, } @article {pmid39872952, year = {2023}, author = {Wang, J and Zhou, XF and Wang, YJ}, title = {Continuous antioxidant drug exposure: a bridge from ideal world to real world of therapy for amyotrophic lateral sclerosis.}, journal = {Life medicine}, volume = {2}, number = {1}, pages = {lnac042}, pmid = {39872952}, issn = {2755-1733}, } @article {pmid39867453, year = {2024}, author = {Rong, P and Heidrick, L and Pattee, G}, title = {A novel muscle network approach for objective assessment and profiling of bulbar involvement in ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1491997}, pmid = {39867453}, issn = {1662-4548}, abstract = {INTRODUCTION: As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement significantly impacts psychosocial, emotional, and physical health. A validated objective marker is however lacking to characterize and phenotype bulbar involvement, positing a major barrier to early detection, progress monitoring, and tailored care. This study aimed to bridge this gap by constructing a multiplex functional mandibular muscle network to provide a novel objective measurement tool of bulbar involvement.

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

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

CONCLUSION: The functional muscle network shows promise for an objective quantifiable measurement tool to improve early detection and profiling of bulbar involvement across the prodromal and symptomatic stages. This tool has various strengths, including the use of a clinically readily available noninvasive instrument, fully automated data processing and analytics, and generation of interpretable objective outcome measures (i.e., latent factors), together rendering it highly scalable in routine clinical practice for assessing and monitoring of bulbar involvement.}, } @article {pmid39866212, year = {2025}, author = {Wang, W and Cooper, C}, title = {Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: A dual threat to cardiac dysfunction progression.}, journal = {World journal of cardiology}, volume = {17}, number = {1}, pages = {102467}, pmid = {39866212}, issn = {1949-8462}, abstract = {Metabolic dysfunction-associated steatotic liver disease (MASLD), particularly in patients with type 2 diabetes mellitus (T2DM), is increasingly recognized as a multi-system disease that affects both hepatic and cardiovascular health. This study explores the association between MASLD-related liver fibrosis and cardiac dysfunction, focusing on how liver fibrosis contributes to cardiac remodeling and dysfunction. Cernea et al's research highlights the strong correlation between liver fibrosis and changes in left ventricular mass, left atrial dimensions, and systolic and diastolic function in diabetic patients. Notably, the study suggests a protective role of sex-hormone binding protein against cardiac remodeling. These findings underline the importance of early detection of liver fibrosis using non-invasive markers like fibrosis-4 index and nonalcoholic fatty liver disease fibrosis scores, which may offer dual protection for both liver and heart health in T2DM patients. Moreover, this study calls for further research into the shared pathogenic mechanisms, including inflammation and fibrosis pathways, between the liver and heart. It advocates for the integration of liver fibrosis screening into cardiovascular risk management, urging clinicians to adopt a more holistic approach in treating patients with MASLD and T2DM. The research has broad implications for preventing cardiovascular complications and improving outcomes in this high-risk population.}, } @article {pmid39865792, year = {2025}, author = {Murakami, E and Shibata, T and Tomemori, M and Kawai, G and Nakatani, K}, title = {The role of spatial arrangement of aromatic rings on the binding of N,N'-diheteroaryl guanidine ligands to the G2C4/G2C4 motif DNA.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {}, number = {}, pages = {}, doi = {10.1039/d4cp03213f}, pmid = {39865792}, issn = {1463-9084}, abstract = {Non-canonical DNA structures formed by aberrantly expanded repeat DNA are implicated in promoting repeat instability and the onset of repeat expansion diseases. Small molecules that target these disease-causing repeat DNAs hold promise as therapeutic agents for such diseases. Specifically, 1,3-di(quinolin-2-yl)guanidine (DQG) has been identified to bind to the disease-causing GGCCCC (G2C4) repeat DNA associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we investigate the structure-binding relationships between DQG analogs and double-stranded DNA (dsDNA) containing a G2C4/G2C4 unit. Our findings, derived from UV melting temperature, circular dichroism spectra, and surface plasmon resonance (SPR) analyses of DQG analogs, highlight the crucial role of the spatial arrangements of aromatic rings in binding to the G2C4/G2C4 unit. Among the tested DQG analogs, N,N'-di(quinazolin-2-yl)guanidine (DQzG) stands out for its ability to form seven planar conformers. These conformers enable ADD-DAA hydrogen bonding with cytosine and multiple spatial arrangements of aromatic rings, including those resembling DQG. Our binding analyses revealed that DQzG exhibits the highest affinity binding for the G2C4/G2C4 unit. NMR analysis of the DQzG-bound G2C4/G2C4-dsDNA further suggested that DQzG binds to the G2C4/G2C4 unit via hydrogen bonding. Moreover, SPR analysis demonstrated that DQzG binds more strongly to G2C4 repeat DNA compared to DQG. These results position DQzG as a promising lead compound for targeting the G2C4 repeat, offering potential therapeutic avenues for the treatment of ALS/FTD and other repeat expansion diseases.}, } @article {pmid39865616, year = {2025}, author = {Dong, S and Liu, X and Zhou, Y and Li, J and Qi, Z and Wang, Z and Yang, W and Chen, X}, title = {Prognostic Value of Cerebrospinal Fluid and Serum Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Correlation Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70256}, doi = {10.1002/brb3.70256}, pmid = {39865616}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Prognosis ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: The diagnostic and prognostic values of serum neurofilament light chain (sNfL), in comparison to cerebrospinal fluid (CSF) neurofilament light chain (cNfL), and other clinical parameters in amyotrophic lateral sclerosis (ALS) at the time of diagnosis remain elusive.

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

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

CONCLUSION: Our study underscores the robust correlation between sNfL and cNfL in ALS patients and establishes baseline sNfL as a potent and independent prognostic marker for mortality.}, } @article {pmid39863573, year = {2025}, author = {Ting, HC and Guo, YT and Su, HL and Chen, YS and Lin, SZ and Harn, HJ and Chang, CY}, title = {Rapid iPSC-derived neuromuscular junction model uncovers motor neuron dominance in amyotrophic lateral sclerosis cytopathy.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {23}, pmid = {39863573}, issn = {2058-7716}, abstract = {The neuromuscular junction (NMJ) is essential for transmitting signals from motor neurons (MNs) to skeletal muscles (SKMs), and its dysfunction can lead to severe motor disorders. However, our understanding of the NMJ is limited by the absence of accurate human models. Although human induced pluripotent stem cell (iPSC)-derived models have advanced NMJ research, their application is constrained by challenges such as limited differentiation efficiency, lengthy generation times, and cryopreservation difficulties. To overcome these limitations, we developed a rapid human NMJ model using cryopreserved MNs and SKMs derived from iPSCs. Within 12 days of coculture, we successfully recreated NMJ-specific connectivity that closely mirrors in vivo synapse formation. Using this model, we investigated amyotrophic lateral sclerosis (ALS) and replicated ALS-specific NMJ cytopathies with SOD1 mutant and corrected isogenic iPSC lines. Quantitative analysis of 3D confocal microscopy images revealed a critical role of MNs in initiating ALS-related NMJ cytopathies, characterized by alterations in the volume, number, intensity, and distribution of acetylcholine receptors, ultimately leading to impaired muscle contractions. Our rapid and precise in vitro NMJ model offers significant potential for advancing research on NMJ physiology and pathology, as well as for developing treatments for NMJ-related diseases.}, } @article {pmid39863029, year = {2025}, author = {Liu, X and Li, T and Tu, X and Xu, M and Wang, J}, title = {Mitochondrial fission and fusion in neurodegenerative diseases:Ca[2+] signalling.}, journal = {Molecular and cellular neurosciences}, volume = {}, number = {}, pages = {103992}, doi = {10.1016/j.mcn.2025.103992}, pmid = {39863029}, issn = {1095-9327}, abstract = {Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca[2+] signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca[2+] signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca[2+] signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca[2+] signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.}, } @article {pmid39862884, year = {2025}, author = {Moens, TG and Da Cruz, S and Neumann, M and Shelkovnikova, TA and Shneider, NA and Van Den Bosch, L}, title = {Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {166-178}, doi = {10.1016/S1474-4422(24)00517-9}, pmid = {39862884}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *RNA-Binding Protein FUS/genetics ; *Mutation/genetics ; Animals ; }, abstract = {Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3-0·9% of patients with ALS are FUS mutation carriers. FUS-mutation-associated ALS (FUS-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in FUS can result in markedly different age at symptom onset and rate of disease progression. Most FUS mutations disrupt its nuclear localisation, leading to its cytoplasmic accumulation in the CNS. FUS also forms inclusions in around 5% of patients with the related neurodegenerative condition frontotemporal dementia. However, there are key differences between the two diseases at the genetic and neuropathological level, which suggest distinct pathogenic processes. Experimental models have uncovered potential pathogenic mechanisms in FUS-ALS and informed therapeutic strategies that are currently in development, including the silencing of FUS expression using an intrathecally administered antisense oligonucleotide.}, } @article {pmid39862877, year = {2025}, author = {Feldman, EL and Sattler, R and Kiernan, MC and Goutman, SA and Chiò, A and Al-Chalabi, A}, title = {Transforming amyotrophic lateral sclerosis into a liveable disease.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {100-101}, doi = {10.1016/S1474-4422(24)00523-4}, pmid = {39862877}, issn = {1474-4465}, } @article {pmid39861520, year = {2025}, author = {Tripolskaja, L and Kazlauskaite-Jadzevice, A and Razukas, A and Baksiene, E}, title = {Perennial Grasses on Stony Sandy Loam Arenosol: Summary of Results of Long-Term Experiment in Northern Europe Region (1995-2024).}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, doi = {10.3390/plants14020166}, pmid = {39861520}, issn = {2223-7747}, support = {"Improvement of the preparation of highly skilled professionals for development of science-intensive economic entities-NKPDOKT" (project code No: VP1-3.1-ŠMM-01-V-03-001)//Lietuvos mokslų taryba/ ; }, abstract = {Grasses can sustain soil functions despite nutrient depletion, which can have serious consequences for soil processes and ecosystem services. This paper summarizes the results of the long-term experiment (1995-2024) carried out in Arenosol within a temperate climate zone, focusing on the productivity of natural and managed grasslands; their succession changes over time, and so do the effects on soil chemical properties, and soil organic carbon (SOC) sequestration. The results indicated that two land uses-abandoned land (AL) and grassland fertilized with mineral fertilizers (MGf)-can be effectively applied to prevent Arenosol soil degradation. SOC accumulation occurs more rapidly in AL soils, and their chemical properties show less change over time. The ability of grasses to sequester SOC is better reflected by SOC stocks across the Ah horizon, where thickness varies over long-term grassland use. Significant changes in soil properties were observed more than 20 years after converting arable to herbaceous land use. While MGf has the highest biomass productivity, the use of fertilizers leads to soil acidification. The biomass productivity of AL and MGf increased with longer grassland use; however, in MG, productivity decreased without fertilizers, reaching AL's productivity levels after 20 years. As the age of AL increased, plant biodiversity decreased, and drought-resistant plants began to spread.}, } @article {pmid39860557, year = {2025}, author = {Chmiel, J and Stępień-Słodkowska, M}, title = {Resting-State EEG Oscillations in Amyotrophic Lateral Sclerosis (ALS): Toward Mechanistic Insights and Clinical Markers.}, journal = {Journal of clinical medicine}, volume = {14}, number = {2}, pages = {}, doi = {10.3390/jcm14020545}, pmid = {39860557}, issn = {2077-0383}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a complex, progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the brain, brainstem, and spinal cord. Several neuroimaging techniques can help reveal the pathophysiology of ALS. One of these is the electroencephalogram (EEG), a noninvasive and relatively inexpensive tool for examining electrical activity of the brain with excellent temporal precision. Methods: This mechanistic review examines the pattern of resting-state EEG activity. With a focus on publications published between January 1995 and October 2024, we carried out a comprehensive search in October 2024 across a number of databases, including PubMed/Medline, Research Gate, Google Scholar, and Cochrane. Results: The literature search yielded 17 studies included in this review. The studies varied significantly in their methodology and patient characteristics. Despite this, a common biomarker typical of ALS was found-reduced alpha power. Regarding other oscillations, the findings are less consistent and sometimes contradictory. As this is a mechanistic review, three possible explanations for this biomarker are provided. The main and most important one is increased cortical excitability. In addition, due to the limitations of the studies, recommendations for future research on this topic are outlined to enable a further and better understanding of EEG patterns in ALS. Conclusions: Most studies included in this review showed alpha power deficits in ALS patients, reflecting pathological hyperexcitability of the cerebral cortex. Future studies should address the methodological limitations identified in this review, including small sample sizes, inconsistent frequency-band definitions, and insufficient functional outcome measures, to solidify and extend current findings.}, } @article {pmid39859339, year = {2025}, author = {Yashooa, RK and Duranti, E and Conconi, D and Lavitrano, M and Mustafa, SA and Villa, C}, title = {Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, doi = {10.3390/ijms26020626}, pmid = {39859339}, issn = {1422-0067}, mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Mitochondria/metabolism/genetics ; Animals ; Gene Expression Regulation ; DNA, Mitochondrial/genetics/metabolism ; }, abstract = {MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.}, } @article {pmid39859258, year = {2025}, author = {Szablewski, L}, title = {Associations Between Diabetes Mellitus and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, doi = {10.3390/ijms26020542}, pmid = {39859258}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/etiology ; *Diabetes Mellitus, Type 2/complications/metabolism ; Parkinson Disease/metabolism/pathology ; Oxidative Stress ; Alzheimer Disease/metabolism/etiology/pathology ; Amyotrophic Lateral Sclerosis/metabolism/etiology/pathology ; Diabetes Mellitus, Type 1/complications/metabolism ; Huntington Disease/metabolism/pathology ; Diabetes Mellitus/metabolism ; Animals ; }, abstract = {Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.}, } @article {pmid39858428, year = {2024}, author = {Argueti-Ostrovsky, S and Barel, S and Kahn, J and Israelson, A}, title = {VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.}, journal = {Biomolecules}, volume = {15}, number = {1}, pages = {}, doi = {10.3390/biom15010033}, pmid = {39858428}, issn = {2218-273X}, support = {#284/19 and #485/24//Israel Science Foundation/ ; }, mesh = {Humans ; *Voltage-Dependent Anion Channel 1/metabolism/genetics ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; alpha-Synuclein/metabolism/genetics ; Alzheimer Disease/metabolism/pathology/genetics ; Superoxide Dismutase-1/metabolism/genetics ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Mitochondrial Membranes/metabolism ; }, abstract = {Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration.}, } @article {pmid39857761, year = {2025}, author = {Sun, C and Chen, Y and Xu, L and Wang, W and Zhang, N and Fournier, CN and Li, N and Fan, D}, title = {Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale as a Novel Tool to Measure Disease Progression.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, doi = {10.3390/biomedicines13010178}, pmid = {39857761}, issn = {2227-9059}, support = {82001347//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; 81701067//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {Background: A valuable outcome measure to monitor amyotrophic lateral sclerosis (ALS) disease progression is crucial in clinical trials. Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a novel questionnaire assessing ALS disability. Currently, there are no studies on the relationship between ROADS and ALS survival. This study explored the value of Chinese ROADS as a novel tool for measuring disease progression and the correlation between ROADS and ALS survival. Methods: A total of 170 ALS participants were included in this study. Clinical characteristics and baseline ROADS, ΔROADS, ALSFRS-R, and ΔFRS of patients were collected. Participants were followed for 18 months to assess time to tracheostomy and survival. Scales were collected every 3 to 6 months. We evaluated the association of baseline ROADS and ΔROADS with survival using Cox regression analyses. Linear mixed effects models were used to assess changes over time in ROADS and ALSFRS-R. Results: Multivariate Cox models confirmed that baseline ROADS positively correlated with ALS survival (HR = 0.95, p < 0.001), while baseline ΔROADS negatively correlated with survival (HR = 1.26, p < 0.001). Additionally, linear mixed effects models suggested that ROADS, similar to ALSFRS-R, declined significantly over time, but there was no significant difference between these two. Conclusions: Our study indicates that Chinese ROADS is strongly related to ALS survival. Changes in ROADS with disease progression are similar to those in ALSFRS-R. These findings support Chinese ROADS as a reliable outcome measure for clinical trials, potentially enhancing the dimension of evaluating treatment effectiveness in ALS trials.}, } @article {pmid39857633, year = {2024}, author = {Zhang, G and Cao, W and Wang, Z and Xia, K and Deng, B and Fan, D}, title = {Associations of Abnormal Sleep Duration and Chronotype with Higher Risk of Incident Amyotrophic Lateral Sclerosis: A UK Biobank Prospective Cohort Study.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, doi = {10.3390/biomedicines13010049}, pmid = {39857633}, issn = {2227-9059}, support = {82301601 81873784 82071426//National Natural Science Foundation of China/ ; }, abstract = {Background: The occurrence of sleep disturbances in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, there is still a lack of reliable evidence of a relationship between sleep disturbances and the risk of developing ALS. The aim of this study was to prospectively investigate the longitudinal associations between sleep traits and the risk of incident ALS. Methods: We included information from 409,045 individuals from the prospective cohort of the UK Biobank. Sleep traits at baseline were measured using a standardized questionnaire. All sleep traits were analyzed in relation to the subsequent incidence of ALS using Cox proportional hazards models. Results: Multivariate analysis showed that 6-7 h of sleep was related to the lowest risk for ALS. A long sleep duration (≥8 h) was associated with an increased risk of ALS incidence (HR: 1.31, 95% CI: 1.07-1.61; p = 0.009). A short sleep duration (<6 h) was associated with an increased risk of ALS incidence (HR: 1.91, 95% CI: 1.10-3.30, p = 0.021) in females. In participants aged ≥65 years, eveningness was associated with increased ALS risk (HR: 1.32, 95% CI: 1.08-1.61; p = 0.006). Conclusion: Our results hint at a sleep duration that is too short or too long, and certain chronotypes might be related to the risk of developing ALS. Despite the limitations imposed by the study design and the subjectivity of sleep information, our findings suggest that sleep disturbances may influence the risk of developing ALS.}, } @article {pmid39857620, year = {2024}, author = {Frawley, L and Taylor, NT and Sivills, O and McPhillamy, E and To, TD and Wu, Y and Chin, BY and Wong, CY}, title = {Stem Cell Therapy for the Treatment of Amyotrophic Lateral Sclerosis: Comparison of the Efficacy of Mesenchymal Stem Cells, Neural Stem Cells, and Induced Pluripotent Stem Cells.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, doi = {10.3390/biomedicines13010035}, pmid = {39857620}, issn = {2227-9059}, support = {Australian Government New Colombo Plan (NCP) scheme//Australian Government New Colombo Plan (NCP) scheme/ ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a debilitating, incurable neurodegenerative disorder characterised by motor neuron death in the spinal cord, brainstem, and motor cortex. With an incidence rate of about 4.42 cases per 100,000 people annually, ALS severely impacts motor function and quality of life, causing progressive muscle atrophy, spasticity, paralysis, and eventually death. The cause of ALS is largely unknown, with 90% of cases being sporadic and 10% familial. Current research targets molecular mechanisms of inflammation, excitotoxicity, aggregation-prone proteins, and proteinopathy.

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

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

CONCLUSIONS: This research is significant for advancing ALS treatment beyond symptomatic relief and modest survival extensions to actively modifying disease progression and improving patient outcomes. Successful stem cell therapies could lead to new ALS treatments, slowing motor function loss and reducing symptom severity.}, } @article {pmid39857328, year = {2025}, author = {Stoccoro, A}, title = {Epigenetic Mechanisms Underlying Sex Differences in Neurodegenerative Diseases.}, journal = {Biology}, volume = {14}, number = {1}, pages = {}, doi = {10.3390/biology14010098}, pmid = {39857328}, issn = {2079-7737}, support = {GR-2021-12374436//Italian Ministry of Health, Ricerca Finalizzata/ ; }, abstract = {Neurodegenerative diseases are characterized by profound differences between females and males in terms of incidence, clinical presentation, and disease progression. Furthermore, there is evidence suggesting that differences in sensitivity to medical treatments may exist between the two sexes. Although the role of sex hormones and sex chromosomes in driving differential susceptibility to these diseases is well-established, the molecular alterations underlying these differences remain poorly understood. Epigenetic mechanisms, including DNA methylation, histone tail modifications, and the activity of non-coding RNAs, are strongly implicated in the pathogenesis of neurodegenerative diseases. While it is known that epigenetic mechanisms play a crucial role in sexual differentiation and that distinct epigenetic patterns characterize females and males, sex-specific epigenetic patterns have been largely overlooked in studies aiming to identify epigenetic alterations associated with neurodegenerative diseases. This review aims to provide an overview of sex differences in epigenetic mechanisms, the role of sex-specific epigenetic processes in the central nervous system, and the main evidence of sex-specific epigenetic alterations in three neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Understanding the sex-related differences of these diseases is essential for developing personalized treatments and interventions that account for the unique epigenetic landscapes of each sex.}, } @article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology & therapeutics}, volume = {}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, } @article {pmid39854930, year = {2025}, author = {Drouet, C and Priou, P and Gagnadoux, F and Trzepizur, W}, title = {Constraints to the initiation of home non-invasive ventilation and short-term efficacy in different diagnostic groups (as a prelude to an ambulatory shift).}, journal = {Respiratory medicine and research}, volume = {87}, number = {}, pages = {101154}, doi = {10.1016/j.resmer.2025.101154}, pmid = {39854930}, issn = {2590-0412}, abstract = {INTRODUCTION: Non-invasive ventilation (NIV) is the reference treatment for chronic respiratory failure (CRF) due to impairment of the ventilatory system. Home initiation is increasingly practiced. To better support this ambulatory shift, we aimed to assess the implementation constraints and short-term efficacy according to different aetiologies of CRF.

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

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

CONCLUSION: Each aetiological group has specific constraints in the initiation of NIV that should be considered when initiating NIV in the outpatient setting.}, } @article {pmid39854095, year = {2025}, author = {Hansen, G and Shaw, A and Bolt, K and Verity, R and Nataraj, RT and Schellenberg, KL}, title = {Thoracic Electric Impedance Tomography Detects Lung Volume Changes in Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28354}, pmid = {39854095}, issn = {1097-4598}, support = {//ALS Society of Saskatchewan/ ; }, abstract = {INTRODUCTION/AIMS: Spirometry is the conventional means to measure lung function in amyotrophic lateral sclerosis (ALS), but is dependent on patient effort and bulbar strength. We aimed to use electric impedance tomography (EIT), an emerging non-invasive imaging modality, to measure dynamic lung volume changes.

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

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

DISCUSSION: EIT is an emerging alternative to existing measures of lung function in ALS, but without need for patient effort or bulbar strength. Significant losses in lung volume are seen on supine compared to upright position in patients with respiratory dysfunction. Further study is needed to determine relationships to existing clinical measures.}, } @article {pmid39853150, year = {2025}, author = {Shune, S and Gray, LT and Perry, S and Kosty, D and Namasivayam-MacDonald, A}, title = {Validation of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) Screening Tool for Neurodegenerative Disease.}, journal = {American journal of speech-language pathology}, volume = {}, number = {}, pages = {1-13}, doi = {10.1044/2024_AJSLP-24-00253}, pmid = {39853150}, issn = {1558-9110}, abstract = {PURPOSE: Swallowing difficulties have a substantial impact on the burden experienced by care partners of individuals with neurodegenerative disease. Given this, there is a clear need to easily identify and quantify the unique aspects of swallowing-related burden. The purpose of this study was to establish the validity and reliability of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) screening tool in care partners of individuals with neurodegenerative disease.

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

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

CONCLUSIONS: Results establish the CARES as a valid and reliable screening tool that can detect burden related to swallowing difficulties among care partners of individuals living with neurodegenerative disease (score ≥ 4). Clinical implementation of the CARES requires the concerted efforts of the larger multidisciplinary team who can collaboratively identify the presence of burden and target the multifaceted sources of burden that a care partner may be experiencing.}, } @article {pmid39852553, year = {2025}, author = {Tang, X and Chen, Y and Ren, Y and Yang, W and Yu, W and Zhou, Y and Guo, J and Hu, J and Chen, X and Gu, Y and Wang, C and Dong, Y and Yang, H and Sato, C and He, J and Fan, D and You, L and Zinman, L and Rogaeva, E and Chen, Y and Zhang, M}, title = {Deep learning analyses of splicing variants identify the link of PCP4 with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf025}, pmid = {39852553}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with most sporadic cases lacking clear genetic causes. Abnormal pre-mRNA splicing is a fundamental mechanism in neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) loss-of-function (LOF) causes widespread RNA mis-splicing events in ALS. Additionally, splicing mutations are major contributors to neurological disorders. However, the role of intronic variants driving RNA mis-splicing in ALS remains poorly understood. To address this, we developed Spliformer to predict RNA splicing. Spliformer is a transformer-based deep learning model trained and tested on splicing events from the GENCODE database, as well as RNA-seq data from blood and central nervous system tissues. We benchmarked Spliformer against SpliceAI and Pangolin using testing datasets and paired whole-genome sequencing (WGS) with RNA-seq data. We further developed the Spliformer-motif model to identify splicing regulatory motifs. We analyzed Clinvar dataset to identify the link of splicing variants with disease pathogenicity. Additionally, we analyzed WGS data of ALS patients and controls to identify common intronic splicing variants linked to ALS risk or disease phenotypes. We also profiled rare intronic splicing variants in ALS patients to identify known or novel ALS-associated genes. Minigene assays were employed to validate candidate splicing variants. Finally, we measured spine density in neurons with a specific gene knockdown or those expressing a TDP-43 disease-causing mutant. Spliformer accurately predicts the possibilities of a nucleotide within a pre-mRNA sequence being a splice donor, acceptor, or neither. Spliformer outperformed SpliceAI and Pangolin in both speed and accuracy in tested splicing events and/or paired WGS/RNA-seq data. Spliformer-motif successfully identified canonical and novel splicing regulatory motifs. In Clinvar dataset, splicing variants are highly related to disease pathogenicity. Genome-wide analyses of common intronic splicing variants nominated one variant linked to ALS progression. Deep learning analyses of WGS data from 1,370 ALS patients revealed rare splicing variants in reported ALS genes (such as PTPRN2 and CFAP410, validated through minigene assays and RNA-seq), and TDP-43 LOF related RNA mis-splicing genes (such as PTPRD). Further genetic analysis and minigene assays nominated PCP4 and TMEM63A as ALS-associated genes. Functional assays demonstrated that PCP4 is critical for maintaining spine density and can rescue spine loss in neurons expressing a disease-causing TDP-43 mutant. In summary, we developed Spliformer and Spliformer-motif that accurately predict and interpret pre-mRNA splicing. Our findings highlight an intronic genetic mechanism driving RNA mis-splicing in ALS and nominate PCP4 as an ALS-associated gene.}, } @article {pmid39852477, year = {2025}, author = {Bennett, SA and Cobos, SN and Fisher, RMA and Son, E and Frederic, R and Segal, R and Yousuf, H and Chan, K and Dansu, DK and Torrente, MP}, title = {Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, doi = {10.3390/jof11010058}, pmid = {39852477}, issn = {2309-608X}, support = {R15NS125394//NIH NINDS/ ; K22NS09131401//NIH NINDS/ ; R15NS125394-01S1//NIH NINDS/ ; K12GM102778//NIH NIGMS/ ; R35NS111604//NIH NINDS/ ; N/A//The Graduate Center, CUNY/ ; N/A//Brooklyn College, CUNY/ ; 1S01OD010582-01A1/GF/NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the FUS gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109-responsible for installing H3S10ph and H3K56ac-are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.}, } @article {pmid39851451, year = {2025}, author = {Milligan, C and Cowley, DO and Stewart, W and Curry, AM and Forbes, E and Rector, B and Hastie, A and Liu, L and Hawkins, GA}, title = {Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models.}, journal = {Brain sciences}, volume = {15}, number = {1}, pages = {}, doi = {10.3390/brainsci15010084}, pmid = {39851451}, issn = {2076-3425}, support = {DoD W81XWH1810377//US Department of the Army/ ; 1R03AI137866-21A1/NH/NIH HHS/United States ; Neuroscience Clinical Trial and Innovation Center//Wake Forest University School of Medicine/ ; Hope for Tomorrow ALS Fund//Wake Forest University School of Medicine/ ; TAB Williams Endowment//Wake Forest University School of Medicine/ ; }, abstract = {Background/Objectives: Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. Methods: We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred SOD1[G93A] mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. Results: The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. Conclusions: Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common Il6R Asp[358]Ala variant.}, } @article {pmid39850989, year = {2025}, author = {Matsuda, C and Nakayama, Y and Haraguchi, M and Morishima, R and Itagaki, Y and Bokuda, K and Kimura, H and Takahashi, K and Shimizu, T}, title = {Patients' choices regarding ventilatory support affect opioid use in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2453463}, pmid = {39850989}, issn = {2167-9223}, abstract = {OBJECTIVE: To investigate the impact of different ventilatory support options on opioid use among patients with amyotrophic lateral sclerosis (ALS).

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

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

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

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

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

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

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

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

DISCUSSION: Treg levels remained stable during the ALS observation period and were not significantly associated with ALSFRS-r variations, suggesting that Treg numbers alone may have limited utility as a pharmaco-dynamic biomarker for ALS trials. However the observed changes in Treg phenotypes, such as the decrease in PD1+Tregs, indicate that phenotypic variations may warrant further investigation for their potential role in ALS progression and therapeutic targeting.}, } @article {pmid39845577, year = {2025}, author = {Ludolph, A and Wiesenfarth, M}, title = {Tofersen and other antisense oligonucleotides in ALS.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251313915}, pmid = {39845577}, issn = {1756-2856}, abstract = {The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?}, } @article {pmid39844967, year = {2025}, author = {de Melo, R and Alcantara, L and Sarmet, M and Sheers, NL and Berlowitz, DJ and Maldaner, V}, title = {Use of Lung Volume Recruitment Technique in Patients With Chronic Respiratory Disease Among Brazilian Health Professionals.}, journal = {Pulmonary medicine}, volume = {2025}, number = {}, pages = {4073171}, pmid = {39844967}, issn = {2090-1844}, mesh = {Humans ; Brazil ; Cross-Sectional Studies ; Chronic Disease ; Adult ; Surveys and Questionnaires ; *Allied Health Personnel ; Male ; Respiratory Therapy/methods ; }, abstract = {Background: Lung volume recruitment (LVR) is a stacked-breath assisted inflation technique in which consecutive insufflations are delivered, without exhaling in between, until the maximum tolerable inflation capacity is reached. Although LVR is recommended in some neuromuscular disease guidelines, there is little information detailing when and how allied health professionals (AHPs) prescribe LVR. Objective: This study is aimed at describing the use of LVR in practice across Brazil. Methods: A cross-sectional e-survey (Sep-Nov 2023) explored LVR practices among qualified clinical or home care AHPs in Brazil. It gathered participant data on geographical region, profession, and experience. It delved into LVR specifics: clinical population and indications for use, prescription (frequency, dosage, and interfaces), related side effects, outcomes assessed, and combined therapies. Results were presented descriptively. Results: One hundred two surveys (74 physical therapists (PTs) and 28 speech and language pathologists (SLPs)) from diverse locations were collected. LVR was predominantly prescribed for adults (57%), with the most common diagnosis being amyotrophic lateral sclerosis (84%). Changes in peak cough flow and vital capacity were the most common reasons for LVR prescription. Maximal insufflation capacity was reportedly measured by 58% of PTs and 22% of SLPs. Chest wall soreness and discomfort were the most common side effects, and many respondents did not provide warnings about potential side effects (42% PTs and 50% SLPs). The study highlighted common use of other respiratory therapy devices alongside LVR. Conclusion: LVR is available in routine clinical and home care settings in Brazil. There is a lack of standardization regarding indications, prescription, and outcome measures among PTs and SLPs in Brazil. Clear recommendations and guidelines are needed to standardize these parameters, enabling more objective data and facilitating comparisons between centers.}, } @article {pmid39844875, year = {2024}, author = {Kõks, S and Rallmann, K and Muldmaa, M and Price, J and Pfaff, AL and Taba, P}, title = {Whole blood transcriptome profile identifies motor neurone disease RNA biomarker signatures.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {249}, number = {}, pages = {10401}, pmid = {39844875}, issn = {1535-3699}, mesh = {Humans ; *Motor Neuron Disease/genetics/blood/diagnosis ; Female ; Male ; *Biomarkers/blood ; *Transcriptome/genetics ; Middle Aged ; *Gene Expression Profiling/methods ; Aged ; RNA/blood/genetics ; Case-Control Studies ; Adult ; }, abstract = {Blood-based biomarkers for motor neuron disease are needed for better diagnosis, progression prediction, and clinical trial monitoring. We used whole blood-derived total RNA and performed whole transcriptome analysis to compare the gene expression profiles in (motor neurone disease) MND patients to the control subjects. We compared 42 MND patients to 42 aged and sex-matched healthy controls and described the whole transcriptome profile characteristic for MND. In addition to the formal differential analysis, we performed functional annotation of the genomics data and identified the molecular pathways that are differentially regulated in MND patients. We identified 12,972 genes differentially expressed in the blood of MND patients compared to age and sex-matched controls. Functional genomic annotation identified activation of the pathways related to neurodegeneration, RNA transcription, RNA splicing and extracellular matrix reorganisation. Blood-based whole transcriptomic analysis can reliably differentiate MND patients from controls and can provide useful information for the clinical management of the disease and clinical trials.}, } @article {pmid39844762, year = {2025}, author = {Theuriet, J and Bernard, E and Guy, N and Taithe, F and Even, C and Maisonobe, T and Sangaré, A and Lardeux, P and Tilikete, CF and Couratier, P and Lenglet, T and Pegat, A}, title = {Electrophysiological Abnormalities in Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease: Three New Patients and Review of the Literature.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28357}, pmid = {39844762}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease (FEWDON-MND) is characterized by motor weakness predominantly affecting finger extension, accompanied by downbeat nystagmus. To date, only 11 patients have been reported. The present study adds a further three and aims to provide a more detailed description of the electrodiagnostic features of these patients.

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

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

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

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

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

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

CONCLUSION: Mood disorders appeared independent of cognitive profiles but related to behavioral changes. This is particularly relevant for clinicians discussing end-of-life decisions with patients.}, } @article {pmid39841674, year = {2025}, author = {Grapperon, AM and El Mendili, MM and Maarouf, A and Ranjeva, JP and Guye, M and Verschueren, A and Attarian, S and Zaaraoui, W}, title = {In vivo mapping of sodium homeostasis disturbances in individual ALS patients: A brain 23Na MRI study.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0316916}, doi = {10.1371/journal.pone.0316916}, pmid = {39841674}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Middle Aged ; *Homeostasis ; *Sodium/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Aged ; Sodium Isotopes ; Adult ; Brain Mapping/methods ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by significant heterogeneity among patients. 23Na MRI maps abnormal sodium homeostasis that reflects metabolic alterations and energetic failure contributing to the neurodegenerative process. In this study, we investigated disease severity at the individual level in ALS patients using brain 23Na MRI.

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

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

DISCUSSION: This study mapping sodium homeostasis disturbances at the individual level in ALS patients through 23Na MRI evidenced heterogeneity of TSC increase among patients associated with clinical presentation and disease severity. These findings suggest that TSC increase detected at the individual level by 23Na MRI may be a useful marker of the clinical heterogeneity of ALS patients, a factor that is likely to greatly influence the results of therapeutic trials.}, } @article {pmid39841625, year = {2025}, author = {Hoengenaert, L and Anders, C and Van Doorsselaere, J and Vanholme, R and Boerjan, W}, title = {Transgene-free genome editing in poplar.}, journal = {The New phytologist}, volume = {}, number = {}, pages = {}, doi = {10.1111/nph.20415}, pmid = {39841625}, issn = {1469-8137}, support = {//Universiteit Gent/ ; G011620N//Fonds Wetenschappelijk Onderzoek/ ; //Energy Transition Fund/ ; //Advanced ERC grant POPMET/ ; }, abstract = {Precise gene-editing methods are valuable tools to enhance genetic traits. Gene editing is commonly achieved via stable integration of a gene-editing cassette in the plant's genome. However, this technique is unfavorable for field applications, especially in vegetatively propagated plants, such as many commercial tree species, where the gene-editing cassette cannot be segregated away without breaking the genetic constitution of the elite variety. Here, we describe an efficient method for generating gene-edited Populus tremula × P. alba (poplar) trees without incorporating foreign DNA into its genome. Using Agrobacterium tumefaciens, we expressed a base-editing construct targeting CCoAOMT1 along with the ALS genes for positive selection on a chlorsulfuron-containing medium. About 50% of the regenerated shoots were derived from transient transformation and were free of T-DNA. Overall, 7% of the chlorsulfuron-resistant shoots were T-DNA free, edited in the CCoAOMT1 gene and nonchimeric. Long-read whole-genome sequencing confirmed the absence of any foreign DNA in the tested gene-edited lines. Additionally, we evaluated the CodA gene as a negative selection marker to eliminate lines that stably incorporated the T-DNA into their genome. Although the latter negative selection is not essential for selecting transgene-free, gene-edited Populus tremula × P. alba shoots, it may prove valuable for other genotypes or varieties.}, } @article {pmid39814069, year = {2025}, author = {Uhl, J and Schönfeld, S and Meyer, L and Reus, A and Neumann, C and Langer, L and Michaelsen, MM and Esch, T}, title = {(Digital) Mind-Body Intervention to Promote Health and Subjective Well-Being of Residents in Nursing Homes: A Cluster-Randomized Controlled Pilot Study.}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2517-8263}, pmid = {39814069}, issn = {1439-4421}, abstract = {BACKGROUND: Nursing care insurance companies in Germany have the legal mandate to develop measures to strengthen the health resources of residents of nursing homes. The present study aimed to examine a mindfulness-informed mind-body intervention (on-site and app) adapted for residents in nursing homes regarding their effect on health-related parameters.

METHODS: A pilot study (DRKS00030409) was carried out with three groups in twelve nursing homes (RCT). There was an on-site intervention in a group (O), an individual app application with technical support (A) and a passive control group (C). The participating residents (nO=28; nA=29; nC=19) were cluster-randomized. Before, after, and three months after the intervention period (December 2022 - January 2023), among other things, subjective well-being (WHO-5, primary outcome) and mindfulness (KIMS-D, including four subscales) were assessed. Differences within and between study groups and participants with different participation intensity were tested. In addition, a sensitivity analysis was carried out with people who did not have severe cognitive impairments at all three survey times.

RESULTS: Indications of differences were found in subjective well-being during the intervention period between the study groups of medium size. While a decrease was observed in the control group, there was no change in the intervention groups. When the intensity of participation was taken into account, the difference between the groups became clearer. In addition, the app group showed an increase in mindfulness (subscale Observing) immediately after the intervention compared to the control group.

DISCUSSION: Although further studies with larger samples are needed, the results already indicate that the intervention improves the well-being and mindfulness of the target group. Individual support could explain the higher effectiveness in the app group. The influence of the Covid-19 pandemic and the season (winter) on effectiveness must also be examined. Hintergrund: Pflegeversicherungen in Deutschland haben den gesetzlichen Auftrag, Maßnahmenvorschläge zur Stärkung von Gesundheitsressourcen der Bewohnenden in stationären Pflegeeinrichtungen zu entwickeln. Ziel der vorliegenden Studie war es, für diese Zielgruppe eine partizipativ angepasste achtsamkeitsinformierte Mind-Body-Maßnahme (Präsenz und App) hinsichtlich ihrer Wirkung auf gesundheitsbezogene Parameter zu untersuchen.

METHODIK: Es wurde eine Pilotstudie (DRKS00030409) als RCT mit drei Gruppen in zwölf Pflegeeinrichtungen durchgeführt. Hierbei gab es eine Präsenz-Gruppe (O), eine Gruppe mit App-Einzelanwendung und technischer Unterstützung (A) und eine passive Kontrollgruppe (C). Die teilnehmenden Bewohnenden (nO=28; nA=29; nC=19) wurden Cluster-randomisiert. Vor, nach und drei Monate nach dem Interventionszeitraum (Dezember 2022 - Januar 2023) wurde mittels eines Fragebogens u.a. das subjektive Wohlbefinden (WHO-5, primäres Outcome) und Achtsamkeit (KIMS-D, inkl. vier Subskalen) erhoben. Es wurde auf Unterschiede innerhalb und zwischen den Studiengruppen und entsprechend der Teilnahmeintensität getestet. Außerdem wurde eine Sensitivitätsanalyse mit Personen durchgeführt, die keine kognitiven Einschränkungen aufwiesen (T0-T2). Ergebnisse: Es gab einen Hinweis auf eine unterschiedliche Entwicklung des subjektiven Wohlbefindens während des Interventionszeitraums von mittlerer Größe. Während in der Kontrollgruppe eine Verschlechterung zu beobachten war, lag in den Interventionsgruppen keine Reduktion vor. Bei Berücksichtigung der Teilnahmeintensität wurde der Unterschied deutlicher. Außerdem zeigte die App-Gruppe direkt nach der Intervention eine Erhöhung der Achtsamkeit (Subskala Beobachten) im Vergleich zur Kontrollgruppe.

DISKUSSION: Weitere Studien mit größeren Stichproben sind erforderlich. Die vorliegenden Ergebnisse weisen jedoch darauf hin, dass die Interventionen das Wohlbefinden und die Achtsamkeit der Zielgruppe verbessert. Die höhere Wirksamkeit in der App-Gruppe könnte durch die Einzelbetreuung erklärt werden. Der Einfluss von Corona-Maßnahmen sowie der Jahreszeit (Winter) auf die Wirksamkeit sind zu prüfen.}, } @article {pmid39840922, year = {2025}, author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O'Connell, C}, title = {Associations between water exposure and the development of amyotrophic lateral sclerosis: a matched case-control study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2453450}, pmid = {39840922}, issn = {2167-9223}, abstract = {OBJECTIVE: Previous studies have hinted at an association between water exposure and the development of ALS. However, proximity measures to these water sources have been limited to questionnaires or large buffers due to a lack of fine geospatial measures. They also do not distinguish the various classes of hydrographic features. Thus, we created a robust database to investigate the association between proximity to water bodies at place of residence and the development of ALS.

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

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

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

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

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

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

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

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

CONCLUSION: During RNS test, assessing area decrement significantly enhances our ability to detect the impairment of neuromuscular transmission in patients with ALS. Independent factors contributing to decremental response need to be considered in drug development and clinical trials targeting NMJ in patients with ALS.}, } @article {pmid39838960, year = {2025}, author = {Min, SM and Bashore, FM and Smith, JL and Havener, TM and Howell, S and Li, H and Couñago, RM and Popov, KI and Axtman, AD}, title = {Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.4c02531}, pmid = {39838960}, issn = {1520-4804}, abstract = {We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn's disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability.}, } @article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

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

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

CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.}, } @article {pmid39838446, year = {2025}, author = {Ou, K and Jia, Q and Li, D and Li, S and Li, XJ and Yin, P}, title = {Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {4}, pmid = {39838446}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Huntington Disease/genetics/drug therapy/therapy ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; Genetic Therapy/methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.}, } @article {pmid39838017, year = {2025}, author = {McCaig, CD}, title = {Neurological Diseases can be Regulated by Phase Separation.}, journal = {Reviews of physiology, biochemistry and pharmacology}, volume = {187}, number = {}, pages = {273-338}, pmid = {39838017}, issn = {0303-4240}, mesh = {Humans ; *Nervous System Diseases ; Animals ; Superoxide Dismutase/metabolism ; Motor Neuron Disease ; Neurons/metabolism ; Phase Separation ; }, abstract = {Several neurological diseases arise from abnormal protein aggregation within neurones and this is closely regulated by phase separation. One such is motor neurone disease and aberrant aggregation of superoxide dismutase. Again these events are regulated by electrical forces that are examined.}, } @article {pmid39837582, year = {2025}, author = {Brubacher, LJ and Yellappa, V and Lestari, BW and Heitkamp, P and Aguilera Vasquez, N and Sassi, A and Olusola-Faleye, B and Thapa, P and Shyam Klinton, J and Sheokand, S and Pai, M and Oga-Omenka, C}, title = {Health and tuberculosis systems resilience, the role of the private sector and pandemic preparedness: insights from a cross-country qualitative study with policy-makers in India, Indonesia and Nigeria.}, journal = {BMJ global health}, volume = {10}, number = {1}, pages = {}, doi = {10.1136/bmjgh-2024-016180}, pmid = {39837582}, issn = {2059-7908}, mesh = {Humans ; *COVID-19/epidemiology ; India ; Nigeria ; Indonesia ; *Tuberculosis/prevention & control ; *Qualitative Research ; *Private Sector ; Delivery of Health Care/organization & administration ; Administrative Personnel ; SARS-CoV-2 ; Pandemics ; Health Policy ; Pandemic Preparedness ; }, abstract = {INTRODUCTION: The COVID-19 pandemic was an unprecedented challenge to health systems worldwide and had a severe impact on tuberculosis (TB) case notifications and service delivery. India, Indonesia and Nigeria are high TB-burden countries where the majority of initial care-seeking happens in the private health sector. The objectives of this study were to (1) explore policy-makers' perspectives on the impact of the COVID-19 pandemic on private sector TB service delivery in India, Indonesia and Nigeria and (2) identify cross-cutting insights for pandemic preparedness with respect to TB service delivery.

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

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

CONCLUSIONS: Countries implemented varied measures to support TB service delivery during the COVID-19 pandemic. This study presents insights from three countries (India, Indonesia and Nigeria) that together offer a 'menu' of possibilities for supporting pandemic preparedness with respect to TB care vis-à-vis strengthening health systems resilience.}, } @article {pmid39837546, year = {2025}, author = {Szabó, G and Bokor, A and Fancsovits, V and Darici Kurt, E and Hudelist, T and Hudelist, G}, title = {Standardized measurement of the piriformis muscle and the proximal portion of the sacral nerve roots using transvaginal ultrasound.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2521-9321}, pmid = {39837546}, issn = {1438-8782}, abstract = {OBJECTIVE: To identify the sonomorphological appearance and to measure the thickness of the piriformis muscle (PM) and the proximal portion of the sacral nerve roots S1-S3 in healthy premenopausal women.

MATERIALS AND METHODS: This prospective multicentric observational study included a consecutive series of women undergoing transvaginal sonography (TVS) at two tertiary gynecological referral centers. Standardized assessment of the pelvic organs was performed followed by an attempt to visualize the right and left PM and sacral nerve roots S1-S3 at their origin in proximity to the sacral neuroforamen. Visualization rates, diameters of the muscle and nerve thickness and the time needed to identify the PM were recorded.

RESULTS: 305 patients were included in the study. In 293 women (96.1%) PM was identified bilaterally. The median diameter of the right PM was 18.3mm and 18.4mm on the left side. S1 nerve roots were succesfully identified bilaterally in 224 (73.4%) patients. Their right and left median diameters were 4.8mm. Both S2 nerves were succesfully identified in 215 (70.5%) patients. Their median diameter were 4.3mm on both sides. S3 nerve roots were succesfully identified in 203 (66.6%) patients. Their median diameter were 3.2mm on both sides.

CONCLUSION: We describe methods which allow consistent and rapid identification of the PM and the S1-S3 sacral nerve roots using TVS. Visualization of the PM and the proximal portion of the sacral plexus may be useful regarding identification of pathological changes in PM thickness and could help to distinguish perineural cysts from other gynecological pathologies. Ziel: Die Beschreibung der sonomorphologischen Merkmale als auch die standardisierte Messung des Durchmessers des Musculus piriformis (PM) und der proximalen Anteile der Sakralnervenwurzel (SNW) S1-S3 bei prämenopausalen Frauen.

MATERIAL UND METHODEN: Diese prospektive Beobachtungsstudie umfasste konsekutiv untersuchte Patientinnen an zwei tertiären gynäkologischen Referenzzentren. Nach standardisierter Beurteilung der Beckenorgane wurde versucht beide PM, deren Durchmesser und die proximalen Anteile der SNW S1-S3 an ihrem Ursprung in der Nähe des Sakralneuroforamens transvaginalsonografisch (TVS) darzustellen. Ergebnisse: Von 305 wurden bei 293 (96,1%) Patientinnen der PM beidseitig detektiert. Der mediane Durchmesser des rechten PM betrug 18,3 mm und des linken PM lag bei 18,4 mm. Die S1-Nervenwurzel (NW) wurde beidseitig bei 224/305 (73,4%) Patientinnen erfolgreich identifiziert. Der mediane Durchmesser der S1-NW betrug an beiden Seiten 4,8 mm. Beide S2-NW wurden bei 215/305 (70,5%) Patientinnen erfolgreich identifiziert. Der mediane Durchmesser der S2-NW betrug 4,3 mm an beiden Seiten. Schließlich wurden bei 203/305 (66,6%) Patientinnen S3-NW erfolgreich identifiziert. Der mediane Durchmesser der S3-NW betrug 3,2 mm an beiden Seiten. Schlussfolgerungen: Die Identifizierung des PM durch TVS ist allermeist möglich mit obig angegebenen Referenzwerten der PM-Dicke. Die SNW S1-S3 können bei der Mehrheit der Patientinnen mittels TVS an ihrem Ursprung identifiziert werden. Die Visualisierung des PM und des proximalen Anteils des Plexus Sacralis ist bei pathologischen Veränderungen des PM oder der Differentialdiagnose von Adnextumoren und Perineuralzysten von Bedeutung.}, } @article {pmid39837305, year = {2025}, author = {Tan, Y and Yang, T and Cheng, Y and Zhang, S and Xiao, Y and Liu, J and Shang, H}, title = {Association Between Psychiatric Disorders and Amyotrophic Lateral Sclerosis: A Prospective Cohort Study from the UK.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000543473}, pmid = {39837305}, issn = {1423-0208}, abstract = {INTRODUCTION: Psychiatric disorders have been reported to be associated with amyotrophic lateral sclerosis (ALS). However, evidence for the association remains inconsistent, and it is unclear whether specific categories of psychiatric disorders constitute risk factors for ALS. The study aimed to investigate the association between different categories of psychiatric disorders and the risk of ALS.

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

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

CONCLUSION: This large prospective cohort study indicated the association between schizophrenia, depression and a higher risk of subsequent ALS. These findings suggest potential implications for early process of global neurodegeneration in ALS, underlining the need for further research to explore the underlying mechanisms.}, } @article {pmid39836386, year = {2025}, author = {Babu, S and Sharfstein, JM and Feldman, EL}, title = {Reimagining Care and Research for Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2024.4757}, pmid = {39836386}, issn = {2168-6157}, } @article {pmid39836043, year = {2025}, author = {Berry, JD and Hagan, M and Zhang, J and Liu, Y and Ciepielewska, M}, title = {Longer disease progression milestone-free time in people with amyotrophic lateral sclerosis treated versus not treated with intravenous edaravone: results from an administrative claims analysis.}, journal = {Journal of comparative effectiveness research}, volume = {}, number = {}, pages = {e240007}, doi = {10.57264/cer-2024-0007}, pmid = {39836043}, issn = {2042-6313}, abstract = {Aim: To estimate time-to-progression milestones in people with amyotrophic lateral sclerosis (PALS) treated versus not treated with intravenous (IV) edaravone (Radicava[®] IV, Mitsubishi Tanabe Pharma America [MTPA], hereafter "IV edaravone") in a real-world setting. Background: IV edaravone is US FDA approved for the treatment of ALS and was shown in clinical trials to slow the rate of physical functional decline. Patients & methods: This retrospective observational analysis included PALS continuously enrolled in Optum's Clinformatics[®] Data Mart between 8 August 2017 and 31 December 2021. Cases treated with IV edaravone and controls not treated with IV edaravone were propensity score matched for: age, sex, race, US region of residence, pre-index disease duration, insurance, riluzole prescription; and pre-index claims for cardiovascular disease, artificial nutrition/gastrostomy tube, noninvasive ventilation and all-cause hospitalization. The index date was the first IV edaravone claim for cases; for controls, the index date was randomly assigned after IV edaravone market availability. Restricted mean time lost was calculated for the following disease progression milestones: new use of canes/walkers/wheelchairs, artificial nutrition, noninvasive ventilation, invasive ventilation, speech-generating devices and hospice. Results: Cases (n = 395) were matched to controls (n = 395). Cases had less restricted mean time lost, indicating longer disease progression milestone-free time, for all disease progression milestones. From 0 to 24 months post index, more cases (n = 129) than controls (n = 103) reported no milestones and more controls (n = 232) than cases (n = 131) reported deaths. Conclusion: In a US-based real-world setting, IV edaravone-treated PALS had a longer time to disease progression milestone events and fewer deaths in 2 years compared with PALS not treated with IV edaravone.}, } @article {pmid39835561, year = {2025}, author = {Rai, A and Shukla, S and Gupta, RK and Mishra, A}, title = {ALS: A Silent Slayer of Motor Neurons. Traditional Chinese Herbal Medicine as an Effective Therapy.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128329141241205063352}, pmid = {39835561}, issn = {1873-4286}, abstract = {Amyotrophic Lateral Sclerosis (ALS), is a progressive neurodegenerative disease characterized by motor symptoms, and cognitive impairment. The complexity in treating ALS arises from genetic and environmental factors, contributing to the gradual decline of lower and upper motor neurons. The anticipated pharmaceutical market valuation for ALS is projected to reach $1,038.94 million by 2032. This projection underscores the escalating impact of ALS on global healthcare systems. ALS prevalence is expected to surge to 376,674 cases by 2040. In 2022, India ranked among the top 3 Asian-Pacific nations, while North America dominated the global ALS market. Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese Medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management.}, } @article {pmid39835009, year = {2024}, author = {Frolov, A and D'sa, E and Henderson, C and Guzman, MA and Hayat, G and Martin, JR}, title = {Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e76027}, doi = {10.7759/cureus.76027}, pmid = {39835009}, issn = {2168-8184}, abstract = {A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts to develop effective disease-modifying drugs for the cure of this rapidly progressive, fatal neuromuscular disease. We have previously shown that clinical heterogeneity of sporadic ALS (sALS) could be explained, at least in part, by its polygenic nature as well as by the presence of mutated genes linked to non-ALS neurological diseases and genes known to mediate ALS-related pathologies. We hypothesized that a similar genetic framework could also be present in patients with familial ALS (fALS). To test this hypothesis, we conducted post-mortem genetic screening of an individual with fALS and a mutation in the C9ORF72 gene. C9ORF72 mutations are highly penetrant and are present in the majority of fALS patients. Genetic screening by whole exome sequencing (WES) on the next generation sequencing (NGS) Illumina platform (San Diego, CA, USA) followed by examination of the respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious genetic variants yielded results consistent with our hypothesis of the presence of a complex genetic framework in fALS. Additional members of this genetic framework were identified when the low-frequency (0.01 < MAF < 0.05) pathological/deleterious genetic variants were analyzed with the low-frequency biallelic AHNAK2, GLI3, PTIRM1, and ZNF254 variants, warranting a closer look at their potentially important role in fALS as C9ORF72 genetic modifiers as well as their link to both neuromuscular disorders/ALS and cancer. Therefore, in addition to the current genetic screening using a standard panel of ALS-related genes, a supplementary screening by WES could be very beneficial for the development of personalized treatment of ALS patients as well as in search of the respective efficient disease-modifying drugs.}, } @article {pmid39834841, year = {2024}, author = {Coutinho, KMD and Fernandes, F and Medeiros, KC and Coutinho, KD and Dias, AP and Valentim, RAM and Leite-Lais, L and Lima, KC}, title = {Data Report: Educational pathway addressing food and nutrition in amyotrophic lateral sclerosis on the AVASUS platform.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1476293}, doi = {10.3389/fdgth.2024.1476293}, pmid = {39834841}, issn = {2673-253X}, } @article {pmid39834554, year = {2025}, author = {Sarallah, R and Jahani, S and Soltani Khaboushan, A and Moaveni, AK and Amiri, M and Majidi Zolbin, M}, title = {The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100932}, doi = {10.1016/j.bbih.2024.100932}, pmid = {39834554}, issn = {2666-3546}, abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal loss and cognitive impairment (CI). The: Cysteine-X-cysteine chemokine ligand 12(CXCL12)/CXC chemokine receptor type 4 (CXCR4)/CXC chemokine receptor type 7 (CXCR7) axis has emerged as a critical molecular pathway in the development of CI in these disorders. This review explores the role of this axis in the pathogenesis of CI across these neurodegenerative diseases, synthesizing current evidence and its implications for targeted therapies. In AD, dysregulation of this axis contributes to amyloid-β accumulation and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. PD studies reveal that CXCL12/CXCR4 signaling influences dopaminergic neuron survival and microglial activation, affecting cognitive function. In MS, the axis modulates neuroinflammation and demyelination processes, impacting cognitive performance. ALS research indicates that the CXCL12/CXCR4/CXCR7 pathway is involved in motor neuron degeneration and associated cognitive deficits. Across these diseases, the axis influences neuroinflammation, synaptic plasticity, and neuronal survival through various signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways. Emerging evidence suggests that modulating this axis could provide neuroprotective effects and potentially alleviate cognitive symptoms. This review highlights the potential of the CXCL12/CXCR4/CXCR7 axis as a therapeutic target for addressing CI in neurodegenerative diseases. It also underscores the need for further research to fully elucidate its role and develop effective interventions, potentially leading to improved clinical management strategies for these devastating disorders.}, } @article {pmid39834320, year = {2025}, author = {Lero, CM and Park, S and Mroz, EL}, title = {Mapping the evidence of self-compassion in caregiver wellbeing for caregivers of persons with neurodegenerative disease: A scoping review.}, journal = {Palliative & supportive care}, volume = {23}, number = {}, pages = {e38}, doi = {10.1017/S1478951524001639}, pmid = {39834320}, issn = {1478-9523}, mesh = {Humans ; *Caregivers/psychology ; *Neurodegenerative Diseases/psychology/complications ; *Empathy ; }, abstract = {OBJECTIVES: Caregivers of those with neurodegenerative disease (ND) manage complex symptoms which impact their wellbeing. Self-compassion can promote maintenance of wellbeing during challenging experiences, including caregiving. Little guidance exists for observationally studying self-compassion or targeted interventions for this population. Our objective was to complete a scoping review of research describing self-compassion in the context of caregiver wellbeing of caregivers of those living with ND.

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

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

SIGNIFICANCE OF RESULTS: The study of self-compassion with caregivers of individuals living with ND is growing. Current literature is somewhat unfocussed, leading to gaps in understanding conceptualization to achieve maximum intervention benefits. Clarifying the role of self-compassion in caregiver wellbeing will provide a lens through which non-pharmacologic, psychotherapeutic, and behavioral intervention development may be framed to reduce negative psychological outcomes. The most frequently represented ND is Alzheimer's disease or other dementia, obscuring other NDs like amyotrophic lateral sclerosis, Parkinson's disease, and others.}, } @article {pmid39834142, year = {2025}, author = {Stikvoort García, DJL and van den Berg, LH and Sleutjes, BTHM and Goedee, HS}, title = {Diagnostic Accuracy of Median Nerve Cross-Sectional Area in Suspected Amyotrophic Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28326}, pmid = {39834142}, issn = {1097-4598}, support = {//Stichting ALS Nederland/ ; }, abstract = {INTRODUCTION/AIMS: Reduced nerve sizes obtained by nerve ultrasound (NUS) have been proposed as a potential diagnostic marker for amyotrophic lateral sclerosis (ALS). However, prospective studies evaluating patients with suspected ALS are currently lacking. We, therefore, evaluated the diagnostic accuracy of a standardized NUS protocol in a large sample of suspected ALS patients.

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

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

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

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

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

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

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

STUDY TYPE: Systematic review and meta-analysis.

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

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

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

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

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

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

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

LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.}, } @article {pmid39831450, year = {2025}, author = {Hoehne, SN and Cary, JA and Bailey, LN and Davidow, EB and Martin, LG and DeJong, TL}, title = {An exploratory study on the effect of rescuer team size on basic and advanced life support technical skills in a high-fidelity simulation of canine cardiopulmonary arrest.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {}, number = {}, pages = {}, doi = {10.1111/vec.13445}, pmid = {39831450}, issn = {1476-4431}, support = {//Converse Fund, Washington State University College of Veterinary Medicine 2021-2022 CVM Intramural Research Grants/ ; }, abstract = {OBJECTIVE: To evaluate the effect of rescuer team size on objective skill measures of basic life support (BLS) and advanced life support (ALS) using high-fidelity canine CPR simulation.

DESIGN: Prospective, experimental study.

SETTING: Veterinary clinical simulation center.

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

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

CONCLUSIONS: Although the achievement of BLS tasks was comparable in teams of 4 rescuers, teams of 6 rescuers may be preferable based on differences in the rate of guideline-incompliant treatments and ALS task efficiency. Teams of 8 rescuers were neither more efficient nor more accurate at conducting BLS and ALS tasks.}, } @article {pmid39831399, year = {2025}, author = {Wang, F and Jing, Z and Wang, Q and Li, M and Lu, B and Huo, A and Zhao, C and Zhou, H and Liang, W and Hu, W and Fu, X}, title = {Bidirectional Mendelian Randomization Analysis of the Association Between Mitochondrial Proteins and Neurodegenerative Diseases.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70283}, doi = {10.1002/brb3.70283}, pmid = {39831399}, issn = {2162-3279}, support = {82303029//National Natural Science Foundation of China/ ; 2024YLZDJH027//the Zhengzhou Science and Technology Innovation Project for Healthcare/ ; YXKC2022020//Health Commission of Henan Province/ ; 232102311134//Science and Technology Department of Henan Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; *Mitochondrial Proteins/genetics ; *Genome-Wide Association Study ; Alzheimer Disease/genetics ; }, abstract = {BACKGROUND: Neurodegenerative diseases involve progressive neuronal dysfunction and cognitive decline, posing substantial global challenges. Although the precise causes remain unclear, several studies highlight the role of protein metabolism abnormalities in disease development. This study investigates the causal links between variations in mitochondrial protein genes and neurodegenerative diseases, aiming to elucidate their potential contributions to disease progression and identify novel therapeutic strategies.

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

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

CONCLUSIONS: Using MR, we identified significant links between mitochondrial protein gene mutations and the risk of neurodegenerative diseases. These results highlight reciprocal relationships where certain neurodegenerative diseases influence mitochondrial protein expression levels. These findings underscore the pivotal role of mitochondrial proteins in neurodegenerative diseases, offering critical insights into disease mechanisms and potential therapeutic avenues.}, } @article {pmid39831374, year = {2025}, author = {Risi, B and Imarisio, A and Cuconato, G and Padovani, A and Valente, EM and Filosto, M}, title = {Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70014}, doi = {10.1111/ene.70014}, pmid = {39831374}, issn = {1468-1331}, mesh = {Humans ; *DNA, Mitochondrial/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid/blood ; *Neurodegenerative Diseases/cerebrospinal fluid/genetics/diagnosis/blood ; Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/blood/diagnosis ; }, abstract = {BACKGROUND: Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation-driven neurodegeneration.

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

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

CONCLUSIONS: Additional well-designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of "mitochondrial subtypes" of disease may enable novel precision medicine strategies to counteract neurodegeneration.}, } @article {pmid39831022, year = {2025}, author = {Okpete, UE and Byeon, H}, title = {Brain-derived neurotrophic factor alterations and cognitive decline in schizophrenia: Implications for early intervention.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {102131}, doi = {10.5498/wjp.v15.i1.102131}, pmid = {39831022}, issn = {2220-3206}, abstract = {This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in first-episode schizophrenia patients. The study revealed that higher levels of interleukin-6 and tumor necrosis factor-α correlated with reduced BDNF levels and poorer cognitive performance. Schizophrenia is a severe psychiatric disorder impacting approximately 1% of the global population, characterized by positive symptoms (hallucinations and delusions), negative symptoms (diminished motivation and cognitive impairments) and disorganized thoughts and behaviors. Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting. The findings from Cui et al's study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes. Effective treatment approaches involve a combination of pharmacological and non-pharmacological interventions tailored to individual patient needs. Hence, monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life. Consequently, this manuscript highlights the need for an integrated approach to schizophrenia management, considering both clinical symptoms and underlying neurobiological changes.}, } @article {pmid39829394, year = {2025}, author = {Buddenhagen, CE and Ngow, Z and Wynne-Jones, B and Rolston, MP}, title = {Resistance to the herbicides haloxyfop and iodosulfuron is common in commercial ryegrass (Lolium) seed lines.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8665}, pmid = {39829394}, issn = {1526-4998}, support = {//AgResearch Ltd via its contribution to the Better Border Biosecurity (B3) research collaboration, www.b3nz.org/ ; }, abstract = {BACKGROUND: Ryegrass (Lolium spp.) is a key forage providing a $14 billion contribution to New Zealand's gross domestic product (GDP). However, ryegrass can also act as a weed and evolve resistance to herbicides used for its control. Farmers suspected that imported seed might contribute to resistance issues. Herbicide resistance frequencies were investigated in commercial ryegrass seed lines intended for multiplication in New Zealand. Samples from 56 basic seed lots and 52 unique cultivars sourced from regions including New Zealand, United States, Europe and Japan were planted in field trials. Seedlings were then sprayed with three common herbicides: glyphosate, iodosulfuron, and haloxyfop. Surviving plants were retested to confirm resistance.

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

CONCLUSIONS: It was found that 63% of resistant lines had resistance frequencies rarer than 0.1%, but this is potentially problematic considering typical sowing rates. Imported versus domestic seed sources were not significantly different; they pose similar levels of resistance risk to farmers. Lolium multiflorum had a higher resistance frequency compared to Lolium perenne (although only six L. multiflorum lots were evaluated). Breeders should screen progeny of early crosses for herbicide resistance. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39829368, year = {2025}, author = {Bedlack, R}, title = {Stitching strength: things I've learned about hope and how I am trying to weave them into my in ALS practice.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2025.2454903}, pmid = {39829368}, issn = {2167-9223}, } @article {pmid39829311, year = {2025}, author = {Falanga, AP and Piccialli, I and Greco, F and D'Errico, S and Nolli, MG and Borbone, N and Oliviero, G and Roviello, GN}, title = {Nanostructural Modulation of G-Quadruplex DNA in Neurodegeneration: Orotate Interaction Revealed Through Experimental and Computational Approaches.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16296}, doi = {10.1111/jnc.16296}, pmid = {39829311}, issn = {1471-4159}, support = {IR0000010 "ELIXIRxNextGenIT"//European Commission/ ; PNRRMUR-M4C2-I//European Commission/ ; FOE 2020-ISBE-IT Joint Research Unit//Ministero dell'Università e della Ricerca/ ; }, mesh = {*G-Quadruplexes/drug effects ; Humans ; *Orotic Acid/pharmacology ; DNA/genetics ; Molecular Docking Simulation ; Neurodegenerative Diseases/genetics/metabolism ; Nanostructures/chemistry ; }, abstract = {The natural compound orotic acid and its anionic form, orotate, play a pivotal role in various biological processes, serving as essential intermediates in pyrimidine de novo synthesis, with demonstrated connections to dietary, supplement, and neurodrug applications. A novel perspective on biomolecular aggregation at the nanoscale, particularly pertinent to neurodegeneration, challenges the established paradigm positing that peptide (amyloid beta) and protein (tau) aggregation mainly govern the molecular events underlying prevalent neuropathologies. Emerging biological evidence indicates a notable role for G-quadruplex (G4) DNA aggregation in neurodegenerative processes affecting neuronal cells, particularly in the presence of extended (G4C2)n repeats in nuclear DNA sequences. Our study concerns d[(GGGGCC)3GGGG], a G4-forming DNA model featuring G4C2 repeats that is in correlation with neurodegeneration. Through different investigations utilizing spectroscopic techniques (CD, UV, and thermal denaturations), PAGE electrophoresis, and molecular docking, the study explores the influence of orotate on the aggregation of this neurodegeneration-associated DNA. A computational approach was employed to construct an in silico model of the DNA aggregate, which involved the docking of multiple G4 units and subsequent integration of the ligand into both the DNA monomer and its in silico aggregated model. The convergence of computational analyses and empirical data collectively supports the hypothesis that orotate possesses the capability to modulate the aggregation of neurodegeneration-related DNA. Notably, the findings suggest the potential utility of orotate as a neurodrug, especially for the therapy of amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD), with its current status as a dietary supplement indicating minimal safety concerns. Additionally, orotate demonstrated a slight increase in mitochondrial dehydrogenase activity as assessed by the MTT assay, which is beneficial for a neurodrug as it suggests a potential role in enhancing mitochondrial function and supporting neuronal health.}, } @article {pmid39828328, year = {2025}, author = {Yorimoto, K and Ariake, Y and Kawaguchi, T and Hara, T}, title = {Long-term lung volume recruitment therapy maintains ventilator weaning in a patient with ALS following tracheostomy.}, journal = {BMJ case reports}, volume = {18}, number = {1}, pages = {}, doi = {10.1136/bcr-2024-262945}, pmid = {39828328}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Tracheostomy ; Middle Aged ; *Ventilator Weaning/methods ; Male ; Respiratory Therapy/methods ; Vital Capacity ; }, abstract = {We report a case of amyotrophic lateral sclerosis (ALS) in a patient in their 50s, presenting with spastic paraparesis and bulbar palsy, treated with lung volume recruitment therapy (LVRT). From early stage in the disease, vital capacity (VC), lung insufflation capacity (LIC) and ALS Functional Rating Scale-Revised scores were regularly measured, and LVRT was continuously performed at home. After 10 years, the patient had complete limb function loss and required nutritional management via gastrostomy and full assistance with daily activities. Despite this, the gap between VC and LIC remained approximately 2000 mL, and the patient was not ventilator-dependent during the day after tracheostomy. Chest CT showed improvement in lower lobe atelectasis due to LVRT. Typically, respiratory physiotherapy is challenging in patients with bulbar palsy or post-tracheostomy, but in this case, LVRT successfully maintained lung mobility. Early LVRT implementation may improve ALS patients' survival prognosis and warrants further exploration.}, } @article {pmid39828029, year = {2025}, author = {Fantini, J and Azzaz, F and Di Scala, C and Aulas, A and Chahinian, H and Yahi, N}, title = {Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow.}, journal = {Pharmacology & therapeutics}, volume = {}, number = {}, pages = {108797}, doi = {10.1016/j.pharmthera.2025.108797}, pmid = {39828029}, issn = {1879-016X}, abstract = {The traditional model of protein structure determined by the amino acid sequence is today seriously challenged by the fact that approximately half of the human proteome is made up of proteins that do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered proteins (IDPs), are involved in numerous physiological functions and are associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), and type 2 diabetes. Targeting these proteins is challenging for two reasons: i) we need to preserve their physiological functions, and ii) drug design by molecular docking is not possible due to the lack of reliable starting conditions. Faced with this challenge, the solutions proposed by artificial intelligence (AI) such as AlphaFold are clearly unsuitable. Instead, we suggest an innovative approach consisting of mimicking, in short synthetic peptides, the conformational flexibility of IDPs. These peptides, which we call adaptive peptides, are derived from the domains of IDPs that become structured after interacting with a ligand. Adaptive peptides are designed with the aim of selectively antagonizing the harmful effects of IDPs, without targeting them directly but through selected ligands, without affecting their physiological properties. This"target the target, not the arrow" strategy is promised to open a new route to drug discovery for currently undruggable proteins.}, } @article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A Promising Ally in Combating Neurodegenerative Disorders.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, } @article {pmid39827940, year = {2025}, author = {Jinno, J and Abdelhamid, RF and Morita, J and Saga, R and Yamasaki, Y and Kadowaki, A and Ogawa, K and Kimura, Y and Ikenaka, K and Beck, G and Baba, K and Nagai, Y and Kasahara, E and Sekiyama, A and Hirayama, T and Hozumi, I and Hasegawa, T and Araki, T and Mochizuki, H and Nagano, S}, title = {TDP-43 transports ferritin heavy chain mRNA to regulate oxidative stress in neuronal axons.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {105934}, doi = {10.1016/j.neuint.2025.105934}, pmid = {39827940}, issn = {1872-9754}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (Fth1) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether Fth1 mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed Fth1 mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via Fth1 mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.}, } @article {pmid39827337, year = {2025}, author = {Mwale, PF and Hsieh, CT and Yen, TL and Jan, JS and Taliyan, R and Yang, CH and Yang, WB}, title = {Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {7}, pmid = {39827337}, issn = {1750-1326}, support = {NSTC 112-2320-B-038 -018 -MY3//National Science and Technology Council/ ; CGH-MR-A11315//Cathay General Hospital/ ; CGH-MR-A11314//Cathay General Hospital/ ; }, mesh = {Humans ; *Chitinase-3-Like Protein 1/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism ; Animals ; }, abstract = {Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood-brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.}, } @article {pmid39825381, year = {2025}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Correction: Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {18}, number = {1}, pages = {5}, pmid = {39825381}, issn = {1756-0381}, } @article {pmid39824815, year = {2025}, author = {Leau, C and Wang, Y and Gervillié-Mouravieff, C and Boles, ST and Zhang, XH and Coudray, S and Boussard-Plédel, C and Tarascon, JM}, title = {Tracking solid electrolyte interphase dynamics using operando fibre-optic infra-red spectroscopy and multivariate curve regression.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {757}, pmid = {39824815}, issn = {2041-1723}, abstract = {As batteries drive the transition to electrified transportation and energy systems, ensuring their quality, reliability, lifetime, and safety is crucial. While the solid electrolyte interphase (SEI) is known to govern these performance characteristics, its dynamic nature makes understanding its nucleation, growth, and composition an ambitious, yet elusive aspiration. This work employs chalcogenide fibres embedded in negative electrode materials for operando Infra-red Fibre-optic Evanescent Wave Spectroscopy (IR-FEWS), combined with Multivariate Curve Resolution by Alternating Least Squares (MCR-ALS) algorithms for spectra analysis. By establishing molecular fingerprints that can be used to identify reaction products, IR-FEWS combined with MCR-ALS enables improved understanding of SEI evolution during cell formation with notable differences stemming from electrolyte or anode material. For example, despite operating at an elevated potential, lithium titanate's SEI has intrinsic instability, evidenced by continued carbonate formation. This approach leads the hunt for the SEI down a new path, giving empirical formulations theoretical roots.}, } @article {pmid39824736, year = {2025}, author = {Chow, G and Scher, M and Krisciunas, GP and Tracy, LF}, title = {Comprehensive Review of Multilingual Patient-Reported Outcome Measures for Dysphonia.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.01.005}, pmid = {39824736}, issn = {1873-4588}, abstract = {INTRODUCTION: Patient-reported outcome measures (PROMs) represent an important part of a comprehensive voice assessment for clinical care and research. Access to multilingual PROMs enables inclusion of information from diverse patient populations. This review compares available translated and validated PROMs for adult dysphonia.

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

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

CONCLUSION: Multilingual PROMs for dysphonia are widely available, but linguistic representation varied. VHI, VFI, S-VHI, and V-RQOL are the most widely translated. The most represented languages were Persian, Kannada, and Turkish. Few studies adequately followed cross-cultural adaptation standards. Efforts to translate and validate questionnaires into different languages may allow more diverse assessment and comparison of larger populations with dysphonia. This review identifies translated PROMs for dysphonia and analyzes their level of cultural validation for future use.}, } @article {pmid39824655, year = {2025}, author = {Jia, M and Li, P and Yan, Y and Liu, X and Gao, L and Zhu, G and Chen, Z}, title = {Antimicrobial Susceptibility and Genomic Characterization of Vibrio cholerae Non-O1/non-O139 Isolated from Clinical and Environmental Samples in Jiaxing City, China.}, journal = {FEMS microbiology letters}, volume = {}, number = {}, pages = {}, doi = {10.1093/femsle/fnaf009}, pmid = {39824655}, issn = {1574-6968}, abstract = {Non-O1/non-O139 (NOVC) strains inhabit aquatic environments and sporadically induce human illnesses. This study involved the virulence and antimicrobial genetic characterization of 176 NOVC strains, comprising 25 from clinical samples and 151 from environmental sources, collected between 2021 and 2023. The antimicrobial susceptibility of the examined NOVC population was predominantly high, exhibiting only poor susceptibility to colistin, with 89.2% resistance. The examination of virulence genes revealed that the majority of strains were positive for glucose metabolism (als gene) (169/176, 96.0%). Through multilocus sequence typing, the 176 NOVC strains were categorised into 121 sequence types, 79 of which were novel. NOVC strains demonstrate significant genetic variability and frequently engage in recombination. This work offers genetic characterization of the pathogenicity and antimicrobial resistance of a NOVC community. Our findings offer insights that may aid in the development of preventative and treatment methods for this pathogen.}, } @article {pmid39823474, year = {2025}, author = {Zhang, Y and He, L and Gundelach, J and Ge, A and Edlund, H and Norlin, S and Bram, RJ}, title = {Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.}, journal = {PLoS genetics}, volume = {21}, number = {1}, pages = {e1011547}, pmid = {39823474}, issn = {1553-7404}, mesh = {Animals ; Mice ; *Motor Neurons/metabolism ; Mice, Transgenic ; Humans ; Endoplasmic Reticulum/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Neuromuscular Junction/metabolism ; Qa-SNARE Proteins/metabolism/genetics ; Spinal Cord/metabolism ; Disease Models, Animal ; Protein Transport ; Dystonin ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is valuable to identify additional genes that can impact motor neuron survival and function. In this report, we describe mice that express globally reduced levels of calcium-modulating cyclophilin ligand (CAML) protein. CAML is an essential component in the transmembrane domain recognition complex (TRC) pathway, responsible for inserting C-terminal tail anchored (TA) proteins into the endoplasmic reticulum membrane. The primary phenotype observed in these mice was rapid development of hind limb weakness and paralysis. Spinal cord sections revealed a loss of motor neuron cell bodies. Targeting CAML loss specifically to neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating that CAML plays a cell autonomous role in this process. We found that intracellular trafficking was perturbed in cells depleted of CAML, with aberrant release of procathepsin D and defective retention of CD222 within the trans-Golgi network, as well as reduced levels and mislocalization of syntaxin 5 (Stx5). Dysfunctional lysosomes and abnormal protein glycosylation were also revealed in CAML deficient cells, further indicating a defect in Golgi trafficking. In addition, we observed an identical phenotype in mice lacking ASNA1 in neurons, suggesting that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway. Together, these findings implicate motor neuron survival as a key role for the TA protein insertion machinery in mice, which may shed light on the pathogenesis of neuromuscular disease in humans.}, } @article {pmid39823433, year = {2025}, author = {Tindale, A and Cretu, I and Gomez, N and Haynes, R and Meng, H and Mason, MJ and Francis, DP}, title = {Central venous pressure as a method of optimising atrio-ventricular delay after cardiac surgery.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0310905}, doi = {10.1371/journal.pone.0310905}, pmid = {39823433}, issn = {1932-6203}, mesh = {Humans ; *Central Venous Pressure/physiology ; *Cardiac Surgical Procedures/methods ; Female ; Male ; Aged ; Middle Aged ; Hemodynamics ; Pacemaker, Artificial ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Haemodynamic atrioventricular delay (AVD) optimisation has primarily focussed on signals that are not easy to acquire from a pacing system itself, such as invasive left ventricular catheterisation or arterial blood pressure (ABP). In this study, standard clinical central venous pressure (CVP) signals are tested as a potential alternative.

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

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

CONCLUSIONS: Central venous pressure signals could be used to optimise AVD, because they have a reliable inverse relationship with ABP when pacemaker settings undergo protocolised testing. However, protocols need careful design to circumvent spontaneous biological variability.}, } @article {pmid39822067, year = {2025}, author = {Zhu, Y and Verkhratsky, A and Chen, H and Yi, C}, title = {Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.}, journal = {Acta physiologica (Oxford, England)}, volume = {241}, number = {2}, pages = {e14283}, doi = {10.1111/apha.14283}, pmid = {39822067}, issn = {1748-1716}, support = {RCJC20231211090018040//Shenzhen Fundamental Research Program/ ; ZDSYS20220606100801003//Shenzhen Fundamental Research Program/ ; 2022B1515020012//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 32170980//National Natural Science Foundation of China/ ; }, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; Animals ; *Insulin/metabolism ; *Glucose/metabolism ; Brain/metabolism ; }, abstract = {The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.}, } @article {pmid39821843, year = {2025}, author = {Zhang, J and Guo, R and Zhou, Z and Fu, Z and Akogo, HY and Li, Y and Zhang, X and Wang, N and Liu, Y and Li, H and Feng, B and Cui, H and Ma, J}, title = {Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39821843}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.}, } @article {pmid39820998, year = {2025}, author = {Hamad, AA and Alkhawaldeh, IM and Nashwan, AJ and Meshref, M and Imam, Y}, title = {Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39820998}, issn = {1590-3478}, abstract = {OBJECTIVE: Tofersen, an antisense oligonucleotide, has recently received FDA and EMA approval for treating amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations. This systematic review and meta-analysis synthesized evidence on tofersen's safety and efficacy in patients with SOD1-related ALS.

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

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

CONCLUSION: Current evidence suggests that tofersen effectively reduces SOD1 and NfL levels and slow disease progression in SOD1 ALS, showing promise as a targeted therapeutic option.}, } @article {pmid39820861, year = {2025}, author = {van Zundert, B and Montecino, M}, title = {Epigenetics in Neurodegenerative Diseases.}, journal = {Sub-cellular biochemistry}, volume = {108}, number = {}, pages = {73-109}, pmid = {39820861}, issn = {0306-0225}, mesh = {Humans ; *Epigenesis, Genetic ; Animals ; *Neurodegenerative Diseases/genetics/metabolism ; Alzheimer Disease/genetics/metabolism ; DNA Methylation ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {Healthy brain functioning requires a continuous fine-tuning of gene expression, involving changes in the epigenetic landscape and 3D chromatin organization. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are three multifactorial neurodegenerative diseases (NDDs) that are partially explained by genetics (gene mutations and genetic risk factors) and influenced by non-genetic factors (i.e., aging, lifestyle, and environmental conditions). Examining comprehensive studies of global and locus-specific (epi)genomic and transcriptomic alterations in human and mouse brain samples at the cell-type resolution has uncovered important phenomena associated with AD. First, DNA methylation and histone marks at promoters contribute to transcriptional dysregulation of genes that are directly implicated in AD pathogenesis (i.e., APP), neuroplasticity and cognition (i.e., PSD95), and microglial activation (i.e., TREM2). Second, the presence of AD genetic risk variants in cell-type-specific distal enhancers (i.e., BIN1 in microglia) alters transcription, presumably by disrupting associated enhancer-promoter interactions and chromatin looping. Third, epigenomic erosion is associated with widespread transcriptional disruption and cell identity loss. And fourth, aging, high cholesterol, air pollution, and pesticides have emerged as potential drivers of AD by inducing locus-specific and global epigenetic modifications that impact key AD-related pathways. Epigenetic studies in ALS/FTD also provide evidence that genetic and non-genetic factors alter gene expression profiles in neurons and astrocytes through aberrant epigenetic mechanisms. We additionally overview the recent development of potential new therapeutic strategies involving (epi)genetic editing and the use of small chromatin-modifying molecules (epidrugs).}, } @article {pmid39820267, year = {2025}, author = {Martinez-Thompson, JM and Mazurek, KA and Parra Cantu, C and Naddaf, E and Gogineni, V and Botha, H and Jones, DT and Laughlin, RS and Barnard, L and Staff, NP}, title = {Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf014}, pmid = {39820267}, issn = {1460-2156}, abstract = {Nerve conduction F-wave studies contain critical information about subclinical motor dysfunction which may be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial Intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46,802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular, and tibial nerves. Wavelet coefficient statistics, onset age, sex, and BMI were features for training a Gradient Boosting Machine model on 40,095 (5,329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis (IBM), cervical radiculopathy, lumbar radiculopathy, or peripheral neuropathy which can mimic ALS symptoms. Factors affecting survival were estimated through cox proportional hazards regression. The model trained using wavelet-features on the full waveform had 90% recall, 87% precision, and 88% accuracy. Similar model performance was measured using features only from the M-Wave or F-Wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (p<0.001, ANOVA, Tukey's post-hoc), Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient's likelihood of ALS and their survival risks. Although the model can make predictions at specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS compared to other mimicking diagnoses such as IBM, cervical or lumbar radiculopathy, or peripheral neuropathy. These probabilities provide clinicians with additional information they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians diagnose ALS sooner and manage treatment based on estimated survival, which may improve outcomes and patients' quality of life.}, } @article {pmid39819944, year = {2025}, author = {Kristensen, RK and Andersen, PT and Bilenberg, N and Milling, ED and Dalgaard Guldager, J}, title = {Mapping the landscape and evidence of cross-sectoral collaboration models targeting individuals referred for assessment of attention-deficit hyperactivity disorder or autism spectrum disorder: protocol for a scoping review.}, journal = {BMJ open}, volume = {15}, number = {1}, pages = {e088850}, doi = {10.1136/bmjopen-2024-088850}, pmid = {39819944}, issn = {2044-6055}, mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity ; *Autism Spectrum Disorder ; Research Design ; Review Literature as Topic ; Cooperative Behavior ; Referral and Consultation ; }, abstract = {INTRODUCTION: Neurodevelopmental disorders, notably attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), present substantial challenges in mental health. Individuals referred for assessment in a psychiatric unit experience complex needs. This implies that their needs necessitate coordination across multiple sectors. Cross-sectoral collaboration models have emerged as essential strategies for addressing the complexities of these disorders. However, evidence of their existence, implementation and success remains limited. This protocol aims to outline a scoping review where we will explore existing collaboration models, evaluate their implementation and gain an understanding of how cross-sectoral collaboration models can be developed to ultimately benefit individuals referred for assessment of ADHD or ASD.

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

ETHICS AND DISSEMINATION: Ethical approval is not required for this protocol since it involves the review of existing literature without the involvement of human participants or personal data. Findings will be disseminated at national and international conferences and will be integrated into future efforts to develop cross-sectoral collaboration models in Denmark.}, } @article {pmid39819841, year = {2025}, author = {Cintora-Sanz, AM and Horrillo-García, C and Quesada-Cubo, V and Pérez-Alonso, AM and Gutiérrez-Misis, A}, title = {Prevalence and Economic Impact of Acute Respiratory Failure in the Prehospital Emergency Medical Service of the Madrid Community: Retrospective Cohort Study.}, journal = {JMIR public health and surveillance}, volume = {11}, number = {}, pages = {e66179}, doi = {10.2196/66179}, pmid = {39819841}, issn = {2369-2960}, mesh = {Humans ; Spain/epidemiology ; Retrospective Studies ; *Emergency Medical Services/economics/statistics & numerical data ; *Respiratory Insufficiency/epidemiology/therapy ; Male ; Aged ; Female ; *COVID-19/epidemiology ; Prevalence ; Middle Aged ; Aged, 80 and over ; Adult ; Health Care Costs/statistics & numerical data ; Cohort Studies ; Acute Disease ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and acute pulmonary edema (APE) are serious illnesses that often require acute care from prehospital emergency medical services (EMSs). These respiratory diseases that cause acute respiratory failure (ARF) are one of the main reasons for hospitalization and death, generating high health care costs. The prevalence of the main respiratory diseases treated in a prehospital environment in the prepandemic period and during the COVID-19 pandemic in Spain is unknown. The Madrid Community EMS is a public service that serves all types of populations and represents an epidemiological reference for supporting a population of 6.4 million inhabitants. The high volume of patients treated by Madrid's medical advanced life supports (ALSs) allows us to analyze this little-studied problem.

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

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

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

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

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

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

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

CONCLUSION: This study identifies glymphatic dysfunction in ALS, as evidenced by changes in the ALPS index and CPV. Larger studies are warranted to validate these findings and assess their potential as biomarkers for ALS.}, } @article {pmid39817908, year = {2025}, author = {Aikio, M and Odeh, HM and Wobst, HJ and Lee, BL and Chan, Ú and Mauna, JC and Mack, KL and Class, B and Ollerhead, TA and Ford, AF and Barbieri, EM and Cupo, RR and Drake, LE and Smalley, JL and Lin, YT and Lam, S and Thomas, R and Castello, N and Baral, A and Beyer, JN and Najar, MA and Dunlop, J and Gitler, AD and Javaherian, A and Kaye, JA and Burslem, GM and Brown, DG and Donnelly, CJ and Finkbeiner, S and Moss, SJ and Brandon, NJ and Shorter, J}, title = {Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115205}, doi = {10.1016/j.celrep.2024.115205}, pmid = {39817908}, issn = {2211-1247}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.}, } @article {pmid39817235, year = {2024}, author = {Cicardi, ME and Trotti, D}, title = {C9orf72 role in myeloid cells: new perspectives in the investigation of the neuro-immune crosstalk in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Annals of translational medicine}, volume = {12}, number = {6}, pages = {120}, pmid = {39817235}, issn = {2305-5839}, } @article {pmid39817215, year = {2025}, author = {Liu, SQ and Wang, D and Tang, CC}, title = {Association between age at diagnosis of diabetes and ocular disease: Insights from a recent article.}, journal = {World journal of diabetes}, volume = {16}, number = {1}, pages = {94846}, pmid = {39817215}, issn = {1948-9358}, abstract = {In this article, we discuss Ye et al's recent article on the association between age at diabetes diagnosis and subsequent risk of age-related ocular diseases. The study, which utilized United Kingdom Biobank data, highlighted a strong link between early diabetes onset and major eye conditions, such as cataracts, glaucoma, age-related macular degeneration, and vision loss, independent of glycemic control and disease duration. This finding challenges the previous belief that diabetic eye disease primarily correlates with hyperglycemia. As lifestyles evolve and the age of diabetes diagnosis decreases, understanding this relationship may reveal the complex pathogenesis underlying diabetes-related complications. This editorial summarizes potential mechanisms connecting the age of diabetes onset with four types of ocular diseases, emphasizing the significance of early diagnosis.}, } @article {pmid39817143, year = {2025}, author = {Chew, FY and Tsai, CH and Chang, KH and Chang, YK and Chou, RH and Liu, YJ}, title = {Exosomes as promising frontier approaches in future cancer therapy.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {100713}, pmid = {39817143}, issn = {1948-5204}, abstract = {In this editorial, we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology. They explored an innovative approach to enhancing gemcitabine (GEM) delivery and efficacy using human bone marrow mesenchymal stem cells (HU-BMSCs)-derived exosomes. The manufacture of GEM-loaded HU-BMSCs-derived exosomes (Exo-GEM) has been optimized. The Tang et al's study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM, highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer. Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.}, } @article {pmid39817131, year = {2025}, author = {Lampridis, S}, title = {Unraveling the landscape of pediatric pancreatic tumors: Insights from Japan.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {101477}, pmid = {39817131}, issn = {1948-5204}, abstract = {Pediatric pancreatic tumors, though rare, pose significant diagnostic and management challenges. The recent, 22-year nationwide survey on pediatric pancreatic tumors in Japan by Makita et al offers valuable insights into this uncommon entity, revealing striking geographical variations and questioning current treatment paradigms. This editorial commentary analyzes the study's key findings, including the predominance of solid pseudopapillary neoplasms and their younger age of onset, which contrast sharply with Western data. It explores the implications for clinical practice and research, emphasizing the need for population-specific approaches to diagnosis and treatment. The revealed limited institutional experience and surgical management patterns prompt a reevaluation of optimal care delivery for these complex cases, suggesting benefits of centralizing healthcare services. Furthermore, the commentary advocates for international collaborative studies to elucidate the genetic, environmental, and lifestyle factors influencing the development and progression of pediatric pancreatic tumors across diverse populations. It also outlines future directions, calling for advancements in precision medicine and innovative care delivery models to improve global patient outcomes. Unraveling Makita et al's findings within the broader landscape of pediatric oncology can stimulate further research and clinical advancements in managing pancreatic and other rare tumors in children.}, } @article {pmid39816800, year = {2025}, author = {Shokr, MM and Badawi, GA and Elshazly, SM and Zaki, HF and Mohamed, AF}, title = {Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {1}, pages = {47-65}, pmid = {39816800}, issn = {2575-9108}, abstract = {Sigma 1 receptor (S1R) is a multifunctional, ligand-activated protein located in the membranes of the endoplasmic reticulum (ER). It mediates a variety of neurological disorders, including epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease. The wide neuroprotective effects of S1R agonists are achieved by a variety of pro-survival and antiapoptotic S1R-mediated signaling functions. Nonetheless, relatively little is known about the specific molecular mechanisms underlying S1R activity. Many studies on S1R protein have highlighted the importance of maintaining normal cellular homeostasis through its control of calcium and lipid exchange between the ER and mitochondria, ER-stress response, and many other mechanisms. In this review, we will discuss S1R different cellular localization and explain S1R-associated biological activity, such as its localization in the ER-plasma membrane and Mitochondrion-Associated ER Membrane interfaces. While outlining the cellular mechanisms and important binding partners involved in these processes, we also explained how the dysregulation of these pathways contributes to neurodegenerative disorders.}, } @article {pmid39816195, year = {2025}, author = {Yildiz, O and Hunt, GP and Schroth, J and Dhillon, G and Spargo, TP and Al-Chalabi, A and Koks, S and Turner, MR and Shaw, PJ and Henson, SM and Iacoangeli, A and Malaspina, A}, title = {Lipid-mediated resolution of inflammation and survival in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae402}, pmid = {39816195}, issn = {2632-1297}, abstract = {Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1n-3 DPA were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b[+] integrin from fast-progressing pwALS, including those with bulbar onset disease (P < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8[+] T cells from pwALS compared to non-neurological controls (P < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, P = 0.003) and unswitched memory B cells (hazard ratio: 0.44, P = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.}, } @article {pmid39814005, year = {2025}, author = {Teive, HAG and Coutinho, L and Cardoso, FEC and Tsuji, S}, title = {Neurology pioneers in Japan.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {1}, pages = {1-3}, doi = {10.1055/s-0044-1791661}, pmid = {39814005}, issn = {1678-4227}, mesh = {*Neurology/history ; Japan ; History, 20th Century ; History, 19th Century ; Humans ; }, abstract = {The pioneers of neurology in Japan were professors Hiroshi Kawahara and Kinnosuke Miura. Kawahara published the first description of progressive bulbar palsy and wrote the first neurology textbook in Japan. Miura, on the other hand, published studies about amyotrophic lateral sclerosis, in addition to participating in the founding of the Japanese Society of Neurology. The influence of European neurology, particularly French and German, in the figures of Professor Jean-Martin Charcot and Professor Erwin Bälz, was fundamental in the consolidation of neurology in Japan.}, } @article {pmid39813072, year = {2025}, author = {Raines, C and Mefferd, A}, title = {Disease-Specific Speech Movement Characteristics of the Tongue and Jaw.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-14}, doi = {10.1044/2024_JSLHR-24-00351}, pmid = {39813072}, issn = {1558-9102}, abstract = {PURPOSE: To advance our understanding of disease-specific articulatory impairment patterns in speakers with dysarthria, this study investigated the articulatory performance of the tongue and jaw in speakers with differing neurological diseases (Parkinson's disease [PD], amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease).

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

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

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

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

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

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

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

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

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

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

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

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

ETHICS AND DISSEMINATION: Throughout the entire process of this systematic review, no personal information was used, hence ethical review is not required. The results of this meta-analysis will be disseminated through publication in peer-reviewed journals and/or conference presentations.}, } @article {pmid39810199, year = {2025}, author = {Eck, RJ and Valdmanis, PN and Liachko, NF and Kraemer, BC}, title = {Alternative 3' UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD.}, journal = {Molecular brain}, volume = {18}, number = {1}, pages = {1}, pmid = {39810199}, issn = {1756-6606}, support = {R21AG082032/NH/NIH HHS/United States ; F99AG088436/NH/NIH HHS/United States ; R01AG066729/NH/NIH HHS/United States ; RF1AG078374/NH/NIH HHS/United States ; IK6BX006467//U.S. Department of Veterans Affairs/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Polyadenylation ; *3' Untranslated Regions/genetics ; *Disease Models, Animal ; Humans ; DNA-Binding Proteins/metabolism/genetics ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Mice ; }, abstract = {Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice. Some conservation exists between alternative polyadenylation in rNLS8 mice and human disease models including in disease relevant genes and biological pathways. Together, these findings support both TDP-43 loss and toxic gain-of-function phenotypes as contributors to the neurodegeneration in rNLS8 mice, nominating its continued utility as a preclinical model for investigating mechanisms of neurodegeneration in ALS/FTLD-TDP.}, } @article {pmid39810183, year = {2025}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Souza, CDS and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {10}, pmid = {39810183}, issn = {1755-8794}, support = {899-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; 899-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; NF-SI-0617-10077//National Institute for Health and Care Research/ ; IS-BRC-1215-20017//NIHR Sheffield Biomedical Research Centre/ ; CEGS 5P50HG00773504//NIH (USA)/ ; 216596/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Motor Neurons/metabolism/pathology ; *Biomarkers/blood ; *DNA Methylation ; Cell-Free Nucleic Acids/blood/genetics ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, } @article {pmid39809929, year = {2025}, author = {Antico, O and Thompson, PW and Hertz, NT and Muqit, MMK and Parton, LE}, title = {Targeting mitophagy in neurodegenerative diseases.}, journal = {Nature reviews. Drug discovery}, volume = {}, number = {}, pages = {}, pmid = {39809929}, issn = {1474-1784}, abstract = {Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.}, } @article {pmid39809899, year = {2025}, author = {Cui, Y and Arnold, FJ and Li, JS and Wu, J and Wang, D and Philippe, J and Colwin, MR and Michels, S and Chen, C and Sallam, T and Thompson, LM and La Spada, AR and Li, W}, title = {Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {39809899}, issn = {1546-1718}, abstract = {Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3'-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer's disease.}, } @article {pmid39808939, year = {2025}, author = {Prakash, P and Lei, T and Flint, RD and Hsieh, JK and Fitzgerald, Z and Mugler, EM and Templer, J and Goldrick, MA and Tate, MC and Rosenow, JM and Glaser, JI and Slutzky, MW}, title = {Decoding speech intent from non-frontal cortical areas.}, journal = {Journal of neural engineering}, volume = {}, number = {}, pages = {}, doi = {10.1088/1741-2552/adaa20}, pmid = {39808939}, issn = {1741-2552}, abstract = {Brain-machine interfaces (BMIs) have advanced greatly in decoding speech signals originating from the speech motor cortices. Primarily, these BMIs target individuals with intact speech motor cortices but who are paralyzed by disrupted connections between frontal cortices and their articulators due to brainstem stroke or motor neuron diseases such as amyotrophic lateral sclerosis. A few studies have shown some information outside the speech motor cortices, such as in parietal and temporal lobes, that also may be useful for BMIs. The ability to use information from outside the frontal lobes could be useful not only for people with locked-in syndrome but also to people with frontal lobe damage, which can cause nonfluent aphasia or apraxia of speech. However, temporal and parietal lobes are predominantly involved in perceptive speech processing and comprehension. Therefore, to be able to use signals from these areas in a speech BMI, it is important to ascertain that they are related to production. Here, using intracranial recordings, we sought evidence for whether, when and where neural information related to speech intention could be found in the temporal and parietal cortices. Causal information enabled us to distinguish speech intent from resting state and other processes involved in language processing or working memory. Information related to speech intent was distributed widely across the temporal and parietal lobes, including superior temporal, medial temporal, angular, and supramarginal gyri. This provides evidence of a decodable production-related signal in these areas. This insight may help in designing speech brain-machine interfaces that could benefit people with locked-in syndrome, aphasia or apraxia of speech.}, } @article {pmid39806943, year = {2024}, author = {Lee, K and Kim, SI and Shim, YM and Kim, EE and Yoo, S and Won, JK and Park, SH}, title = {Current Status and Future Perspective of Seoul National University Hospital-Dementia Brain Bank with Concordance of Clinical and Neuropathological Diagnosis.}, journal = {Experimental neurobiology}, volume = {33}, number = {6}, pages = {295-311}, doi = {10.5607/en24027}, pmid = {39806943}, issn = {1226-2560}, abstract = {This paper introduces the current status of Seoul National University Hospital Dementia Brain Bank (SNUH-DBB), focusing on the concordance rate between clinical diagnoses and postmortem neuropathological diagnoses. We detail SNUH-DBB operations, including protocols for specimen handling, induced pluripotent stem cells (iPSC) and cerebral organoids establishment from postmortem dural fibroblasts, and adult neural progenitor cell cultures. We assessed clinical-neuropathological diagnostic concordance rate. Between 2015 and September 2024, 162 brain specimens were collected via brain donation and autopsy. The median donor age was 73 years (1-94) with a male-to -female ratio of 2:1. The median postmortem interval was 9.5 hours (range: 2.5-65). Common neuropathological diagnoses included pure Lewy body disease (10.6%), Lewy body disease (LBD) with other brain diseases (10.6%), pure Alzheimer's disease-neuropathological change (ADNC) (6.0%), ADNC with other brain diseases (10.7%), vascular brain injury (15.2%), and primary age-related tauopathy (7.3%). APOE genotype distribution was following: ε3/ε3: 62.3%, ε2/ε3: 9.6%, ε2/ε4: 3.4%, ε3/ε4: 24.0%, and ε4/ε4: 0.7%. Concordance rates between pathological and clinical diagnoses were: ADNC/AD at 42.4%; LBD at 59.0%; PSP at 100%; ALS at 85.7%; Huntington's disease 100%. The varying concordance rates across different diseases emphasize the need for improved diagnostic criteria and biomarkers, particularly for AD and LBD. Tissues have been distributed to over 40 national studies. SNUH-DBB provides high-quality brain tissues and cell models for neuroscience research, operating under standardized procedures and international guidelines. It supports translational research in dementia and neurodegenerative diseases, potentially advancing diagnostic and therapeutic strategies.}, } @article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Neuroprotective Agents/pharmacology ; Mice ; *Mice, Transgenic ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Proton Magnetic Resonance Spectroscopy/methods ; Brain/drug effects/metabolism/diagnostic imaging ; Disease Models, Animal ; Male ; Magnetic Resonance Imaging/methods ; Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Our implementation can be found in https://github.com/ngominhhoang/Quantum-Motif-Identification.git.}, } @article {pmid39801516, year = {2024}, author = {Kamiyama, D and Nishida, Y and Kamiyama, R and Sego, A and Vining, G and Bui, K and Fitch, M and Do, H and Avraham, O and Chihara, T}, title = {The VAPB Axis Precisely Coordinates the Timing of Motoneuron Dendritogenesis in Neural Map Development.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-5684747/v1}, pmid = {39801516}, issn = {2693-5015}, abstract = {In Drosophila motoneurons, spatiotemporal dendritic patterns are established in the ventral nerve cord. While many guidance cues have been identified, the mechanisms of temporal regulation remain unknown. Previously, we identified the actin modulator Cdc42 GTPase as a key factor in this process. In this report, we further identify the upstream factors that activate Cdc42. Using single-cell genetics, FRET-based imaging, and biochemical techniques, we demonstrate that the guanine nucleotide exchange factor Vav is anchored to the plasma membrane via the Eph receptor tyrosine kinase, enabling Cdc42 activation. VAMP-associated protein 33 (Vap33), an Eph ligand supplied non-cell-autonomously, may induce Eph autophosphorylation, initiating downstream signaling. Traditionally known as an ER-resident protein, Vap33 is secreted extracellularly at the onset of Cdc42 activation, acting as a temporal cue. In humans, VAPB-the ortholog of Vap33-is similarly secreted in the spinal cord, and its dysregulation leads to amyotrophic lateral sclerosis type 8 (ALS8) and spinal muscular atrophy (SMA). Our findings provide a framework linking VAPB signaling to motor circuitry formation in both health and disease.}, } @article {pmid39801319, year = {2025}, author = {Oliveira Santos, M and Domingues, S and Simão, S and Gromicho, M and Alves, I and de Carvalho, M}, title = {The Role of Gastrostomy and Noninvasive Ventilation in Primary Lateral Sclerosis.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28346}, pmid = {39801319}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Literature on the role of gastrostomy and noninvasive ventilation (NIV) in primary lateral sclerosis (PLS) is limited. We aim to investigate whether PLS patients develop dysphagia requiring feeding tubes or respiratory failure necessitating NIV.

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

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

DISCUSSION: Dysphagia requiring gastrostomy was common in our PLS cohort, but survival after gastrostomy recommendation did not differ between groups. Patients who developed respiratory impairment may represent a distinct group with faster disease progression and shorter survival. Our findings may contribute to a deeper understanding and improved management of PLS.}, } @article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, doi = {10.1002/jbt.70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Apoptosis ; *Oxidative Stress ; *Nitrosative Stress ; *Oxidation-Reduction ; Animals ; *Signal Transduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, } @article {pmid39799393, year = {2025}, author = {Valenzuela, V and Becerra, D and Astorga, JI and Fuentealba, M and Diaz, G and Bargsted, L and Chacón, C and Martinez, A and Gozalvo, R and Jackson, K and Morales, V and Heras, ML and Tamburini, G and Petrucelli, L and Sardi, P and Plate, L and Hetz, C}, title = {Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2025.01.004}, pmid = {39799393}, issn = {1525-0024}, abstract = {Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAV) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended life span of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD.}, } @article {pmid39799324, year = {2025}, author = {Freiha, J and Grand, E and Marshall, B and Arunchalam, R and Pinto, A and Osman, C}, title = {Amyotrophic lateral sclerosis in a patient with chronic lymphocytic leukaemia and drug related sarcoid-like reaction.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {16}, pmid = {39799324}, issn = {1471-2377}, mesh = {Humans ; Male ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/complications ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Sarcoidosis/diagnosis/complications ; Rituximab/therapeutic use/adverse effects ; Central Nervous System Diseases ; }, abstract = {Sarcoid-like reaction is an immunological reaction that can affect lymph nodes and organs but does not meet the diagnostic criteria for systemic sarcoidosis. Anti-CD20 auto-antibodies have been reported to be responsible for such reactions. There are several reported associations between Chronic lymphocytic leukaemia (CLL), Amyotrophic lateral sclerosis (ALS) and Sarcoid-like reactions (SLR). We report a case of ALS developing in a patient with treated CLL and drug related SLR one day after exposure to Venetoclax and Rituximab. A 60-year-old male presented with lower limb rash, left leg weakness followed by bulbar symptoms which progressed over 12-months. Workup demonstrated a Cerebrospinal fluid (CSF) pleocytosis and inguinal lymphadenopathy. Skin and inguinal lymph node biopsies showed non-necrotising granulomata. Electromyography met diagnostic criteria for ALS. He was treated for presumed neurosarcoidosis mimicking ALS. Despite prednisolone and infliximab treatment, the motor symptoms rapidly progressed; Hence, we made a clinical diagnosis of ALS. We discuss the diagnostic and treatment challenges of this case.}, } @article {pmid39799044, year = {2024}, author = {Bracca, V and Premi, E and Cotelli, MS and Micheli, A and Altomare, D and Cantoni, V and Gasparotti, R and Borroni, B}, title = {Loss of Insight in Syndromes Associated with Frontotemporal Lobar Degeneration: Clinical and Imaging Features.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2024.12.005}, pmid = {39799044}, issn = {1545-7214}, abstract = {OBJECTIVES: The present study aims to assess the prevalence, associated clinical symptoms, longitudinal changes, and imaging correlates of Loss of Insight (LOI), which is still unexplored in syndromes associated with Frontotemporal Lobar Degeneration (FTLD).

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

SETTING: Tertiary Frontotemporal Dementia research clinic.

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

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

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

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

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

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

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

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

CONCLUSION: This study demonstrates that the glyphosate-resistant L. rigidum population (NLR70) also exhibits resistance to pyroxsulam and identifies six candidate genes associated with non-target site resistance to pyroxsulam. © 2025 Society of Chemical Industry.}, } @article {pmid39796536, year = {2024}, author = {Cuffaro, F and Lamminpää, I and Niccolai, E and Amedei, A}, title = {Nutritional and Microbiota-Based Approaches in Amyotrophic Lateral Sclerosis: From Prevention to Treatment.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, doi = {10.3390/nu17010102}, pmid = {39796536}, issn = {2072-6643}, support = {PNRR-MAD-2022-12375798//Ministero della Salute/ ; PE0000006//Ministry of University and Research (MUR)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Gastrointestinal Microbiome ; *Dysbiosis/therapy ; Probiotics/therapeutic use ; Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation ; Fatty Acids, Omega-3 ; Prebiotics/administration & dosage ; Oxidative Stress ; Nutritional Status ; Diet, Mediterranean ; Antioxidants ; }, abstract = {Metabolic alterations, including hypermetabolism, lipid imbalances, and glucose dysregulation, are pivotal contributors to the onset and progression of Amyotrophic Lateral Sclerosis (ALS). These changes exacerbate systemic energy deficits, heighten oxidative stress, and fuel neuroinflammation. Simultaneously, gastrointestinal dysfunction and gut microbiota (GM) dysbiosis intensify disease pathology by driving immune dysregulation, compromising the intestinal barrier, and altering gut-brain axis (GBA) signaling, and lastly advancing neurodegeneration. Therapeutic and preventive strategies focused on nutrition offer promising opportunities to address these interconnected pathophysiological mechanisms. Diets enriched with antioxidants, omega-3 fatty acids, and anti-inflammatory compounds-such as the Mediterranean diet-have shown potential in reducing oxidative stress and systemic inflammation. Additionally, microbiota-targeted approaches, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation, are emerging as innovative tools to restore microbial balance, strengthen gut integrity, and optimize GBA function. This review highlights the critical need for personalized strategies integrating immunonutrition and microbiota modulation to slow ALS progression, improve quality of life, and develop preventive measures for neurodegenerative and neuroinflammatory diseases. Future research should prioritize comprehensive dietary and microbiota-based interventions to uncover their therapeutic potential and establish evidence-based guidelines for managing ALS and related disorders.}, } @article {pmid39795334, year = {2024}, author = {Bhattacharya, S and Sen, MK and Hamouzová, K and Košnarová, P and Bharati, R and Menendez, J and Soukup, J}, title = {Pyroxsulam Resistance in Apera spica-venti: An Emerging Challenge in Crop Protection.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, doi = {10.3390/plants14010074}, pmid = {39795334}, issn = {2223-7747}, support = {QL24010167//National Agency for Agricultural Research (NAZV)/ ; }, abstract = {Apera spica-venti, a prevalent weed in Czech winter wheat fields, has developed resistance to ALS-inhibiting herbicides due to their frequent use. This study reports a biotype of A. spica-venti resistant to pyroxsulam, with cross and multiple resistance to iodosulfuron, propoxycarbazone, pinoxaden, and chlortoluron. Dose-response experiments revealed high resistance of both R1 and R2 biotypes to pyroxsulam, with resistance factors (RF) of 6.69 and 141.65, respectively. Pre-treatment with malathion reduced RF by 2.40× and 1.25× in R1 and R2, indicating the potential involvement of cytochrome P450 (CytP450). NBD-Cl pre-treatment decreased RF only in R2, suggesting possible GST involvement. Gene analysis revealed no mutations (at previously reported sites) or overexpression in the acetolactate synthase (ALS) gene. However, a significant difference in ALS enzyme activity between resistant and susceptible biotypes points to target-site resistance mechanisms. Studies with [14]C-labeled pyroxsulam showed that reduced absorption and translocation were not likely resistance mechanisms. In summary, herbicide resistance in A. spica-venti appears to result from multiple mechanisms. Possible causes include target-site resistance from an unidentified ALS mutation (within coding or regulatory regions). Enhanced herbicide metabolism via CytP450s and GSTs is also a contributing factor. Further experimental validation is needed to confirm these mechanisms and fully understand the resistance. This evolution underscores the adaptive capacity of weed populations under herbicide pressure, emphasizing the need for alternative control strategies.}, } @article {pmid39794401, year = {2025}, author = {Cheng, J and Wu, BT and Liu, HP and Lin, WY}, title = {Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1564}, pmid = {39794401}, issn = {2045-2322}, support = {CMU110-MF-92//China Medical University, Taiwan/ ; CMU112-MF-62//China Medical University, Taiwan/ ; MOST 111-2314-B-039-017-MY3//National Science and Technology Council of Taiwan/ ; DMR-112-125//China Medical University Hospital, Taiwan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Iron/metabolism ; Humans ; *Machine Learning ; *Lipid Metabolism ; *Endosomes/metabolism ; *Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Although genes causing familial cases have been identified, those of sporadic ALS, which occupies the majority of patients, are still elusive. In this study, we adopted machine learning to build binary classifiers based on the New York Genome Center (NYGC) ALS Consortium's RNA-seq data of the postmortem spinal cord of ALS and non-neurological disease control. The accuracy of the classifiers was greater than 83% and 77% for the training set and the unseen test set, respectively. The classifiers contained 114 genes. Among them, 41 genes have been reported in previous ALS studies, and others are novel in this field. These genes are involved in mitochondrial respiration, lipid metabolism, endosomal trafficking, and iron metabolism, which may promote the progression of ALS pathology.}, } @article {pmid39794859, year = {2025}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Correction: Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {5}, pmid = {39794859}, issn = {2051-5960}, } @article {pmid39793633, year = {2025}, author = {Baker, RS and Wang, JT and Rouatbi, N and Lu, Y and Al-Adhami, T and Asker, D and Rahman, KM and Al-Chalabi, A and Forbes, B and Bansal, S and Al-Jamal, KT}, title = {Brain distribution study of [[14]C]-Riluzole following intranasal administration in mice.}, journal = {International journal of pharmaceutics}, volume = {}, number = {}, pages = {125195}, doi = {10.1016/j.ijpharm.2025.125195}, pmid = {39793633}, issn = {1873-3476}, abstract = {Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [[14]C]-RLZ was synthesised using an optimised one-pot method. [[14]C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance ([1]H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 %Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % injected dose/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % injected dose/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of intranasal RLZ and intranasal RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.}, } @article {pmid39521135, year = {2024}, author = {Sajid, SL and Ur Rehman, MA and Sajid, SA and Shahid, N}, title = {Response to Valerio Nardone et al's "Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.08.084}, pmid = {39521135}, issn = {1097-6787}, } @article {pmid39792652, year = {2025}, author = {Mercadante, S and Petronaci, P and Lo Cascio, A}, title = {Living Will and Advance Care Planning in Patients With Amyotrophic Lateral Sclerosis Admitted to Specialistic Home Palliative Care.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091241312906}, doi = {10.1177/10499091241312906}, pmid = {39792652}, issn = {1938-2715}, abstract = {Objectives: In Italy a recent law was approved for providing patients' wishes regarding end of life issues, commonly referred internationally to as "living wills", (Dichiarazione anticipata di trattamento, DAT). Regardless of this official document, advance care planning (ACP) is often used in a palliative care setting to share the treatments to start, to continue, to withdraw, thus preventing the stress on an acute decision. The aim of this study was to assess DAT and ACP in patients with amyotropic lateral sclerosis admitted to home palliative care. Methods: Patients consecutively admitted to speciliazed home palliative care were prospectively assessed. The presence of DAT or ACP was recorded. Results: Sixty-eight patients were enrolled in the period taken into consideration. No patient had drown up DAT, and only one patient provided his ACP prior to home palliative care admission. Along the course of home palliative care care assistance, 30.9% of patients provided their ACP. Discussion: In Italy DAT resulted scarcely widespread, despite an existing law, as no patient officially provided their indication on end of life issues. In addition, ACP was given only after starting specialized home palliative care in less than 1/3 of patients. Home palliative care seems to be a fundamental resource for improving communication and soliciting expression of patients' wishes regarding end of life issues.}, } @article {pmid39792557, year = {2025}, author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Miller, MR and Bai, J and Shahzad, S and Nedumaran, N and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, PM and Ward, M and Todd, PK and Barmada, SJ}, title = {TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115113}, doi = {10.1016/j.celrep.2024.115113}, pmid = {39792557}, issn = {2211-1247}, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and underscore the consequences of aberrant sTDP43 accumulation in disease.}, } @article {pmid39792201, year = {2025}, author = {Fu, Z and Feng, B and Akogo, HY and Ma, J and Liu, Y and Quan, H and Zhang, X and Hou, Y and Zhang, X and Ma, J and Cui, H}, title = {Amyotrophic Lateral Sclerosis and Parkinson's Disease: Brain Tissue Transcriptome Analysis Reveals Interactions.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39792201}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, abstract = {This study utilises amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) human brain samples from the GEO database and employs differential expression gene (DEG) analysis to identify genes that are pivotal in both neurodegenerative diseases. Through in depth GO and KEGG enrichment analyses, we elucidated the biological functions and potential pathways associated with these DEGs. Furthermore, by constructing protein‒protein interaction networks, we highlight the significance of shared DEGs in both cellular physiology and disease contexts. Analysis of drug‒gene associations revealed potential therapeutic compounds linked to ALS and PD treatment. Additionally, we explored the interactions between transcription factors, miRNAs, and common DEGs, revealing aspects of gene regulatory networks. This study provides insights into the molecular mechanisms of ALS and PD, offering valuable contributions to ongoing research and potential therapeutic avenues.}, } @article {pmid39791815, year = {2025}, author = {Rossi, A and Cuccioloni, M and Pellegrino, F and Giovannetti, R and Alladio, E}, title = {Discriminating Analysis of Metal Ions via Multivariate Curve Resolution-Alternating Least Squares Applied to Silver Nanoparticle Sensor.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, doi = {10.3390/nano15010057}, pmid = {39791815}, issn = {2079-4991}, abstract = {Heavy metals are life-threatening pollutions because of their great toxicity, long-term persistence in nature and their bioaccumulation in living organisms. In this work, we performed multivariate curve resolution-alternating least squares analysis of UV-Vis raw spectra received by a colorimetric sensor constructed on mercaptoundecanoic acid functionalized silver nanoparticles (AgNPs@11MUA) to detect Cd[2+], Cu[2+], Mn[2+], Ni[2+], and Zn[2+] in water. This combined approach allowed the rapid identification and quantification of multiple heavy metals and showed adequate sensitivity and selectivity, thus representing a promising analytical and computational method for both laboratory and field applications such as environmental safety and public health monitoring.}, } @article {pmid39791748, year = {2025}, author = {Moss, KR and Saxena, S}, title = {Schwann Cells in Neuromuscular Disorders: A Spotlight on Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, doi = {10.3390/cells14010047}, pmid = {39791748}, issn = {2073-4409}, mesh = {*Schwann Cells/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Humans ; Animals ; Neuromuscular Diseases/pathology ; Motor Neurons/pathology/metabolism ; Charcot-Marie-Tooth Disease/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease primarily affecting motor neurons, leading to progressive muscle atrophy and paralysis. This review explores the role of Schwann cells in ALS pathogenesis, highlighting their influence on disease progression through mechanisms involving demyelination, neuroinflammation, and impaired synaptic function. While Schwann cells have been traditionally viewed as peripheral supportive cells, especially in motor neuron disease, recent evidence indicates that they play a significant role in ALS by impacting motor neuron survival and plasticity, influencing inflammatory responses, and altering myelination processes. Furthermore, advancements in understanding Schwann cell pathology in ALS combined with lessons learned from studying Charcot-Marie-Tooth disease Type 1 (CMT1) suggest potential therapeutic strategies targeting these cells may support nerve repair and slow disease progression. Overall, this review aims to provide comprehensive insights into Schwann cell classification, physiology, and function, underscoring the critical pathological contributions of Schwann cells in ALS and suggests new avenues for targeted therapeutic interventions aimed at modulating Schwann cell function in ALS.}, } @article {pmid39791705, year = {2024}, author = {Sun, D and Amiri, M and Meng, Q and Unnithan, RR and French, C}, title = {Calcium Signalling in Neurological Disorders, with Insights from Miniature Fluorescence Microscopy.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, doi = {10.3390/cells14010004}, pmid = {39791705}, issn = {2073-4409}, support = {DP170100363//Australian Research Council under Discovery Project/ ; }, mesh = {*Calcium Signaling ; Humans ; *Nervous System Diseases/metabolism/pathology ; Animals ; *Microscopy, Fluorescence/methods ; Calcium/metabolism ; Neurons/metabolism ; }, abstract = {Neurological disorders (NDs), such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia, represent a complex and multifaceted health challenge that affects millions of people around the world. Growing evidence suggests that disrupted neuronal calcium signalling contributes to the pathophysiology of NDs. Additionally, calcium functions as a ubiquitous second messenger involved in diverse cellular processes, from synaptic activity to intercellular communication, making it a potential therapeutic target. Recently, the development of the miniature fluorescence microscope (miniscope) enabled simultaneous recording of the spatiotemporal calcium activity from large neuronal ensembles in unrestrained animals, providing a novel method for studying NDs. In this review, we discuss the abnormalities observed in calcium signalling and its potential as a therapeutic target for NDs. Additionally, we highlight recent studies that utilise miniscope technology to investigate the alterations in calcium dynamics associated with NDs.}, } @article {pmid39791335, year = {2025}, author = {Dogan, EO and Simonini, SR and Bouley, J and Weiss, A and Brown, RH and Henninger, N}, title = {Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1[G93A] Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27174}, pmid = {39791335}, issn = {1531-8249}, support = {NS131756/NS/NINDS NIH HHS/United States ; //Moloney Fellowship/ ; //Angel Fund for ALS Research/ ; }, abstract = {OBJECTIVE: Approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Epidemiological data have identified traumatic brain injury (TBI) as an exogenous risk factor for ALS; however, the mechanisms by which TBI may worsen SOD1 ALS remain largely undefined.

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

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

INTERPRETATION: SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1[G93A] mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025.}, } @article {pmid39789167, year = {2025}, author = {Kassubek, J and Roselli, F and Witzel, S and Dorst, J and Ludolph, AC and Rasche, V and Vernikouskaya, I and Müller, HP}, title = {Hypothalamic atrophy in primary lateral sclerosis, assessed by convolutional neural network-based automatic segmentation.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1551}, pmid = {39789167}, issn = {2045-2322}, mesh = {Humans ; Female ; Male ; *Hypothalamus/pathology/diagnostic imaging ; Middle Aged ; *Neural Networks, Computer ; *Magnetic Resonance Imaging/methods ; *Atrophy/pathology ; Aged ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Adult ; Motor Neuron Disease/pathology/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Case-Control Studies ; }, abstract = {Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy. Very limited weight loss is observed in patients with PLS, which raises the question of whether there are also less hypothalamic alterations. The purpose of this study was to quantitatively investigate the hypothalamic volume in a group of PLS patients and to compare it with ALS and controls. Recently, we have introduced automatic hypothalamic quantification method based on the use of convolutional neural network (CNN) to reduce human variability and enhance analysis robustness. This CNN of U-Net architecture was applied for automatic segmentation of the hypothalamus and intracranial volume (ICV) to allow adjustments of the hypothalamic volume between subjects with different head sizes respectively. Automatic segmentation and volumetric analysis were performed in high resolution T1 weighted MRI volumes (acquired on a 1.5 T MRI scanner) of 46 PLS patients in comparison to 107 healthy controls and 411 `classical` ALS patients, respectively. Significant hypothalamic volume reduction was observed in PLS (818 ± 73 mm[3]) when compared to controls (852 ± 77 mm[3]); significant hypothalamic volume reduction was also confirmed in ALS (823 ± 84 mm[3]), in support of previous studies. No significant differences were found in normalized hypothalamic volumes between ALS patients and PLS patients at the group level. This unbiased CNN-based hypothalamus volume quantification study demonstrated similarly reduced hypothalamus volume in PLS and ALS patients, despite the clinical phenotypic differences.}, } @article {pmid39788313, year = {2025}, author = {Cassina, P and Miquel, E and Martínez-Palma, L and Cassina, A}, title = {Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2024.12.058}, pmid = {39788313}, issn = {1873-7544}, abstract = {In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.}, } @article {pmid39786806, year = {2025}, author = {Yang, S and Song, J and Deng, M and Cheng, S}, title = {Identification of Drug-Targetable Genes for Eczema and Dermatitis Using Integrated Genomic and Proteomic Approaches.}, journal = {Dermatitis : contact, atopic, occupational, drug}, volume = {}, number = {}, pages = {}, doi = {10.1089/derm.2024.0429}, pmid = {39786806}, issn = {2162-5220}, abstract = {Background: Eczema and dermatitis are common inflammatory skin conditions with significant morbidity. Identifying drug-targetable genes can facilitate the development of effective treatments. Methods: This study analyzed data obtained by meta-analysis of 2 genome-wide association studies on eczema/dermatitis (57,311 cases and 896,779 controls, European ancestry). We identified drug-targetable genes from the Drug-Gene Interaction Database and Finan et al's findings. Cis-expression quantitative trait loci (eQTL) data from human blood and skin tissues were used for Mendelian randomization (MR) analysis. Bayesian colocalization, proteomic MR, and meta-analysis validated the causal relationships. Finally, protein-protein interactions (PPIs) and correlation analysis of potential drug targets and cytokines were performed. Results: We identified 2532 drug-targetable genes; 3378 Single Nucleotide Polymorphism (SNPs) were associated with 1531 genes in blood cis-eQTLs, 664 SNPs with 667 genes in sun-exposed skin eQTLs, and 572 SNPs with 574 genes in nonsun-exposed skin eQTLs. Five genes (SLC22A5, NOTCH4, AGER, HLA-DRB5, and EHMT2) showed causal relationships with eczema/dermatitis across multiple datasets. Single-variable and multi-variable Mendelian randomization (SMR) and multi-SNP SMR analysis identified 8 genes (PIK3R4, DHODH, CXCR2, Interleukin (IL)18, LGALS9, RPS6KB2, SLC22A5, and AGER) across all tissues. Functional Summary Information for Variants in the Online Network (FUSION) analysis confirmed associations for SLC22A5 and AGER. Bayesian colocalization indicated AGER (PPH4: 0.95) as a shared causal variant. Proteomic MR and meta-analysis showed that increased AGER protein levels were associated with a lower risk of eczema or dermatitis (odds ratio: 0.995, 95% confidence interval: 0.997-0.993, P = 0.0002). A PPI network revealed interactions of AGER with NOTCH4 and multiple cytokines, whereas SLC22A5 showed no cytokine interactions. Conclusions: This study identified potential drug-targetable genes, with AGER showing strong potential as a target for reducing eczema/dermatitis risk. These findings provide a basis for developing targeted therapies.}, } @article {pmid39786727, year = {2025}, author = {Midgley, SD and Bariami, S and Habgood, M and Mackey, M}, title = {Adaptive Lambda Scheduling: A Method for Computational Efficiency in Free Energy Perturbation Simulations.}, journal = {Journal of chemical information and modeling}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jcim.4c01668}, pmid = {39786727}, issn = {1549-960X}, abstract = {Recent increases in the availability of computational power have improved the accessibility of ligand-protein relative binding free energy (RBFE) calculations; however, these calculations remain resource-intensive, which can limit their practical application. RBFE calculations typically use a set of thermodynamic intermediates mediated by the transformation coordinate λ. Optimizing λ offers a way to tune the computational efforts required for a given RBFE calculation. Here, we present Adaptive Lambda Scheduling (ALS), a streamlined approach for on-the-fly bespoke λ scheduling. We show it can achieve substantial reductions in computational cost while retaining predictive performance.}, } @article {pmid39786321, year = {2025}, author = {Kim, K and Kim, S and Katana, M and Terentyev, D and Radwański, PB and Munger, MA}, title = {Riluzole is associated with reduced risk of heart failure.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70033}, pmid = {39786321}, issn = {1468-1331}, support = {R01HL14488/HL/NHLBI NIH HHS/United States ; R01HL155378/HL/NHLBI NIH HHS/United States ; R01HL166604/HL/NHLBI NIH HHS/United States ; R01 NS121234/NS/NINDS NIH HHS/United States ; }, mesh = {*Riluzole/therapeutic use ; Humans ; *Heart Failure/epidemiology/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Amyotrophic Lateral Sclerosis/epidemiology/drug therapy ; Aged, 80 and over ; Cohort Studies ; United States/epidemiology ; }, abstract = {BACKGROUND: Reduction of intracellular Na[+] accumulation through late Na[+] current inhibition has been recognized as a target for cardiac Ca[2+] handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na[+] channel blocker with enhancement of Ca[2+]-activated K[+] channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca[2+] leak and therefore may improve cardiac function.

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

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

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

CONCLUSIONS: Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.}, } @article {pmid39786151, year = {2025}, author = {Harrison, J and Bhardwaj, A and Houck, O and Sather, K and Sekiya, A and Knack, S and Saarunya Clarke, G and Puskarich, MA and Tignanelli, C and Rogers, L and Marmor, S and Beilman, G}, title = {Emergency medical services level of training is associated with mortality in trauma patients: A combined prehospital and in hospital database analysis.}, journal = {The journal of trauma and acute care surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/TA.0000000000004540}, pmid = {39786151}, issn = {2163-0763}, abstract = {BACKGROUND: There is conflicting evidence regarding emergency medical service (EMS) provider level of training and outcomes in trauma. We hypothesized that advanced life support (ALS) provider transport is associated with lower mortality compared with basic life support transport.

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

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

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

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.}, } @article {pmid39783196, year = {2025}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Interaction between riluzole treatment and dietary glycemic index in the disease progression of amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.52294}, pmid = {39783196}, issn = {2328-9503}, support = {K23NS131586/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS).

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

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

INTERPRETATION: High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.}, } @article {pmid39783194, year = {2025}, author = {Smith, SE and McCoy-Gross, K and Malcolm, A and Oranski, J and Markway, JW and Miller, TM and Bucelli, RC}, title = {Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a "real-world" setting.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.52264}, pmid = {39783194}, issn = {2328-9503}, abstract = {OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.

METHODS: This was a single-center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes.

RESULTS: Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: -57.9%; mean change CSF pNFH: -67.6%). There was apparent disease stabilization as assessed by the ALSFRS-R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85).

INTERPRETATION: This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.}, } @article {pmid39779800, year = {2025}, author = {Regondi, S and Donvito, G and Frontoni, E and Kostovic, M and Minazzi, F and Bratières, S and Filosto, M and Pugliese, R}, title = {Artificial intelligence empowered voice generation for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1361}, pmid = {39779800}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy/complications/psychology ; Humans ; *Artificial Intelligence ; *Voice ; Female ; Male ; Middle Aged ; *Quality of Life ; Aged ; Communication Aids for Disabled ; Speech/physiology ; Adult ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that can result in a progressive loss of speech due to bulbar dysfunction, which can have significant negative impact on the patient's mental well-being. Alternative Augmentative Communication (AAC) strategies based on synthetic voices have been shown to assist patients in maintaining communication and improving their Quality of Life (QoL). However, such synthetic voices are often perceived as impersonal and fail to capture the unique voice and identity of the patient. To tackle this issue, combining voice banking (VB) and artificial intelligence (AI) has emerged as a more natural communication strategy, enabling individuals to preserve their voice for use with AAC devices as needed. This involves recording speech samples to generate a synthetic voice closely resembling the individual's own. Despite the increasing interest in VB, there's a lack of clear strategies for its effective implementation in rapidly progressing diseases like ALS. Additionally, the perceptual quality of VB on patients with preserved speech, especially when offered early in the disease, remains poorly understood. In light of these challenges, this study aims to assess the effectiveness and the perceptual impact of AI-generated voices on ALS patients with preserved speech, utilizing a personalized voice synthesis system based on machine learning. The AI-generated patient-specific voice is achieved through voice recording, followed by fine-tuning using a Generative Adversarial Network for Efficient and High Fidelity Speech Synthesis (HiFi-GAN), resulting in a model capable of producing speech highly similar to the patient's own voice, with exceptional expressive and audio quality. By addressing these aspects, this study intends to offer valuable insights into the potential benefits and challenges of combining VB with AI voices to enhance communication support for ALS patients.}, } @article {pmid39779704, year = {2025}, author = {Kempthorne, L and Vaizoglu, D and Cammack, AJ and Carcolé, M and Roberts, MJ and Mikheenko, A and Fisher, A and Suklai, P and Muralidharan, B and Kroll, F and Moens, TG and Yshii, L and Verschoren, S and Hölbling, BV and Moreira, FC and Katona, E and Coneys, R and de Oliveira, P and Zhang, YJ and Jansen, K and Daughrity, LM and McGown, A and Ramesh, TM and Van Den Bosch, L and Lignani, G and Rahim, AA and Coyne, AN and Petrucelli, L and Rihel, J and Isaacs, AM}, title = {Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {459}, pmid = {39779704}, issn = {2041-1723}, support = {648716 - C9ND//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; 217150/Z/19/Z//Wellcome Trust (Wellcome)/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Humans ; *Frontotemporal Dementia/genetics/metabolism ; Animals ; *CRISPR-Cas Systems ; *RNA, Antisense/genetics ; Mice ; HEK293 Cells ; *Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Neurons/metabolism ; Genetic Therapy/methods ; }, abstract = {The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G4C2 repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed C9orf72 sense and antisense repeat transcripts and DPRs in HEK cells. In C9orf72 patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct C9orf72 repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. This highlights the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.}, } @article {pmid39779681, year = {2025}, author = {McCallister, TX and Lim, CKW and Singh, M and Zhang, S and Ahsan, NS and Terpstra, WM and Xiong, AY and Zeballos C, MA and Powell, JE and Drnevich, J and Kang, Y and Gaj, T}, title = {A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {460}, pmid = {39779681}, issn = {2041-1723}, support = {1U01NS122102-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 1R01NS123556-01A1//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 5R01GM141296//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; MDA602798//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 20-IIP-516//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *CRISPR-Cas Systems ; Humans ; Animals ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Mice ; }, abstract = {An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.}, } @article {pmid39779313, year = {2025}, author = {Xiao, Y and Tan, Y and Li, C and Wei, Q and Jiang, Q and Wang, S and Yang, T and Lin, J and Zhang, L and Shang, H}, title = {Genetic and clinical analysis of OPTN in amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {}, number = {}, pages = {}, doi = {10.1136/jmg-2024-109978}, pmid = {39779313}, issn = {1468-6244}, abstract = {BACKGROUND: Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (OPTN) mutations, as reported in prior studies. The study aimed to elucidate the correlation between OPTN genotypes and phenotypes.

METHODS: OPTN gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of OPTN mutations and explore the relationship between the genotype and phenotype of patients with ALS with OPTN.

RESULTS: A total of 33 unrelated patients with ALS with 24 rare OPTN variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of OPTN variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.

CONCLUSION: Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying OPTN variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.}, } @article {pmid39778888, year = {2025}, author = {Etxebeste-Mitxeltorena, M and Flores-Romero, H and Ramos-Inza, S and Masiá, E and Nenchova, M and Montesinos, J and Martinez-Gonzalez, L and Porras, G and Orzáez, M and Vicent, MJ and Gil, C and Area-Gomez, E and Garcia-Saez, AJ and Martinez, A}, title = {Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.4c01368}, pmid = {39778888}, issn = {1520-4804}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24. Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.}, } @article {pmid39778605, year = {2025}, author = {Urano, Y and Iwagaki, A and Takeishi, A and Uchiyama, N and Noguchi, N}, title = {Downregulation of the SREBP pathways and disruption of redox status by 25-hydroxycholesterol predispose cells to ferroptosis.}, journal = {Free radical biology & medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2025.01.010}, pmid = {39778605}, issn = {1873-4596}, abstract = {Enzymatically formed side-chain oxysterols function as signaling molecules regulating cholesterol homeostasis and act as intermediates in the biosynthesis of bile acids. In addition to these physiological functions, an imbalance in oxysterol homeostasis has been implicated in pathophysiology. Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25-OHC), also formed by autoxidation, are associated with amyotrophic lateral sclerosis. However, the effects of 25-OHC on cell viability in glial cells remain unclear. This study demonstrates that 25-OHC induces ferroptosis, an iron-dependent programmed cell death, in mouse Schwann IMS32 cells. Mechanistically, 25-OHC suppressed the expression of selenoprotein glutathione peroxidase 4 (GPX4) at both the transcriptional and translational levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs). In addition, 25-OHC upregulated the expression of NADH-cytochrome b5 reductase 1 (CYB5R1) and NADPH-cytochrome P450 reductase (POR), enzymes that promote lipid peroxidation. We further found that 25-OHC increases the expression of glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) and decreases glutathione levels. Importantly, non-cytotoxic concentrations of 25-OHC enhanced cellular sensitivity to ferroptosis inducers by downregulating GPX4 expression. These findings reveal a multifaceted approach whereby 25-OHC induces ferroptosis through SREBP pathway suppression and redox imbalance in mouse Schwann IMS32 cells.}, } @article {pmid39778593, year = {2025}, author = {Chen, Q and Chen, G and Wang, Q}, title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.}, journal = {Planta medica}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2512-8928}, pmid = {39778593}, issn = {1439-0221}, abstract = {In recent years, the incidence of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has shown a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese Medicine (TCM), with its multi-component and multi-target characteristics, offers a promising approach for the treatment of neurodegenerative diseases. However, it is difficult to comprehensively elucidate the complex mechanisms underlying TCM formulations. As an emerging systems biology approach, network pharmacology has provided a crucial tool for uncovering the multi-target mechanisms of TCM through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases with TCM, analyzes the current status of relevant databases and technological methods, discusses the limitations in the research, and proposes future directions to promote the modernization of TCM and the development of precision medicine. Keywords: Neurodegenerative diseases, Traditional Chinese Medicine, Network pharmacology, Therapeutic targets.}, } @article {pmid39778572, year = {2025}, author = {Je, Y and Park, YE and Shin, YB}, title = {Differentiating Inclusion Body Myositis From Amyotrophic Lateral Sclerosis Based on the Features of Dysphagia: Insights From a Patient With Rapidly Progressive Dysphagia.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {1}, pages = {83-85}, pmid = {39778572}, issn = {1738-6586}, support = {/PNUH/Pusan National University Hospital/Korea ; }, } @article {pmid39777244, year = {2025}, author = {Moura, FA and Siqueira, AIAN}, title = {Gut-liver axis in sepsis-associated liver injury: Epidemiology, challenges and clinical practice.}, journal = {World journal of gastroenterology}, volume = {31}, number = {1}, pages = {99987}, pmid = {39777244}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Sepsis/complications/epidemiology ; *Dysbiosis ; *Liver/metabolism/pathology ; Animals ; *Oxidative Stress ; Bacterial Translocation ; Liver Diseases/epidemiology/microbiology ; Critical Illness ; Intensive Care Units/statistics & numerical data ; Anti-Bacterial Agents/therapeutic use ; }, abstract = {Although the liver has a remarkable regenerative capacity, sepsis-associated liver injury (SLI) is a complication often seen in intensive care units. Due to its role in immune and inflammatory regulation, the liver is particularly vulnerable during severe infections. Understanding the global prevalence, causes, and management of SLI is essential to improve outcomes and reduce healthcare costs. This paper aims to explore these factors, with an emphasis on identifying effective strategies for clinical management. Zhang et al's bibliometric analysis of 787 publications (745 original articles and 42 reviews, mostly in animal models) from 2000 to 2023 highlights the growing interest in SLI, focusing on oxidative stress, gut microbiota, and inflammatory processes. Key components such as nuclear factor-kappa B and the NOD-like receptor thermal protein domain associated protein 3 inflammasome pathway, along with their links to gut microbiota imbalance and oxidative stress, are crucial for understanding SLI pathogenesis. The gut-liver axis, particularly the role of intestinal permeability and bacterial translocation in liver inflammation, is emphasized. In this context, bacterial translocation is especially relevant for critically ill patients, as it can exacerbate liver inflammation. The findings underscore the need for integrated care in intensive care units, prioritizing gut health and careful antibiotic use to prevent dysbiosis. Despite extensive research, there remains a lack of clinical trials to validate therapeutic approaches. The abundance of experimental studies highlights potential therapeutic targets, stressing the need for high-quality randomized clinical trials to translate these findings into clinical practice.}, } @article {pmid39776752, year = {2024}, author = {Schwamburger, J and Brock, K and Cooper, R}, title = {The effect of GV-58, a calcium channel modifier, on synaptic transmission at the larval Drosophila and crayfish neuromuscular junctions.}, journal = {microPublication biology}, volume = {2024}, number = {}, pages = {}, pmid = {39776752}, issn = {2578-9430}, abstract = {GV-58 is known to increase the opening time of the mammalian P-type calcium channel in presynaptic motor nerve terminals. GV-58 is suggested as a therapeutic agent for dampening the symptoms of amyotrophic lateral sclerosis. To further understand the mechanisms of GV-58 actions, the Drosophila and crayfish neuromuscular junctions were used as models. Their presynaptic calcium channels are a P-type based on pharmacology profiles. However, exposure of GV-58 (1mM) did not produce any consistent alteration in synaptic transmission in these two preparations. It is possible that the molecular structure of the P-type channels is different in the Drosophila and crayfish.}, } @article {pmid39776251, year = {2025}, author = {Öijerstedt, L and Foucher, J and Lovik, A and Yazdani, S and Juto, A and Kläppe, U and Fang, F and Ingre, C}, title = {Correction: Repeated cognitive assessments show stable function over time in patients with ALS.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {104}, doi = {10.1007/s00415-024-12833-z}, pmid = {39776251}, issn = {1432-1459}, } @article {pmid39775908, year = {2025}, author = {de Vries, E and Hagbohm, C and Ouellette, R and Granberg, T}, title = {Clinical 7 Tesla magnetic resonance imaging: Impact and patient value in neurological disorders.}, journal = {Journal of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/joim.20059}, pmid = {39775908}, issn = {1365-2796}, abstract = {Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnostics and treatment monitoring, particularly for diseases of the central nervous system. Although 1.5- and 3 Tesla (T) field strengths remain the clinical standard, the advent of 7 T MRI represents a transformative step forward, offering superior spatial resolution, contrast, and sensitivity for visualizing neuroanatomy, metabolism, and function. Recent innovations, including parallel transmission and deep learning-based reconstruction, have resolved many prior technical challenges of 7 T MRI, enabling its routine clinical use. This review examines the diagnostic impact, patient value, and practical considerations of 7 T MRI, emphasizing its role in facilitating earlier diagnoses and improving care in conditions, such as amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis (MS), dementia, parkinsonism, tumors, and vascular diseases. Based on insights from over 1200 clinical scans with a second-generation 7 T system, the review highlights disease-specific biomarkers such as the motor band sign in ALS and the new diagnostic markers in MS, the central vein sign, and paramagnetic rim lesions. The unparalleled ability of 7 T MRI to study neurological diseases ex vivo at ultra-high resolution is also explored, offering new opportunities to understand pathophysiology and identify novel treatment targets. Additionally, the review provides a clinical perspective on patient handling and safety considerations, addressing challenges and practicalities associated with clinical 7 T MRI. By bridging research and clinical practice, 7 T MRI has the potential to redefine neuroimaging and advance the understanding and management of complex neurological disorders.}, } @article {pmid39775401, year = {2025}, author = {Grassi, M and Tarantino, B}, title = {SEMdag: Fast learning of Directed Acyclic Graphs via node or layer ordering.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317283}, pmid = {39775401}, issn = {1932-6203}, mesh = {Humans ; *Algorithms ; *COVID-19 ; SARS-CoV-2 ; Breast Neoplasms ; Software ; }, abstract = {A Directed Acyclic Graph (DAG) offers an easy approach to define causal structures among gathered nodes: causal linkages are represented by arrows between the variables, leading from cause to effect. Recently, industry and academics have paid close attention to DAG structure learning from observable data, and many techniques have been put out to address the problem. We provide a two-step approach, named SEMdag(), that can be used to quickly learn high-dimensional linear SEMs. It is included in the R package SEMgraph and employs a two-stage order-based search using previous knowledge (Knowledge-based, KB) or data-driven method (Bottom-up, BU), under the premise that a linear SEM with equal variance error terms is assumed. We evaluated our framework's for finding plausible DAGs against six well-known causal discovery techniques (ARGES, GES, PC, LiNGAM, CAM, NOTEARS). We conducted a series of experiments using observed expression (or RNA-seq) data, taking into account a pair of training and testing datasets for four distinct diseases: Amyotrophic Lateral Sclerosis (ALS), Breast cancer (BRCA), Coronavirus disease (COVID-19) and ST-elevation myocardial infarction (STEMI). The results show that the SEMdag() procedure can recover a graph structure with good disease prediction performance evaluated by a conventional supervised learning algorithm (RF): in the scenario where the initial graph is sparse, the BU approach may be a better choice than the KB one; in the case where the graph is denser, both BU an KB report high performance, with highest score for KB approach based on topological layers. Besides its superior disease predictive performance compared to previous research, SEMdag() offers the user the flexibility to define distinct structure learning algorithms and can handle high dimensional issues with less computing load. SEMdag() function is implemented in the R package SEMgraph, easily available at https://CRAN.R-project.org/package=SEMgraph.}, } @article {pmid39774976, year = {2025}, author = {Naito, H and Nakamori, M and Toko, M and Hayashi, Y and Tazuma, T and Watanabe, T and Ishihara, K and Tachiyama, K and Yamazaki, Y and Maruyama, H}, title = {A single-center, single-arm, prospective, open-label, and comparative trial to evaluate the safety and tolerability profile of a 90-day oral L-arginine hydrochloride intervention for patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1120}, pmid = {39774976}, issn = {2045-2322}, support = {23K16642//Japan Society for the Promotion of Science/ ; NA//ALS Foundation, Japan ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Female ; Male ; Middle Aged ; *Arginine/administration & dosage/therapeutic use ; Aged ; Prospective Studies ; Administration, Oral ; Treatment Outcome ; Nutritional Status ; }, abstract = {Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were - 0.37 kg, -1.1 kg/m[2], and - 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug.Trial Registration number: Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.}, } @article {pmid39772789, year = {2025}, author = {Stolwyk, K and Lee, I}, title = {Rapid progression of amyotrophic lateral sclerosis after initiation of GLP-1 agonist: a case report.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2024.2446847}, pmid = {39772789}, issn = {2167-9223}, } @article {pmid39771101, year = {2024}, author = {Chetverikova, D and Bakaeva, M and Starikov, S and Kendjieva, A and Chetverikov, S}, title = {The Influence of Plant Growth-Stimulating Bacteria on the Glutathione-S-Transferase Activity and the Toxic Effect of the Herbicide Metsulfuron-Methyl in Wheat and Canola Plants.}, journal = {Toxics}, volume = {12}, number = {12}, pages = {}, pmid = {39771101}, issn = {2305-6304}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {The ability of some rhizosphere bacteria to mitigate herbicidal stress in cultivated plants may be useful in agriculture and bioremediation. There is poor understanding of how bacteria directly or through herbicide degradation affect the biochemical processes in plants exposed to sulfonylurea herbicides. In this study, treatment with a combination of herbicide metsulfuron-methyl (MSM) and bacteria (Pseudomonas protegens DA1.2 or P. chlororaphis 4CH) of wheat (Triticum aestivum L.) and canola (Brassica napus L.) plants was carried out. Activity of glutathione-S-transferase (GST), an important enzyme for the herbicide detoxification, and acetolactate synthase (ALS), a target for MSM in plants, was measured by spectrophotometric assays. MSM residues were analyzed using the HPLC-MS. Then, 24 h after bacterial treatment, GST activity increased by 75-91% in wheat and by 38-94% in canola. On the 30th day, a decrease in MSM in the soil associated with bacterial treatment was 54.6-79.7%. An increase in GST activity and acceleration of MSM degradation were accompanied by a decrease in inhibition of the ALS enzyme in plants, which indicated a mitigation of the toxic effect. The results obtained are evidence that rhizospheric bacteria can have beneficial effects on plants exposed to MSM due to the combination of abilities to directly affect detoxification enzymes in plants and degrade MSM in the soil.}, } @article {pmid39770989, year = {2024}, author = {Pekdemir, B and Raposo, A and Saraiva, A and Lima, MJ and Alsharari, ZD and BinMowyna, MN and Karav, S}, title = {Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, pmid = {39770989}, issn = {2072-6643}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Brain/drug effects/metabolism ; Animals ; Flavonoids/pharmacology/therapeutic use ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.}, } @article {pmid39770252, year = {2024}, author = {Guo, H and Yao, J and Chen, S and Qian, C and Pan, X and Yin, K and Zhu, H and Gao, X and Wang, S and Sun, L}, title = {Enhancing Resistive Switching in AlN-Based Memristors Through Oxidative Al2O3 Layer Formation: A Study on Preparation Techniques and Performance Impact.}, journal = {Micromachines}, volume = {15}, number = {12}, pages = {}, pmid = {39770252}, issn = {2072-666X}, support = {11874105//National Natural Science Foundation of China/ ; }, abstract = {Aluminum nitride (AlN) with a wide band gap (approximately 6.2 eV) has attractive characteristics, including high thermal conductivity, a high dielectric constant, and good insulating properties, which are suitable for the field of resistive random access memory. AlN thin films were deposited on ITO substrate using the radio-frequency magnetron sputtering technique. Al's and Au's top electrodes were deposited on AlN thin films to make a Au/Al/AlN/ITO sandwich structure memristor. The effects of the Al2O3 film on the on/off window and voltage characteristics of the device were investigated. The deposition time and nitrogen content in the sputtering atmosphere were changed to adjust the thickness and composition of AlN films, respectively. The possible mechanism of resistive switching was examined via analyses of the electrical resistive switching characteristics, forming voltage, and switching ratio.}, } @article {pmid39769215, year = {2024}, author = {Wei, Z and Iyer, MR and Zhao, B and Deng, J and Mitchell, CS}, title = {Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769215}, issn = {1422-0067}, support = {1944247//National Science Foundation/ ; R35GM152245/NH/NIH HHS/United States ; U19-AG056169/NH/NIH HHS/United States ; 253558//Chan Zuckerberg Initiative/ ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; *Alzheimer Disease/metabolism/genetics/physiopathology/pathology ; *Artificial Intelligence ; Algorithms ; }, abstract = {The overlapping molecular pathophysiology of Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research.}, } @article {pmid39769213, year = {2024}, author = {Gu, A and Zhang, Y and He, J and Zhao, M and Ding, L and Liu, W and Xiao, J and Huang, J and Liu, M and Liu, X}, title = {Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769213}, issn = {1422-0067}, support = {2016YFC0905100//National Key Research and Development Program of China/ ; 2021JJ30801//Natural Science Foundation of Hunan Province, China/ ; kq2202077//Natural Science Foundation of Changsha, China/ ; 1053320222758//Fundamental Research Funds for the Central Universities of Central South University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; *Oxidative Stress ; *Motor Neurons/metabolism/pathology ; Adaptor Proteins, Signal Transducing/metabolism/genetics ; Stress Granules/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Autophagy ; Cell Cycle Proteins/metabolism/genetics ; Nerve Degeneration/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Sodium Compounds/pharmacology ; }, abstract = {The pathogenesis of neurodegenerative diseases results from the interplay between genetic and environmental factors. Aging and chronic oxidative stress are critical contributors to neurodegeneration. UBQLN2, a ubiquitin-related protein, aids in protein degradation and protects against oxidative stress. In ALS neurons harboring UBQLN2 mutations, oxidative stress accelerates pathological changes, yet the precise mechanisms remain unclear. Using induced motor neurons (iMNs) derived from UBQLN2 P497H iPSCs, we observed ALS-like phenotypes, including TDP-43 mislocalization, increased cell death, and reduced viability. Sodium arsenite (SA)-induced oxidative stress triggered stress granule formation, while autophagy dysfunction exacerbated neuronal degeneration. CHX and bosutinib treatments reduced ubiquitinated protein accumulation and alleviated degeneration, highlighting potential therapeutic pathways. These findings emphasize the role of chronic oxidative stress and stress granule formation in UBQLN2 ALS, offering insights into novel therapeutic targets.}, } @article {pmid39769209, year = {2024}, author = {Xing, C and Chen, H and Bi, W and Lei, T and Hang, Z and Du, H}, title = {Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769209}, issn = {1422-0067}, support = {32300682//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Serotonin/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Parkinson Disease/metabolism/drug therapy ; Receptors, Serotonin/metabolism ; }, abstract = {There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application.}, } @article {pmid39769187, year = {2024}, author = {O'Day, DH}, title = {The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769187}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; alpha-Synuclein/metabolism ; RNA-Binding Protein FUS/metabolism/genetics ; Huntingtin Protein/metabolism/genetics ; Protein Glutamine gamma Glutamyltransferase 2 ; Biomarkers/metabolism ; Transglutaminases/metabolism ; Superoxide Dismutase-1/metabolism/genetics ; Animals ; Calmodulin/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Alzheimer Disease/metabolism/pathology/drug therapy/therapy ; Parkinson Disease/metabolism/pathology/therapy ; }, abstract = {The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.}, } @article {pmid39768371, year = {2024}, author = {Orlova, A and Malygin, Y and Gofman, A and Sotulenko, S and Gandalian, V and Kartashov, I and Brylev, L and Bolevich, S and Nikolic Turnic, T and Jakovljevic, V}, title = {Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, doi = {10.3390/life14121664}, pmid = {39768371}, issn = {2075-1729}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients.

METHOD: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus.

RESULTS: We included seven prospective studies, published in 2010-2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation.

CONCLUSIONS: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.}, } @article {pmid39768167, year = {2024}, author = {Chen, X and Lv, S and Liu, J and Guan, Y and Xu, C and Ma, X and Li, M and Bai, X and Liu, K and Zhang, H and Yan, Q and Zhou, F and Chen, Y}, title = {Exploring the Role of Axons in ALS from Multiple Perspectives.}, journal = {Cells}, volume = {13}, number = {24}, pages = {}, pmid = {39768167}, issn = {2073-4409}, support = {82271483//The National Natural Science Foundation of China/ ; ZR2024MH112; ZR2024QH628//Shandong Province Natural Science Foundation of China/ ; 2023YX036; 2022YX043//Weifang Science and Technology Development Plan Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Axons/pathology/metabolism ; Animals ; Axonal Transport ; Motor Neurons/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as motor neuron disease, is a neurodegenerative disorder characterized by the progressive degeneration of both upper and lower motor neurons. This pathological process results in muscle weakness and can culminate in paralysis. To date, the precise etiology of ALS remains unclear. However, a burgeoning body of research indicates that axonal dysfunction is a pivotal element in the pathogenesis of ALS and significantly influences the progression of disease. Dysfunction of axons in ALS can result in impediments to nerve impulse transmission, leading to motor impairment, muscle atrophy, and other associated complications that severely compromise patients' quality of life and survival prognosis. In this review, we concentrate on several key areas: the ultrastructure of axons, the mechanisms of axonal degeneration in ALS, the impact of impaired axonal transport on disease progression in ALS, and the potential for axonal regeneration within the central nervous system (CNS). Our objective is to achieve a more holistic and profound understanding of the multifaceted role that axons play in ALS, thereby offering a more intricate and refined perspective on targeted axonal therapeutic interventions.}, } @article {pmid39767639, year = {2024}, author = {Wan, M and Zhang, L and Huo, J and Fu, Y and Huang, T and Fan, D}, title = {Genetic Variation in Targets of Antidiabetic Drugs and Amyotrophic Lateral Sclerosis Risk.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, doi = {10.3390/biomedicines12122733}, pmid = {39767639}, issn = {2227-9059}, support = {82101490, and 82071426//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS.

METHODS: Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles.

RESULTS: Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05).

CONCLUSIONS: The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.}, } @article {pmid39766833, year = {2024}, author = {Bisogni, G and Conte, A and Costantino, U and Lattante, S and Bernardo, D and Lucioli, G and Patanella, AK and Cimbolli, P and Del Giudice, E and Vettor, F and Marangi, G and Doronzio, PN and Zollino, M and Sabatelli, M}, title = {Exploring the Role of CCNF Variants in Italian ALS Patients.}, journal = {Genes}, volume = {15}, number = {12}, pages = {}, doi = {10.3390/genes15121566}, pmid = {39766833}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Italy ; Middle Aged ; Aged ; Mutation, Missense ; Cyclins/genetics ; Frontotemporal Dementia/genetics/pathology ; Genetic Association Studies ; High-Throughput Nucleotide Sequencing ; Phenotype ; Adult ; Genetic Predisposition to Disease ; }, abstract = {Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients.}, } @article {pmid39766450, year = {2024}, author = {Donaghy, R and Pioro, EP}, title = {Neurophysiologic Innovations in ALS: Enhancing Diagnosis, Monitoring, and Treatment Evaluation.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766450}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease of both upper motor neurons (UMNs) and lower motor neurons (LMNs) leading invariably to decline in motor function. The clinical exam is foundational to the diagnosis of the disease, and ordinal severity scales are used to track its progression. However, the lack of objective biomarkers of disease classification and progression delay clinical trial enrollment, muddle inclusion criteria, and limit accurate assessment of drug efficacy. Ultimately, biomarker evidence of therapeutic target engagement will support, and perhaps supplant, more traditional clinical trial outcome measures. Electrophysiology tools including nerve conduction study and electromyography (EMG) have already been established as diagnostic biomarkers of LMN degeneration in ALS. Additional understanding of the motor manifestations of disease is provided by motor unit number estimation, electrical impedance myography, and single-fiber EMG techniques. Dysfunction of UMN and non-motor brain areas is being increasingly assessed with transcranial magnetic stimulation, high-density electroencephalography, and magnetoencephalography; less common autonomic and sensory nervous system dysfunction in ALS can also be characterized. Although most of these techniques are used to explore the underlying disease mechanisms of ALS in research settings, they have the potential on a broader scale to noninvasively identify disease subtypes, predict progression rates, and assess physiologic engagement of experimental therapies.}, } @article {pmid39766276, year = {2024}, author = {Wysoczański, B and Świątek, M and Wójcik-Gładysz, A}, title = {Organ-on-a-Chip Models-New Possibilities in Experimental Science and Disease Modeling.}, journal = {Biomolecules}, volume = {14}, number = {12}, pages = {}, pmid = {39766276}, issn = {2218-273X}, mesh = {*Lab-On-A-Chip Devices ; Humans ; Animals ; Models, Biological ; Liver/metabolism/cytology ; Cell Culture Techniques/methods ; Microphysiological Systems ; }, abstract = {'Organ-on-a-chip' technology is a promising and rapidly evolving model in biological research. This innovative microfluidic cell culture device was created using a microchip with continuously perfused chambers, populated by living cells arranged to replicate physiological processes at the tissue and organ levels. By consolidating multicellular structures, tissue-tissue interfaces, and physicochemical microenvironments, these microchips can replicate key organ functions. They also enable the high-resolution, real-time imaging and analysis of the biochemical, genetic, and metabolic activities of living cells in the functional tissue and organ contexts. This technology can accelerate research into tissue development, organ physiology and disease etiology, therapeutic approaches, and drug testing. It enables the replication of entire organ functions (e.g., liver-on-a-chip, hypothalamus-pituitary-on-a-chip) or the creation of disease models (e.g., amyotrophic lateral sclerosis-on-a-chip, Parkinson's disease-on-a-chip) using specialized microchips and combining them into an integrated functional system. This technology allows for a significant reduction in the number of animals used in experiments, high reproducibility of results, and the possibility of simultaneous use of multiple cell types in a single model. However, its application requires specialized equipment, advanced expertise, and currently incurs high costs. Additionally, achieving the level of standardization needed for commercialization remains a challenge at this stage of development.}, } @article {pmid39765493, year = {2024}, author = {Zhang, T and Xu, Q and Zhou, B and Xiao, J and Zheng, S and Li, J and Lv, Q and Zhang, Y and Wang, R and Su, R and Wang, Z}, title = {Development and Validation of a 5K Liquid Chip for Identifying Cashmere Goat Populations in Inner Mongolia Autonomous Region.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {24}, pages = {}, pmid = {39765493}, issn = {2076-2615}, support = {2022YFE0113300，2022YFD1300201,2022YFD1300204//National Key Research and Development Program/ ; BR220112//Project for Enhancing Young Teacher's Research Ability/ ; NJYT22038//Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region/ ; 2023ZD0405102//Project for 2030 Science and Technology Innovation Major/ ; NMGIRT2322//Program for Inner Mongolia Autonomous Region Higher Education Innovation Team Development/ ; }, abstract = {(1) Background: Cashmere goats, as one of the characteristic species, are rich in genetic resources. Protecting and rationally utilizing these genetic resources is of great significance for the genetic improvement of cashmere goats. (2) Methods: In this study, tissue samples were collected from Inner Mongolia white cashmere goats, which included the Arbas type (ARBS); Erlangshan type (ELS); Alashan type (ALS), Hanshan white cashmere goats (HS), and Ujimqin white cashmere goats (WZMQ). Genomic DNA was extracted and subjected to high-depth genome resequencing. GenoBait technology was used for probe design and site optimization, followed by the synthesis of a low-density liquid phase chip. Finally, a total of 281 individuals from five cashmere goat populations in the Inner Mongolia Autonomous Region were randomly selected to verify the chip. (3) Results: The results showed that a total of 5002 SNP sites were finally screened and retained for the synthesis of the low-density liquid chip for identifying cashmere goats in Inner Mongolia Autonomous Region. Principal component analysis and phylogenetic tree construction indicated that the ARBS, ELS, and ALS populations were clustered into one category. (4) Conclusions: This chip can accurately identify the three breeds: Inner Mongolia white cashmere goats, Hanshan white cashmere goats, and Ujimqin white cashmere goats.}, } @article {pmid39764140, year = {2024}, author = {Akif, A and Nguyen, TTM and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-5611378/v1}, pmid = {39764140}, issn = {2693-5015}, abstract = {Background As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD. Methods In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50 [th] day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA. Results AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood. Conclusions The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.}, } @article {pmid39764023, year = {2024}, author = {Patt, E and Schneidman-Duhovny, D and Hammel, M and Classen, S}, title = {Predicting RNA Structure and Dynamics with Deep Learning and Solution Scattering.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.08.598075}, pmid = {39764023}, issn = {2692-8205}, abstract = {While novel deep learning and statistics-based techniques predict accurate structural models for proteins and non-coding RNA, describing their macromolecular conformations in solution is still challenging. Small-angle X-ray scattering (SAXS) in solution is an efficient technique to validate structural predictions by comparing the experimental SAXS profile with those calculated from predicted structures. There are two main challenges in comparing SAXS profiles to RNA structures: the structures often lack cations necessary for stability and charge neutralization, and a single structure inadequately represents the conformational plasticity of RNA. We introduce Solution Conformation Predictor for RNA (SCOPER) to address these challenges. This pipeline integrates kinematics-based conformational sampling with the innovative deep-learning model, IonNet, designed for predicting Mg2+ ion binding sites. Validated through benchmarking against fourteen experimental datasets, SCOPER significantly improved the quality of SAXS profile fits by including Mg2+ ions and sampling of conformational plasticity. We observe that an increased content of monovalent and bivalent ions leads to decreased RNA plasticity. Therefore, carefully adjusting the plasticity and ion density is crucial to avoid overfitting experimental SAXS data. SCOPER is an efficient tool for accurately predicting the solution state of RNAs and providing atomistic models of their structures. The method is available from: https://github.com/dina-lab3d/IonNet Our pipeline is available for use as a web server: https://bilbomd.bl1231.als.lbl.gov/.}, } @article {pmid39763885, year = {2024}, author = {Shelest, O and Tindel, I and Lauzon, M and Dawson, A and Ho, R}, title = {Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.17.628968}, pmid = {39763885}, issn = {2692-8205}, abstract = {The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.}, } @article {pmid39762986, year = {2025}, author = {Berlowitz, DJ and Rowe, D and Howard, ME and Piper, A and Graco, M and Braat, S and Singh, B and Souza, TV and Lannin, N and McLean, A and Sawyer, A and Carey, KA and Ahamed, Y and , }, title = {Polysomnographic titration of non-invasive ventilation in motor neurone disease (3TLA): study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {26}, number = {1}, pages = {10}, pmid = {39762986}, issn = {1745-6215}, mesh = {Humans ; *Noninvasive Ventilation/methods/adverse effects/instrumentation ; *Motor Neuron Disease/therapy/physiopathology ; *Polysomnography ; *Randomized Controlled Trials as Topic ; Treatment Outcome ; Australia ; Multicenter Studies as Topic ; Time Factors ; Sleep ; Respiratory Insufficiency/therapy/physiopathology ; Quality of Life ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) uses positive pressure to assist people with respiratory muscle weakness or severe respiratory compromise to breathe. Most people use this treatment during sleep when breathing is most susceptible to instability. The benefits of using NIV in motor neurone disease (MND) are well-established. However, uptake and usage are low (~ 19%) and there is no consensus on how to best implement NIV in MND in Australia. Consequently, clinical practice models are highly variable. Our team has recently provided evidence that specific and individualised NIV titration using a sleep study (polysomnography; PSG) leads to better outcomes in people with MND. However, for this clinical practice model to result in sustained benefits, evidence of effectiveness across multiple sites, as well as culture and practice change, must occur.

METHODS: A two-arm, assessor-blinded, individual participant randomised controlled trial in MND care centres across Australia will be undertaken. Two-hundred and forty-four participants will be randomised (1:1) to either the intervention group (PSG-assisted commencement of NIV settings; PSG) or a control group (sham PSG). Participants will be asked to use their NIV device for 7 weeks and will then return for follow-up assessments. Respiratory, sleep and patient-reported outcome measures will be collected at baseline and follow-up. The primary aim is to determine if the proportion of participants using NIV for > 4 h/day during the intervention period is higher in the PSG than the control group. A process evaluation, health economic evaluation and 12-month cohort follow-up will be undertaken and reported separately.

DISCUSSION: The results of this trial will demonstrate the effects of PSG-assisted titration of NIV on usage of NIV in people with MND. We hypothesise that the PSG intervention will improve synchrony between the user and the machine, which will lead to greater NIV usage compared to the control group.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05136222. Registered on November 25, 2021.}, } @article {pmid39762711, year = {2025}, author = {Apostolo, D and Ferreira, LL and D'Onghia, D and Vincenzi, F and Vercellino, N and Perazzi, M and Pirisi, M and Cantello, R and Minisini, R and Mazzini, L and Bellan, M and De Marchi, F}, title = {Lower Circulating Gas6 Levels Are Associated with Bulbar Phenotype and Faster Disease Progression in Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39762711}, issn = {1559-1182}, support = {2021-1541//Fondazione Cariplo/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects the motor neurons in the brain and spinal cord. While the exact cause of ALS is not fully understood, a combination of genetic and environmental factors is believed to contribute to its development. Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been recognized to enhance oligodendrocytes and neurons' survival and is associated with different kinds of (neuro)inflammatory conditions. Therefore, we aimed to determine a possible implication of Gas6 in ALS phenotype and progression by evaluating the value of circulating Gas6 and its soluble receptors (sAxl, sMer, sTyro-3) in ALS patients. We conducted a prospective observational study including 65 ALS patients and measured the circulating serum levels of Gas6, sAxl, sMer, soluble Tyro-3 (sTyro-3), and neurofilaments (NfLs). In our ALS cohort, lower serum levels of Gas6 and concomitantly higher levels of NfLs were associated with a more aggressive disease, expressed with bulbar phenotype (p-value for Gas6 = 0.03) and faster progression (p-value for Gas6 = 0.03). Also, serum Gas6 was able to distinguish (area under the curve, cut-off 13.70 ng/mL, sensitivity 69.57%, specificity 72.72%) between fast and slow progressors. Due to its neuroprotective properties, our data suggest that Gas6 could be an intriguing biomarker in ALS patients.}, } @article {pmid39761853, year = {2025}, author = {Weeks, AT and Bird, AJ}, title = {Regulation of sod1 mRNA and protein abundance by zinc in fission yeast is dependent on the CCR4-NOT complex.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {108156}, doi = {10.1016/j.jbc.2025.108156}, pmid = {39761853}, issn = {1083-351X}, abstract = {Zinc is an essential micronutrient that serves as a cofactor in a wide variety of enzymes, including Cu-Zn Superoxide Dismutase 1 (Sod1). We have discovered in Schizosaccharomyces pombe that Sod1 mRNA and protein levels are regulated in response to cellular zinc availability. We demonstrate that lower levels of Sod1 mRNA and protein accumulate under low zinc conditions, and that this regulation does not require the sod1 promoter or known factors that regulate transcription of sod1 in response to zinc and other environmental stresses. Further analyses using yeast deletion strains and an inactive allele of Caf1 revealed that the reduced accumulation of sod1 mRNA and protein under low zinc conditions depends on the Caf1 and Ccr4 deadenylases of the CCR4-NOT complex. We also found that Caf1 and Ccr4 are both required for growth under zinc-limiting conditions. To gain additional mechanistic insight we used immunoblot analysis to map the regions required for the regulation of the Sod1 protein by zinc. We found that the sod1 ORF and 3'UTR are both necessary and sufficient for the zinc-dependent changes in Sod1 protein abundance. Collectively, our studies reveal a novel mechanism of altering mRNA and protein abundance in response to zinc status, which depends on the CCR4-NOT complex.}, } @article {pmid39759580, year = {2025}, author = {Chourpiliadis, C and Lovik, A and Seitz, C and Hu, Y and Wu, J and Ljungman, P and Press, R and Samuelsson, K and Ingre, C and Fang, F}, title = {Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a population-based case-control study.}, journal = {The Lancet regional health. Europe}, volume = {49}, number = {}, pages = {101173}, pmid = {39759580}, issn = {2666-7762}, abstract = {BACKGROUND: The evidence on the link between cardiometabolic diseases (CMDs) and motor neuron diseases (MNDs) remains inconsistent. We aimed to determine whether there is an association of CMDs, namely, any cardiovascular disease, cardiac arrhythmia, heart failure, thromboembolic disease, hypertension, cerebrovascular disease, ischemic heart disease, diabetes mellitus type 2, and hypercholesterolemia with the risk and progression of MNDs.

METHODS: We included 1463 MND patients (amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive spinal muscular atrophy (PSMA), and unspecified MND) diagnosed from January 1, 2015, to July 1, 2023, in Sweden according to the Swedish Motor Neuron Disease Quality Registry (i.e., cases), up to 5 MND-free population controls per case (N = 7311) who were individually matched to the cases on age and sex, and the full siblings (N = 2002) and spouses (N = 1220) of MND patients (i.e., relative controls). Conditional logistic regression models were used to estimate the risk of MND diagnosis in relation to previous CMDs, through comparing MND patients to population controls or relative controls. MND patients were followed from diagnosis to assess the role of pre-diagnostic CMDs on disease progression. A joint longitudinal-survival model was used to estimate risk of mortality (or use of invasive ventilation) in relation to CMDs after taking into account the longitudinal changes of ALS functional rating scale-revised (ALSFRS-R) in the time-to-event analysis. Hierarchical clustering with the Ward's linkage and a dissimilarity matrix created by Gower's method was used to identify clusters of MND patients with distinct phenotypes.

FINDINGS: Among the CMDs studied, a history of diabetes mellitus type 2 (OR 0.75; 95% CI 0.62, 0.93) or hypercholesterolemia (OR 0.82; 95% CI 0.71, 0.94) more than one year before diagnosis was associated with a lower risk for MNDs. The associations persisted for more than five years before MND diagnosis. MND patients with a history of any cardiovascular disease (HR 1.43; 95% CI 1.13, 1.81), arrhythmia (HR 1.42; 95% CI 1.04, 1.93), heart failure (HR 1.79; 95% CI 1.02, 3.14), hypertension (HR 1.41; 95% CI 1.12, 1.77), or hypercholesterolemia (HR 1.28; 95% CI 1.01, 1.62) had an increased mortality risk, compared to others, after taking into consideration the longitudinal changes in ALSFRS-R. Cluster analysis identified two clusters of MND patients, where one cluster demonstrated higher age, worse functional status, and higher prevalence of CMDs at the time of diagnosis as well as a higher mortality and faster functional decline during follow-up, compared to the ones included in the other cluster.

INTERPRETATION: Diabetes mellitus type 2 and hypercholesterolemia were associated with a lower future risk of MND. On the other hand, most of the CMDs were indicative of a poor disease progression after an MND diagnosis.

FUNDING: European Research Council, US Center for Disease Control and Prevention, Swedish Research Council.}, } @article {pmid39759457, year = {2024}, author = {Ahmad, SR and Zeyaullah, M and Khan, MS and AlShahrani, AM and Altijani, AAG and Ali, H and Dawria, A and Mohieldin, A and Alam, MS and Mohamed, AOA}, title = {Pharmacogenomics for neurodegenerative disorders - a focused review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1478964}, pmid = {39759457}, issn = {1663-9812}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.}, } @article {pmid39757610, year = {2024}, author = {Mojgani, N and Dadar, M and Shahali, Y and Simal-Gandara, J and Kumar, P and Ashique, S and Bhowmick, M and Kumar, H}, title = {Antioxidant Nutraceuticals: Their Adjunct Role in the Management of COVID-19 Infections and Post-COVID Syndrome.}, journal = {Infectious disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715265320091241017161919}, pmid = {39757610}, issn = {2212-3989}, abstract = {The COVID-19 epidemic in recent years has been produced by various coronavirus strains that nearly destroyed world health policies and economics. Emerging viral strains exac-erbated the pandemic. Huge investments have been made in preventative vaccines to combat the disease, but the genetic instability of these viruses has hampered their usefulness. However, in addition to traditional therapeutic approaches, nutraceuticals have been considered effica-cious in preventing and or treating COVID-19 and post-COVID syndrome. In this context, nutraceuticals such as vitamins or dietary supplements including multiple vitamins and miner-als and propolis have been widely studied for their significant impact on viral respiratory dis-eases like SARS-CoV-2 and COVID-19. Some of these nutraceuticals having antioxidant, anti-inflammatory, and immune-modulatory properties have been highly recommended for use as an adjunct option to moderate the adverse effects associated with the COVID-19 pandemic. In this review, we intend to present the recent understanding and converse scientific implications for the use of nutraceutical antioxidants such as vitamins, minerals, probiotics, and polyphenols like bee propolis, in the management of viral respiratory diseases and post-COVID-19 syn-drome. Future challenges and limitations regarding the use and bioavailability of these ingre-dients, and dose-response studies are further emphasized.}, } @article {pmid39756374, year = {2025}, author = {Loap, P and Kirova, Y}, title = {Initial Characterization and Outcome Assessment of Anal Lymphomas in a Large-Size Contemporary Cohort: A Population-Based SEER Database Study (2000-2022).}, journal = {Acta haematologica}, volume = {}, number = {}, pages = {1-10}, doi = {10.1159/000541595}, pmid = {39756374}, issn = {1421-9662}, abstract = {INTRODUCTION: Anal Lymphoma (AL) is a rare presentation of extranodal lymphomas, characterized by occurrence in the anal area and largely understudied due to its infrequency. This study aims to address gaps in knowledge about AL's demographic and clinical profiles, treatments, and survival outcomes, leveraging data from the SEER program.

METHODS: We conducted a retrospective analysis of 79 AL cases identified in the SEER database from 2000 to 2022; 36 stage I AL were identified and defined as localized primary anal lymphoma (L-PAL). Data on demographics, tumor specifics, treatment modalities, and survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models.

RESULTS: The majority of AL cases were Diffuse Large B-Cell Lymphoma (70.9%). Other notable subtypes included Anaplastic T-Cell Lymphoma (ATL), Marginal Zone Lymphoma (MZL), B-cell Non-Hodgkin Lymphoma (BCL), Burkitt Lymphoma/Leukemia (BLL, each accounting for 6.3%), followed by Follicular Lymphoma and Mantle-Cell Lymphoma (each at 1.3%). AL primarily affected younger males (median age 50), with a significant majority being Caucasian. Initial stages (I and II) were more commonly observed, and treatments varied, with chemotherapy being most prevalent (67.1%), followed by radiation (30.4%) and surgery (30.4%). The 5- and 10-year overall survival (OS) rates were 59.4% and 44.1%, respectively, while the corresponding cancer-specific survival (CSS) rates were 67.9% and 58.0% respectively. Age was a significant prognostic factor for OS but not for CSS. Radiotherapy tended to improve CSS in the AL population.

CONCLUSION: This research correspond to the first in-depth analysis of AL, highlighting its distinct demographic patterns, clinical features, and responses to various treatments, distinguishing it from other types of anal cancers. Our results underscore the importance of developing specialized diagnostic and treatment strategies. To enhance our understanding and management of this uncommon form of lymphoma, future studies should aim for broader and more collaborative international research efforts.}, } @article {pmid39756021, year = {2025}, author = {Akaree, N and Secco, V and Levy-Adam, F and Younis, A and Carra, S and Shalgi, R}, title = {Regulation of physiological and pathological condensates by molecular chaperones.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.17390}, pmid = {39756021}, issn = {1742-4658}, support = {//AriSLA/ ; //Giovanni Armenise Harvard Foundation/ ; HT94252310319//Congressionally Directed Medical Research Programs/ ; AHA-MCA 2022//AriAlzh/ ; //Rappaport Family Institute for Research in Medical Sciences/ ; //Prince Center for Neurodegenerative Disorders of the Brain/ ; }, abstract = {Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type of physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the cellular stress response and various diseases. SGs, composed of several hundred RNA-binding proteins, form transiently in response to stress to protect mRNAs from translation and disassemble when the stress subsides. Interestingly, SGs contain several aggregation-prone proteins, such as TDP-43, FUS, hnRNPA1, and others, which are typically found in pathological inclusions seen in autopsy tissues from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. Moreover, mutations in these genes lead to the familial form of ALS and FTD. This has led researchers to propose that pathological aggregation is seeded by aberrant SGs: SGs that fail to properly disassemble, lose their dynamic properties, and become pathological condensates which finally 'mature' into aggregates. Here, we discuss the evidence supporting this model for various ALS/FTD-associated proteins. We further continue to focus on molecular chaperone-mediated regulation of ALS/FTD-associated physiological condensates on one hand, and pathological condensates on the other. In addition to SGs, we review ALS/FTD-relevant nuclear condensates, namely paraspeckles, anisosomes, and nucleolar amyloid bodies, and discuss their emerging regulation by chaperones. As the majority of chaperoning mechanisms regulate physiological condensate disassembly, we highlight parallel themes of physiological and pathological condensation regulation across different chaperone families, underscoring the potential for early disease intervention.}, } @article {pmid39755715, year = {2025}, author = {Liu, Q and Sun, Y and He, B and Chen, H and Wang, L and Wang, G and Zhang, K and Zhao, X and Zhang, X and Shen, D and Zhang, X and Cui, L}, title = {Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {2}, pmid = {39755715}, issn = {2051-5960}, support = {2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2022YFC2703904//National Key Research and Development Program/ ; 2022YFC2703900//National Key Research and Development Program/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 81971293//National Natural Science Foundation of China/ ; 82201562//National Natural Science Foundation of China/ ; XDB39040000//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Animals ; *Autophagy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mice ; Humans ; Male ; *Gain of Function Mutation ; Neuroinflammatory Diseases/pathology/genetics/metabolism ; Female ; Annexins/genetics/metabolism ; Mice, Transgenic ; Protein Aggregation, Pathological/genetics/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Middle Aged ; Age of Onset ; Protein Aggregates ; RNA-Binding Proteins/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {Mutations in the ANXA11 gene, encoding an RNA-binding protein, have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the underlying in vivo mechanisms remain unclear. This study examines the clinical features of ALS patients harboring the ANXA11 hotspot mutation p.P36R, characterized by late-onset motor neuron disease and occasional multi-system involvement. To elucidate the pathogenesis, we developed a knock-in mouse model carrying the p.P36R mutation. In both heterozygous and homozygous mutant mice, ANXA11 protein levels were comparable to those in wild-type. Both groups exhibited late-onset motor dysfunction at approximately 10 months of age, with similar survival rates to wild-type (> 24 months) and no signs of dementia. Pathological analysis revealed early abnormal aggregates in spinal cord motor neurons, cortical neurons, and muscle cells of homozygous mice. From 2 months of age, we observed mislocalized ANXA11 aggregates, SQSTM1/p62-positive inclusions, and cytoplasmic TDP-43 mislocalization, which intensified with disease progression. Importantly, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions. Electron microscopy of the gastrocnemius muscle uncovered myofibrillar abnormalities, including sarcomeric disorganization, Z-disc dissolution, and subsarcolemmal electron-dense structures within autophagic vacuoles. Autophagic flux, initially intact at 2 months, was impaired by 9 months, as evidenced by decreased Beclin-1 and LC3BII/I levels and increased SQSTM1/p62 expression, coinciding with mTORC1 hyperactivation. Significant motor neuron loss and neuroinflammation were detected by 9 months, with marked muscle dystrophy apparent by 12 months compared to wild-type controls. These findings implicate the gain-of-function ANXA11 mutation drives late-onset motor neuron disease by early presymptomatic proteinopathy, progressive neuronal degeneration, neuroinflammation, and autophagic dysfunction.}, } @article {pmid39753993, year = {2025}, author = {Cheng, L and Liu, Z and Shen, C and Xiong, Y and Shin, SY and Hwang, Y and Yang, SB and Chen, Z and Zhang, X}, title = {A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {1}, pages = {e70208}, pmid = {39753993}, issn = {1755-5949}, support = {20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; GJJ211812//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; GJJ211813//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; 202131084//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; 202211982//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; RZYB202201//Research project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province/ ; 20224BAB206040//Provincial Natural Science Foundation of Jiangxi Province/ ; 202411843024//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; S202411843050//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; 2022B1010//Administration of Traditional Chinese Medicine of Jiangxi Province/ ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Central Nervous System Diseases/genetics/metabolism/therapy ; RNA Editing ; }, abstract = {BACKGROUND: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.

RESULTS: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.

CONCLUSIONS: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.}, } @article {pmid39753665, year = {2025}, author = {Quintanilla, CA and Fitzgerald, Z and Kashow, O and Radojicic, MS and Ulupinar, E and Bitlis, D and Genc, B and Andjus, P and van Drongelen, W and Ozdinler, PH}, title = {High-density multielectrode arrays bring cellular resolution to neuronal activity and network analyses of corticospinal motor neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {732}, pmid = {39753665}, issn = {2045-2322}, support = {778405 "AUTOIGG"//EU H2020 MSCA RISE/ ; R01 AG061708/AG/NIA NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund of the Republic of Serbia/ ; R01AG061708-03/NH/NIH HHS/United States ; 5T32NS041234-18/NH/NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; Mice ; *Microelectrodes ; Motor Cortex/physiology ; Pyramidal Tracts/physiology ; Nerve Net/physiology ; Mice, Transgenic ; }, abstract = {Corticospinal motor neurons (CSMN), located in the motor cortex of the brain, are one of the key components of the motor neuron circuitry. They are in part responsible for the initiation and modulation of voluntary movement, and their degeneration is the hallmark for numerous diseases, such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and primary lateral sclerosis. Cortical hyperexcitation followed by in-excitability suggests the early involvement of cortical dysfunction in ALS pathology. However, a high-spatiotemporal resolution on our understanding of their functional health and connectivity is lacking. Here, we combine optical imaging with high-density microelectrode array (HD-MEA) system enabling single cell resolution and utilize UCHL1-eGFP mice to bring cell-type specificity to our understanding of the electrophysiological features of healthy CSMN, as they mature and form network connections with other cortical neurons, in vitro. This novel approach lays the foundation for future cell-type specific analyses of CSMN that are diseased due to different underlying causes with cellular precision, and it will allow the assessment of their functional response to compound treatment, especially for drug discovery efforts in upper motor neuron diseases.}, } @article {pmid39753643, year = {2025}, author = {Mravinacová, S and Bergström, S and Olofsson, J and de San José, NG and Anderl-Straub, S and Diehl-Schmid, J and Fassbender, K and Fliessbach, K and Jahn, H and Kornhuber, J and Landwehrmeyer, GB and Lauer, M and Levin, J and Ludolph, AC and Prudlo, J and Schneider, A and Schroeter, ML and Wiltfang, J and Steinacker, P and , and Otto, M and Nilsson, P and Månberg, A}, title = {Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {668}, pmid = {39753643}, issn = {2045-2322}, mesh = {Humans ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; Middle Aged ; Brain/metabolism/pathology ; Alzheimer Disease/cerebrospinal fluid/diagnosis ; Cerebrospinal Fluid Proteins/analysis ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; }, abstract = {Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer's disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins-neurofilament medium and myelin basic protein-showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.}, } @article {pmid39753538, year = {2025}, author = {Larrea, D and Tamucci, KA and Kabra, K and Velasco, KR and Yun, TD and Pera, M and Montesinos, J and Agrawal, RR and Paradas, C and Smerdon, JW and Lowry, ER and Stepanova, A and Yoval-Sanchez, B and Galkin, A and Wichterle, H and Area-Gomez, E}, title = {Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS).}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {379}, pmid = {39753538}, issn = {2041-1723}, support = {R21 NS125466/NS/NINDS NIH HHS/United States ; R01 AG056387/AG/NIA NIH HHS/United States ; F31 NS095571/NS/NINDS NIH HHS/United States ; T32 DK007647/DK/NIDDK NIH HHS/United States ; R01 NS112381/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Animals ; Spinal Cord/metabolism ; Mice ; Glucose/metabolism ; Fatty Acids/metabolism ; Male ; Energy Metabolism ; Pyruvic Acid/metabolism ; Intracellular Membranes/metabolism ; Electron Transport Complex I/metabolism/genetics ; Brain/metabolism ; Mitochondria Associated Membranes ; }, abstract = {Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.}, } @article {pmid39753182, year = {2025}, author = {Swarup, G and Medchalmi, S and Ramachandran, G and Sayyad, Z}, title = {Molecular aspects of cytoprotection by Optineurin during stress and disease.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1872}, number = {3}, pages = {119895}, doi = {10.1016/j.bbamcr.2024.119895}, pmid = {39753182}, issn = {1879-2596}, abstract = {Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection. Here, we discuss the mechanisms involved in cytoprotective functions of OPTN, which possibly depend on its ability to modulate various stress-induced signalling pathways. ALS- and glaucoma-causing mutants of OPTN are altered in this regulation, which may affect cell survival, particularly under various stress conditions. We suggest that OPTN deficiency created by mutations may cooperate with stress-induced signalling to enhance or cause neurodegeneration. Other functions of OPTN, such as neurotrophin secretion and vesicle trafficking, may also contribute to cytoprotection.}, } @article {pmid39752797, year = {2024}, author = {Ju, W and Min, YG and Kim, JS and Ryu, S and Ahn, SW and Hong, YH and Choi, SJ and Sung, JJ}, title = {Clinical features of FOSMN syndrome in Korea: A comparative analysis with bulbar-onset amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123372}, doi = {10.1016/j.jns.2024.123372}, pmid = {39752797}, issn = {1878-5883}, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) syndrome is a rare neurodegenerative disorder initially characterized by facial sensory deficits, which later progress to motor deficits in a rostral-caudal distribution. This study investigated the prevalence, clinical features, and prognosis of FOSMN syndrome and compared these aspects with those of bulbar-onset amyotrophic lateral sclerosis (ALS) within a single institutional cohort of motor neuron diseases. We identified four patients with FOSMN syndrome who had been misclassified as having bulbar-onset ALS, representing approximately 2 % of such ALS cases. The median age of onset for FOSMN syndrome was similar to that of bulbar-onset ALS. However, patients with FOSMN syndrome were often diagnosed at more advanced stages and had lower ALS Functional Rating Scale-revised (ALSFRS-R) scores. Despite the slower progression of FOSMN syndrome, therapeutic interventions such as gastrostomy or non-invasive ventilation were frequently required. In conclusion, this study provides detailed clinical profiles of patients with FOSMN syndrome and deepens our understanding of a heterogeneous group of neurodegenerative disorders.}, } @article {pmid39751824, year = {2025}, author = {Sghaier, I and Kacem, I and Ratti, A and Takout, K and Abida, Y and Peverelli, S and Ticozzi, N and Gargouri-Berrachid, A and Silani, V and Gouider, R}, title = {Impact of APOE and MAPT genetic profile on the cognitive functions among Amyotrophic Lateral Sclerosis Tunisian patients.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {39751824}, issn = {1435-1463}, abstract = {Amyotrophic Lateral Sclerosis(ALS) has traditionally been managed as a neuromuscular disorder. However, recent evidence suggests involvement of non-motor domains. This study aims to evaluate the impact of APOE and MAPT genotypes on the cognitive features of ALS. We included confirmed ALS cases from the Neurology department at Razi University Hospital, Tunisia. APOE and MAPT screening were conducted with Sanger sequencing validation, and preliminary screening for four main ALS genes was performed. Clinical phenotypes and genotypes were analyzed using appropriate tests, with healthy controls (HC) representing the Tunisian population. Two-hundred-seventy ALS patients were included, stratified as 213 spinal cases,49 with bulbar onset and 8 patients with generalized form with 140 HC. Regarding APOE, we reported high frequency of ALS cases carrier of APOE-ε4 isoform compared to controls(p < 0.0001).We found a significant association between APOE-ɛ4 and ALS onset site (p = 0.05,r = 0.33),with higher frequencies in bulbar onset patients. Cognitive signs were more frequent in ɛ4 carriers (r = 0.43,p < 0.01),and a significant link was observed between dysexecutive functions and the APOE risk allele (p = 0.0495).Concerning the MAPT haplotypes, we reported high frequency of ALS cases carrier of MAPT H1-haplotype HC (94.45% and 72.14% respectively, p < 0.001).Among ALS cases,MAPT-H1 showed a stronger positive correlation with the presence of oculomotor signs(p = 0.05,r = 0.28).As well as significant positive association between cognitive impairments(p = 0.039,r = 0.59). Our findings emphasize the correlation between APOE and MAPT genotypes and the cognitive features in our ALS patients. We also observed other interesting, though weak, significant correlations (with coefficients not exceeding 0.20),which require further validation in a larger cohort to confirm our results.}, } @article {pmid39749679, year = {2025}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Bidder, C and Edmonds, E and Ellis, C and Annadale, J and Wilde, L and Sharrack, B and Malaspina, A and Leach, O and Mills, R and Tennant, A}, title = {Determinants and progression of stigma in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2024.2435969}, pmid = {39749679}, issn = {2167-9223}, abstract = {Objective: Stigma in amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) may be felt or enacted; felt stigma covers feeling devalued by the illness, whereas enacted stigma refers to being treated differently because of it. Stigma in ALS/MND has been shown to increase social withdrawal, worsen quality of life, and reduce use of assistive devices, so we explored prevalence and factors influencing stigma. Methods: Participants in the Trajectories of Outcome in Neurological Conditions-ALS study completed scales measuring stigma, fatigue, spasticity, functioning, mood, worry, self-esteem, and perceived health, as well as demographic information and symptoms like head drop or emotional lability. Following transformation to interval-scale estimates, data were analyzed by regression, structural equation modeling, and trajectory models. Results: Stigma was experienced by 83.5% of 1059 respondents. Worry, disease severity (King's stage ≥ 3), emotional lability, fatigue, spasticity, and bulbar onset increase stigma. In contrast, increasing age, living with spouse/partner, and greater self-esteem were associated with reduced stigma. Trajectory analysis over 30 months (N = 1049) showed three groups, the largest (70.2%) had high levels of stigma which significantly increased during follow-up. In a recently diagnosed subset of 347 participants, stigma was experienced early in the disease course (<7 months after diagnosis), and for 77.2% stigma significantly increased over time. Conclusions: Both felt and enacted stigma are frequently perceived by people living with ALS/MND. Younger people and those with bulbar onset, emotional lability, worry, fatigue, and spasticity, or at more advanced clinical stages, are at greater risk.}, } @article {pmid39749674, year = {2025}, author = {Tankéré, P and Cascarano, E and Saint Raymond, C and Mallaret, M and Toribio Ruiz, C and Herquelot, E and Denis, H and Cals Maurette, M and Tamisier, R and Pépin, JL}, title = {Care trajectories and adherence to respiratory management recommendations in persons living with amyotrophic lateral sclerosis: a ten-year cohort study in a French tertiary university centre.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2447911}, pmid = {39749674}, issn = {2167-9223}, abstract = {Objective: This study determined real-life care trajectories before and after initiation of noninvasive ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS). Caregiver adherence to respiratory management recommendations and the associated survival rate of people with ALS were also assessed. Methods: Data were obtained from a tertiary center prospective ALS database that included 10 years of follow-up data for people with ALS. Results are presented numerically and with graphical time sequence analysis through K clustering (TAK) representation. Kaplan Meier and Cox models were used to determine survival and associated prognostic factors. Results: 109 patients with ALS patients were included; median [interquartile range] follow-up was 25.0 months [15.3-43.3]. During study timeframe patients had a median of 4.0 [2.0-6.0] clinical visits; death occurred in 54.1%. Median time between clinical visits was 3.9 [2.8-6.5] months, between arterial blood gases was 4.3 months [3.0-6.6], between spirometry testing was 5.8 months [4.1-8.2], and between nocturnal oximetry was 4.4 months [3.0-7.8]. Visualization of care trajectories TAK show marked heterogeneity in survival, time to NIV initiation, and time from NIV initiation to death. Mortality was correlated with NIV initiation and arterial carbon dioxide pressure increase. Conclusions: The current framework in ALS guidelines should be adapted to the ALS disease stage and individual patient characteristics. Understanding how subgroups of patients with ALS use healthcare services over time could help to highlight fragility areas and priorities in the allocation of care resources and implementation of best practices.}, } @article {pmid39749668, year = {2025}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Berry, J and Punjani, R and Larson, T and Mohidul, S and Horton, DK}, title = {Amyotrophic lateral sclerosis estimated prevalence cases from 2022 to 2030, data from the national ALS Registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2024.2447919}, pmid = {39749668}, issn = {2167-9223}, abstract = {Objective: To estimate the projected number of ALS cases in the United States from 2022 to 2030. Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no known cure. Because ALS is not a notifiable disease in the United States, the accurate ascertainment of prevalent ALS cases continues to be a challenge. To overcome this, the National ALS Registry (Registry) uses novel methods to estimate newly diagnosed and existing cases in the United States. Methods: We estimated ALS prevalence retrospectively from 2022 to 2024 and prospectively from 2025 to 2030 using prevalence obtained through previous CRC analyses on 2018 Registry data (the most current data available) to generate projected observed, missing, and total cases. Projected prevalent cases were then stratified by age, race, and sex. Results: The number of estimated ALS cases in 2022 was 32,893. By 2030, projected cases increase more than 10%, to 36,308. The largest increase occurs for the population ages 66 years and older, with a 25% increase (from 16,349 cases in 2022 to 20,438 cases in 2030). The projected number of cases classified as "other race" will increase by 15% (from 2,473 cases in 2022 to 2,854 cases in 2030). Conclusions: These estimates of projected ALS cases reflect anticipated changes in the underlying demographics of the United States. Our projections are likely an underestimation because emerging therapeutics and improved healthcare will improve survivability in this vulnerable population. These results should inform policy to more efficiently allocate resources for ALS patients and programs.}, } @article {pmid39749172, year = {2024}, author = {Chauhan, A and Begum, J and Lavanya, KM and Gupta, A and Ghosh, S and Kulkarni, S}, title = {Experiential Learning of Active Learning Strategies in Mentor Learner Web-based Discussions: A Perceptions Study.}, journal = {International journal of applied & basic medical research}, volume = {14}, number = {4}, pages = {258-265}, pmid = {39749172}, issn = {2229-516X}, abstract = {BACKGROUND: Active learning strategies (ALSs) in medical education are valued for their effectiveness but face adoption challenges among educators, underscoring the need for a deeper understanding of their implementation and impact.

AIM: The aim of the study was to investigate the perceptions of medical educators regarding the effectiveness and challenges of ALS through mentor-learner (ML) web-based discussions.

SETTINGS AND DESIGN: The retrospective cross-sectional study analyzed data from 32 medical educators enrolled in the Foundation for Advancement of International Medical Education Research course at Christian Medical College, Ludhiana. It utilized a mixed-method approach, gathering both quantitative and qualitative data through ML web discussions.

MATERIALS AND METHODS: The study used a "dual-method" approach, combining traditional online discussions with a "role-reversal" method on an ML web platform, promoting experiential learning. Participant responses on ALS implementation tasks were collected and analyzed within these discussions.

RESULTS: Participants shared various ALS for collaborative learning (20), classroom engagement (26), assessing prior knowledge (12), and note-taking during lectures (10). Further, among the 11 ALS examined, the ease of implementation varied significantly among participants (P < 0.0001). Challenges in ALS implementation included inadequate faculty training (91%), motivation (84%), resource constraints (81%), student (75%), and administrative resistance (69%). Four themes emerged as recommendations for effective ALS implementation: empowering educators, engaging students, streamlining support systems, and monitoring impact.

CONCLUSION: The study highlights a mixed perspective of medical educators on ALS. Although ALS was perceived as effective in fostering critical thinking and developing collaborative learning among students, various challenges, such as a lack of skilled faculty and resources, necessitated robust faculty development initiatives.}, } @article {pmid39748876, year = {2025}, author = {Salter, S and Salter, E and Kim, AJ and Liu, AK}, title = {Rising Voltage-Gated Potassium Channel Antibody Level as a Possible Disease Progression Marker for Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e76760}, pmid = {39748876}, issn = {2168-8184}, abstract = {A subset of amyotrophic lateral sclerosis (ALS) patients tests positive for antibodies commonly associated with autoimmune neurological diseases, including voltage-gated potassium channel (VGKC)-complex antibodies. Although an autoimmune basis for ALS remains speculative, and immunomodulatory therapies have shown minimal benefit as of yet, isolated cases suggest that VGKC-complex antibodies may be relevant to disease type and progression. In this report, we present a case of ALS in which increasing VGKC-complex antibody levels correlated with clinical decline, raising the question of whether such antibodies could serve as biomarkers of progression in VGKC-complex antibody-positive ALS patients. To date, no published studies have systematically evaluated changes in VGKC-complex antibody levels in ALS patients over time. Our findings suggest that tracking VGKC-complex antibodies in ALS may offer insights into disease progression and prompt further investigation into their potential role as prognostic biomarkers, especially in certain subtypes of the disease.}, } @article {pmid39748816, year = {2024}, author = {Li, Z and Liu, X and Zhang, H and Li, P and Yao, F}, title = {Improving resistance to lepidopteran pests and herbicide using Sanming dominant genic male sterile rice (Oryza sativa L.).}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1525620}, pmid = {39748816}, issn = {1664-462X}, abstract = {In order to improve both resistance to lepidopteran pests and resistance to the herbicide imazethapyr in mainstay japonica varieties of the Huang-Huai rice region, Sanming dominant genic male sterile (S-DGMS) rice was used as a platform to facilitate the pyramiding of functional genes and the replacement of the genomic background. Twelve novel lines were developed, each carrying a crystal toxin gene conferring resistance to lepidopteran pests and the ALS[627N] allele conferring resistance to herbicide imazethapyr in the background of a mainstay japonica variety. The genomic background of the 12 novel lines was examined using 48 specified molecular markers, and each line carried less than two polymorphic markers relative to the corresponding mainstay variety. All 12 lines displayed high resistance to lepidopteran pests and the herbicide imazethapyr. The major agronomic traits of the 12 lines showed no difference relative to the responding mainstay variety when sprayed with pesticide. The popularization of the 12 japonica lines could reduce the use of pesticides and provide highly efficient control of weeds and weedy rice in the future, thus promoting the development of japonica rice production. Therefore, S-DGMS rice could be a powerful tool for the genetic improvement of target traits in rice.}, } @article {pmid39748214, year = {2025}, author = {Brown, G and Jesus, S and Leboffe, E and Esch, A and Newport, K}, title = {Advance Care Planning Billing Codes Associated With Decreased Healthcare Utilization in Neurological Disease.}, journal = {Journal of healthcare management / American College of Healthcare Executives}, volume = {70}, number = {1}, pages = {58-73}, pmid = {39748214}, issn = {1096-9012}, mesh = {Humans ; Aged ; Male ; Female ; *Advance Care Planning/statistics & numerical data ; United States ; *Nervous System Diseases/therapy ; Aged, 80 and over ; *Patient Acceptance of Health Care/statistics & numerical data ; Cohort Studies ; }, abstract = {GOALS: Advance care planning (ACP) procedure codes have been established to reimburse meaningful care goal discussions; however, the utilization frequency of these codes in neurological disease is unknown. The objective of this study is to identify the association between ACP codes and healthcare utilization in chronic neurodegenerative diseases.

METHODS: This is a multicenter cohort study using real-world electronic health data. Using the TriNetX database, we collected electronic health data from 92 institutions in the United States. We included patients aged 65 and older who had been diagnosed with one of four neurological diseases: Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis (ALS). Patients with congestive heart failure were included as a reference. From the 64,683,009 total patients in the database, 877,138 had Alzheimer's disease, 544,610 had Parkinson's disease, 208,341 had multiple sclerosis, 9,944 had amyotrophic lateral sclerosis, and 1,500,186 had congestive heart failure. For each disease, we compared hospitalizations and emergency department (ED) visits over a two-year period between patients with and without ACP codes documented. Then, in patients with ACP, we investigated the rates of hospitalizations and ED visits over the two years before ACP and two years after ACP to understand the impact of ACP on the healthcare utilization trend. All patients had records for at least two years after index.

PRINCIPAL FINDINGS: The rate of ACP code documentation ranged from 1.8% of multiple sclerosis patients to 3.6% of Alzheimer's disease patients. After matching for demographic and health variables, usage of ACP codes was associated with significantly fewer hospitalizations for Alzheimer's disease patients. Across all diseases, there was a 20% to 30% decrease in ED visits, which was significant. Furthermore, there was a significant change in the trend of hospitalizations and ED visits for patients after ACP documentation. Patients went from increasing utilization before ACP documentation to decreasing utilization after documentation.

PRACTICAL APPLICATIONS: ACP billing codes are used infrequently in neurological disease, which may indicate that reimbursement alone is not sufficient to drive code usage. Usage of ACP billing codes was associated with decreased healthcare utilization, particularly in terms of ED visits. Beyond the primary objective of providing goal-concordant care, ACP may impact the economic burden of chronic neurodegenerative disease, which has high costs of care in our aging society. There may be particular benefits with Alzheimer's disease, which had an impact on both hospitalizations and ED visits and is the most prevalent neurodegenerative disease. Future work is needed to better understand the best implementation strategy for ACP in a multifaceted approach that emphasizes patient care preferences for their illness.}, } @article {pmid39747792, year = {2025}, author = {Lee, J and Kouznetsova, VL and Kesari, S and Tsigelny, I}, title = {Selective diagnostics of Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases with machine learning and miRNA.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {79}, pmid = {39747792}, issn = {1573-7365}, mesh = {*MicroRNAs/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism ; *Machine Learning ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Parkinson Disease/diagnosis/genetics/metabolism ; *Biomarkers ; }, abstract = {The diagnosis of neurological diseases can be expensive, invasive, and inaccurate, as it is often difficult to distinguish between different types of diseases with similar motor symptoms. However, the dysregulation of miRNAs can be used to create a robust machine-learning model for a reliable diagnosis of neurological diseases. We used miRNA sequence descriptors and gene target data to create machine-learning models that can be used as diagnostic tools. The top-performing machine-learning models, trained on filtered miRNA datasets for Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases of this research yielded 94, 97, and 96, percent accuracies, respectively. Analysis of dysregulated miRNA in neurological diseases elucidated novel biomarkers that could be used to diagnose and distinguish between the diseases. Machine-learning models developed using sequence and gene target descriptors of miRNA biomarkers can achieve favorable accuracies for disease classification and attain a robust discerning capability of neurological diseases.}, } @article {pmid39747573, year = {2025}, author = {Kim, KM and Girdhar, A and Cicardi, ME and Kankate, V and Hayashi, M and Yang, R and Carey, JL and Fare, CM and Shorter, J and Cingolani, G and Trotti, D and Guo, L}, title = {NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {2}, pmid = {39747573}, issn = {2399-3642}, support = {R35GM138109//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31 NS111870/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; 628389//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; F31NS111870//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM140733/GM/NIGMS NIH HHS/United States ; R35GM140733//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; RF1NS121143//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21-NS090912//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128396//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01GM099836//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R21 NS090912/NS/NINDS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; T32GM008275//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 GM099836/GM/NIGMS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Frontotemporal Dementia/metabolism/genetics ; *Dipeptides/metabolism ; beta Karyopherins/metabolism/genetics ; RNA-Binding Protein FUS/metabolism/genetics ; Protein Binding ; HEK293 Cells ; }, abstract = {Arginine-rich dipeptide repeat proteins (R-DPRs) are highly toxic proteins found in patients with C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). R-DPRs can cause toxicity by disrupting the natural phase behavior of RNA-binding proteins (RBPs). Mitigating this abnormal phase behavior is, therefore, crucial to reduce R-DPR-induced toxicity. Here, we use FUS as a model RBP to investigate the mechanism of R-DPR-induced aberrant RBP phase transition. We find that this phase transition can be mitigated by Kapβ2. However, as a nuclear import receptor and phase modifier for PY-NLS-containing RBPs, the function of WT Kapβ2 could lead to undesired interaction with its native substrates when used as therapeutics for C9-ALS/FTD. To address this issue, it is crucial to devise effective strategies that allow Kapβ2 to selectively target its binding to the R-DPRs, instead of the RBPs. We show that NLS-binding deficient Kapβ2W460A:W730A can indeed selectively interact with R-DPRs in FUS assembly without affecting normal FUS phase separation. Importantly, Kapβ2W460A:W730A prevents enrichment of poly(GR) in stress granules and mitigates R-DPR neurotoxicity. Thus, NLS-binding deficient Kapβ2 may be implemented as a potential therapeutic for C9-ALS/FTD.}, } @article {pmid39747563, year = {2025}, author = {Adim, H and Fahmideh, L and Fakheri, BA and Zarrini, HN and Sasanfar, H}, title = {iTRAQ-based quantitative proteomic analysis of herbicide stress in Avena ludoviciana Durieu.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {577}, pmid = {39747563}, issn = {2045-2322}, mesh = {*Herbicides/pharmacology/toxicity ; *Avena/drug effects/genetics/metabolism ; *Proteomics/methods ; *Herbicide Resistance/genetics ; *Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; Stress, Physiological/drug effects ; Acetyl-CoA Carboxylase/metabolism/genetics ; }, abstract = {Winter wild oat (Avena sterilis subsp. ludoviciana (Durieu) Gillet & Magne) has been considered the most common and troublesome weed in wheat fields of Iran. The widespread and continuous use of herbicides has led to the emergence and development of resistant biotypes in A. ludoviciana, making it one of the most important herbicide-resistant weeds within field crops. Considering the importance of understanding the mechanisms underlying resistance to herbicides and identifying key proteins involved in the response to Acetyl-coenzyme A carboxylase (ACCase) and Acetolactate synthase (ALS) inhibitor herbicides in A. ludoviciana. This study aimed to identify the proteins involved in herbicide resistance in A. ludoviciana using the Isobaric Tags for Relative and Absolute Quantification (iTRAQ) technique. In this study, a total of 18,313 peptides were identified with ≤ 0.01 FDR, which could be classified into 484 protein groups. Additionally, 138 differentially expressed proteins (DEPs) were identified in the resistant biotype (R), while 93 DEPs were identified in the susceptible biotype (S). Gene Ontology (GO) analysis revealed that these DEPs mainly consisted of proteins related to photosynthesis, respiration, amino acid synthesis and translation, secondary metabolite biosynthesis, defense proteins, and detoxification. Furthermore, enrichment pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the most important pathways included metabolic pathways, carbohydrate metabolism, secondary metabolites, amino acid synthesis, and photosynthesis. The function of DEPs indicated that some proteins, such as cytochrome P450, play a direct role in herbicide detoxification. Overall, the results of this study demonstrated the complex response of the resistant biotype to herbicides and its ability to increase antioxidant capacity through up-regulated detoxification proteins, particularly cytochrome P450 (Q6YSB4), and defense proteins, particularly superoxide dismutase (Q0DRV6) and polyamine oxidase (Q7XR46). In the resistant A. ludoviciana populations, in addition to the activation of enzymatic and non-enzymatic defense systems, other strategies such as reduced photosynthesis and respiration, increased transcription and translation activity, enhanced lipid metabolism, regulation of cellular processes and homeostasis, and up-regulation of proteins associated with signaling and ion channels play a role in resistance to herbicide. Overall these findings provide new insights into the role of different proteins in resistance to herbicides and contribute to a comprehensive understanding of herbicide resistance in A. ludoviciana.}, } @article {pmid39745174, year = {2025}, author = {Antonelli, S and Castañeda, FN and Olivieri, AC and Carabajal, MD and Pellegrino Vidal, RB}, title = {Novel Data Fusion Strategy for Second-Order Data: Multivariate Curve Resolution for the Determination of Pharmaceuticals by Means of Fluorimetric Measurements.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.4c05725}, pmid = {39745174}, issn = {1520-6882}, abstract = {A new strategy is proposed for second-order data fusion based on the simultaneous modeling of two data sets using the multivariate curve resolution-alternating least-squares (MCR-ALS) model, applying a new constraint during the ALS stage, called "Proportionality of Scores". This approach allows for the fusion of data from different sources, without requiring common dimensionality, and enables the application of specific constraints to each data set. This strategy was applied to the determination of five pharmaceutical contaminants (naproxen, danofloxacin, ofloxacin, sarafloxacin, and enoxacin) in environmental water samples, by fusing two sets of excitation-emission fluorescence matrices, measured before and after photochemical derivatization. The predictive performance of the fused model was compared to individual PARAFAC models built for each fluorescence data set, showing that data fusion significantly increases precision and accuracy, as indicated by the elliptical joint confidence region test. Data fusion allowed improvement of relative errors of prediction, from 13-32% to 8-15% in validation samples and from 25-121% to 13-20% in real samples. The advantages of data fusion were evident in both cases, particularly in instances of substantial signal overlap between analytes or the presence of uncalibrated interferents with similar profiles, as demonstrated by the superior predictive capacity achieved through the proposed strategy.}, } @article {pmid39744204, year = {2024}, author = {Morales-Galicia, AE and Ramírez-Mejía, MM and Ponciano-Rodriguez, G and Méndez-Sánchez, N}, title = {Revolutionizing the understanding of liver disease: Metabolism, function and future.}, journal = {World journal of hepatology}, volume = {16}, number = {12}, pages = {1365-1370}, pmid = {39744204}, issn = {1948-5182}, abstract = {The intersection between metabolic-associated steatotic liver disease (MASLD) and chronic hepatitis B virus (HBV) infection is an emerging area of research with significant implications for public health and clinical practice. Wang et al's study highlights the complexities of managing patients with concurrent MASLD and HBV. The findings revealed that patients with concurrent MASLD-HBV exhibited more severe liver inflammation and fibrosis, whereas those with HBV alone presented a better lipid profile. The growing recognition of metabolic dysfunction in liver disease, reflected in the shift from nonalcoholic liver disease to MASLD, demands updates to clinical guidelines, particularly for patients with dual etiologies. Understanding the biological interactions between MASLD and HBV could lead to novel therapeutic approaches, emphasizing the need for personalized treatment strategies. The coexistence of MASLD and HBV presents therapeutic challenges, particularly in managing advanced fibrosis and cirrhosis, which are more likely in these patients. The aim of this editorial is to analyze the interaction between MASLD and HBV, highlight the pathophysiological mechanisms that exacerbate liver disease when both conditions coexist, and discuss the clinical implications of the findings of Wang et al.}, } @article {pmid39743746, year = {2025}, author = {Wang, Z and Wang, X and Li, P and Xia, H and Yang, X}, title = {Genetic associations between immune-related plasma proteins and neurodegenerative diseases.}, journal = {Neurological research}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/01616412.2024.2448745}, pmid = {39743746}, issn = {1743-1328}, abstract = {BACKGROUND: Immune dysregulation is commonly associated with neurodegenerative diseases (NDs), yet the underlying causes and mechanisms still require further investigation.

OBJECTIVE: This study investigates the correlation between immune-related plasma proteins and the risk of NDs by integrating genome-wide association study (GWAS) data for Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with plasma proteome analysis.

METHODS: By analyzing GWAS data for 4907 immune-related plasma proteins, this research evaluates the direct impact of plasma proteins on the risk of four NDs: AD, PD, ALS, and MS. Additionally, the study conducts an analysis of protein expression levels using single-cell RNA sequencing data.

RESULTS: We have identified plasma proteins that are closely associated with the risk of NDs. Using stringent criteria, we identified 88 proteins associated with AD, 115 with PD, 100 with ALS, and 87 with MS. Additionally, single-cell sequencing analyzed the protein expression and its distribution within different cell types in the brain.

CONCLUSIONS: Our research has demonstrated that plasma proteins may contribute to the risk of NDs, and it has also provided concrete evidence linking genetic susceptibility for these diseases to immune mechanisms. Furthermore, we found that specific proteins influence genetic variations linked to NDs risk via plasma-mediated regulation, emphasizing the importance of interactions between the brain and circulatory system.}, } @article {pmid39743546, year = {2025}, author = {Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {39743546}, issn = {1759-4766}, abstract = {The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.}, } @article {pmid39743298, year = {2024}, author = {Wang, L and Liu, H and Li, L}, title = {Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.}, journal = {Journal of Zhejiang University. Science. B}, volume = {25}, number = {12}, pages = {1115-1119}, pmid = {39743298}, issn = {1862-1783}, support = {81970431//the National Natural Science Foundation of China/ ; 2023JJ50136//the Hunan Provincial Natural Science Foundation of China/ ; }, mesh = {*Autophagy ; Humans ; *Neurodegenerative Diseases/metabolism ; *Protein Aggregates ; Animals ; Organelles/metabolism ; Alzheimer Disease/metabolism ; Neurons/metabolism ; Huntington Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.}, } @article {pmid39743215, year = {2024}, author = {Chiu, Y and Xia, S and Qiao, H and Zhao, Z}, title = {Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2024.11.006}, pmid = {39743215}, issn = {1525-2191}, abstract = {Neurodegenerative diseases, including Alzheimer disease, frontotemporal dementia, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis, are often casually linked to protein aggregation and inclusion. As the origins of those proteinopathies have been biochemically traced and genetically mapped, genetically engineered animal models carrying the specific mutations or variants are widely used for investigating the etiology of these diseases, as well as for testing potential therapeutics. This article focuses on the mouse models of Alzheimer disease and closely related frontotemporal dementia, particularly the ones that have provided most valuable knowledge, or are in a trajectory of doing so. More importantly, some of the major findings from these models are summarized, based on the recent single-cell transcriptomics, multiomics, and spatial transcriptomics studies. While no model is perfect, it is hoped that the new insights from these models and the practical use of these models will continue to help to establish a path forward.}, } @article {pmid39743032, year = {2024}, author = {Li, Y and Zhang, W and Zhang, Q and Li, Y and Xin, C and Tu, R and Yan, H}, title = {Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110283}, doi = {10.1016/j.abb.2024.110283}, pmid = {39743032}, issn = {1096-0384}, abstract = {Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.}, } @article {pmid39742161, year = {2024}, author = {Mashimo, S and Matsuoka, A and Tanese, K and Kano, O and Ishiko, A}, title = {Idiopathic Multiple Localized Lipoatrophy Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e74887}, pmid = {39742161}, issn = {2168-8184}, abstract = {Localized lipoatrophy is a rare condition characterized by the localized loss of subcutaneous adipose tissue. It may occur idiopathically without specific triggers. The pathogenesis of idiopathic localized lipoatrophy remains largely unknown. We present the case of a 53-year-old Japanese woman with multiple localized lipoatrophy who exhibited upper motor neuron signs clinically and panniculitis histologically. She was initially suspected to have amyotrophic lateral sclerosis due to progressive left limb volume loss. Histologically, the lesions showed adipocyte destruction accompanied by predominant plasma infiltration.}, } @article {pmid39741274, year = {2024}, author = {Mandeville, R and Sedghamiz, H and Mansfield, P and Sheean, G and Studer, C and Cordice, D and Ghanbari, G and Malhotra, A and Nemati, S and Koola, J}, title = {Deep learning enhanced transmembranous electromyography in the diagnosis of sleep apnea.}, journal = {BMC neuroscience}, volume = {25}, number = {1}, pages = {80}, pmid = {39741274}, issn = {1471-2202}, support = {R01 HL157985/HL/NHLBI NIH HHS/United States ; T32 HL166127/HL/NHLBI NIH HHS/United States ; R01 HL166485/HL/NHLBI NIH HHS/United States ; R01 AG063925/AG/NIA NIH HHS/United States ; R01 HL154926/HL/NHLBI NIH HHS/United States ; R01 HL148436/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Deep Learning ; *Electromyography/methods ; Male ; Middle Aged ; Female ; Adult ; Sleep Apnea, Obstructive/diagnosis/physiopathology ; Polysomnography/methods ; Aged ; Sleep Apnea Syndromes/diagnosis/physiopathology ; }, abstract = {Obstructive sleep apnea (OSA) is widespread, under-recognized, and under-treated, impacting the health and quality of life for millions. The current gold standard for sleep apnea testing is based on the in-lab sleep study, which is costly, cumbersome, not readily available and represents a well-known roadblock to managing this huge societal burden. Assessment of neuromuscular function involved in the upper airway using electromyography (EMG) has shown potential to characterize and diagnose sleep apnea, while the development of transmembranous electromyography (tmEMG), a painless surface probe, has made this opportunity practical and highly feasible. However, experience and ability to interpret electrical signals from the upper airway are scarce, and much of the pertinent information within the signal is likely difficult to detect visually. To overcome this issue, we explored the use of transformers, a deep learning (DL) model architecture with attention mechanisms, to model tmEMG data and distinguish between electromyographic signals from a cohort of control, neurogenic, and sleep apnea patients. Our approach involved three strategies to train a generalizable model on a relatively small dataset including, (1) transfer learning using an audio spectral transformer (AST), (2) the use of 6,000 simulated EMG recordings, converted to spectrograms and using standard backpropagation for fine-tuning, and (3) application of regularization to prevent overfitting and enhance generalizability. This DL approach was tested using 177 transoral EMG recordings from a prior study's database that included six healthy controls, five moderate to severe OSA patients, and five amyotrophic lateral sclerosis (ALS) patients with evidence of bulbar involvement (neurogenic injury). Sensitivity and specificity for classifying neurogenic cases from controls were 98% and 73%, respectively, while classifying OSA from controls were 88% and 64%, respectively. Notably, by averaging the predicted probabilities of each segment for individual patients, the model correctly classified up to 82% of control and OSA patients. These results not only suggest a potential to diagnose OSA patients accurately, but also to identify OSA endotypes that involve neuromuscular pathology, which has major implications for clinical management, patient outcomes, and research.}, } @article {pmid39741002, year = {2024}, author = {Lembo, A and Schiavetti, I and Serafino, M and Caputo, R and Nucci, P}, title = {Comparison of the performance of myopia control in European children and adolescents with defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL) spectacles.}, journal = {BMJ paediatrics open}, volume = {8}, number = {1}, pages = {}, doi = {10.1136/bmjpo-2024-003187}, pmid = {39741002}, issn = {2399-9772}, mesh = {Humans ; *Eyeglasses ; Adolescent ; Child ; Male ; Female ; Retrospective Studies ; *Myopia/therapy/epidemiology/physiopathology/prevention & control ; *Refraction, Ocular/physiology ; Disease Progression ; Europe/epidemiology ; Equipment Design ; Visual Acuity/physiology ; }, abstract = {PURPOSE: A performance comparison of two myopia control spectacle lens designs, defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL), at slowing myopia progression in a European child/adolescent population. Previous research directly comparing these designs has been limited to Chinese participants and 1-year follow-up. The prevalence of myopia in European child/adolescent has been estimated at 22.60%.

METHODS: Retrospective cohort study of individuals (6-17 years) with myopia progression. Participants wore DIMS (Hoya MiyoSmart) or HAL (Essilor Stellest) spectacles for a minimum of 2 years. Axial length (AL) and cycloplegic autorefraction (spherical equivalent refraction (SER)) were measured at baseline and 1 and 2 years.

RESULTS: Mean 1-year SER changes for DIMS were -0.34D (±0.46 SD) and HAL -0.30D (±0.30); 2-year changes for DIMS were -0.50D (±0.64 SD) and HAL -0.63D (±0.56). Mean 1-year AL increases for DIMS were 0.19 mm (±0.56) and HAL 0.15 mm (±0.47); 2-year increases for DIMS were 0.29 mm (±0.63) and HAL 0.32 mm (±0.72). For equivalence margins of 0.25D and 0.50D for SER at 1 and 2 years, respectively, and similarly 0.20 mm and 0.30 mm margins for AL, DIMS and HAL lenses were equivalent apart from AL at 1 year where the 0.21 mm 95% CI upper limit just exceeded 0.20 mm. At both 1 and 2 years, none of the differences in mean SERs or ALs between DIMS and HAL were clinically or statistically significant (p≥0.05 Mann-Whitney U test). Using linear mixed model analysis, the interaction between lens type and time did not significantly affect SER or AL at 1- or 2-year follow-up (p≥0.05). 38.4% of children/adolescents with DIMS had no SER progression at 2 years, compared with 21.9% with HAL (p=0.047).

CONCLUSION: In a European population, DIMS and HAL lenses are essentially equivalent in their ability to reduce myopia progression and AL elongation over a 2-year follow-up period.}, } @article {pmid39740768, year = {2025}, author = {Jiang, Y and Fan, W and Li, Y and Xue, H}, title = {Genetic Insights Into the Role of Cathepsins in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis: Evidence From Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70207}, pmid = {39740768}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Cathepsins/genetics ; *Genome-Wide Association Study ; Cathepsin B/genetics/metabolism ; Cathepsin H/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Previous studies have confirmed the significant role of cathepsins in the development of neurodegenerative diseases. We aimed to determine whether genetically predicted 10 cathepsins may have a causal effect on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS: We conducted a two-sample bidirectional Mendelian randomization (MR) study using publicly available data from genome-wide association study (GWAS) to assess the causal associations between 10 cathepsins and three neurodegenerative diseases, including AD, PD, and ALS. We employed the following methods, including inverse variance weighting (IVW), MR-Egger, and weighted median (WM). The results were further validated using sensitivity analysis.

RESULTS: The forward MR analysis results indicate that elevated cathepsin H levels increase the risk of AD (p = 0.005, odds ratio [OR] = 1.040, 95% confidence interval [CI] = 1.011-1.069), elevated cathepsin B levels decrease the risk of PD (p < 0.001, OR = 0.890, 95% CI = 0.831-0.954), and no significant association was found between cathepsin levels and ALS. Reverse MR analysis suggests that there is no causal association between 10 cathepsins and three neurodegenerative diseases.

CONCLUSION: Our study provides new genetic insights into the role of cathepsin H in AD and cathepsin B in PD. However, our findings need to be further validated in a wider population, and future research should explore the potential mechanisms of cathepsins in these diseases in order to provide a basis for the development of new therapeutic strategies.}, } @article {pmid39740575, year = {2024}, author = {Fortuna, A and Sorarù, G}, title = {Cervical lower motor neuron syndromes: A diagnostic challenge.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123357}, doi = {10.1016/j.jns.2024.123357}, pmid = {39740575}, issn = {1878-5883}, abstract = {Cervical lower motor neuron (LMN) syndromes, also known as brachial paresis, are characterized by muscle atrophy, weakness, and decreased reflexes in the upper limbs, devoid of sensory symptoms. These syndromes can stem from various factors, including degenerative conditions, immune-mediated diseases, infections, toxic exposures, metabolic disorders, and vascular anomalies.[1] Clinical presentations vary, with motor neuron involvement potentially limited to the cervical area or extending to other regions, affecting prognosis. Misdiagnosis is a significant issue, particularly in lower motor neuron presentations, with an error rate nearing 20 %.[2] This review proposes a classification system based on magnetic resonance imaging (MRI) findings, the onset timing of symptoms (acute, subacute, or chronic), the symmetry and distribution of atrophy, and the etiology (sporadic or hereditary). Acute conditions may include spinal ischemia,[3] whereas subacute or chronic forms can manifest as symmetric (e.g., cervical spondylogenic myelopathy)[4] or asymmetric (e.g., Hirayama disease)[5] presentations. Neurophysiological assessments and cervical MRI are crucial for accurate diagnosis, as they reveal patterns that provide lesion localization and additional clues to the underlying cause. A systematic diagnostic approach is essential for navigating the complexities of these syndromes.}, } @article {pmid39739690, year = {2024}, author = {Tian, Y and Heinsinger, N and Hu, Y and Lim, UM and Wang, Y and Fernandis, AZ and Parmentier-Batteur, S and Klein, B and Uslaner, JM and Smith, SM}, title = {Deciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0308428}, pmid = {39739690}, issn = {1932-6203}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; *Ataxin-2/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Neurons/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Protein Binding ; }, abstract = {Ataxin-2 is a protein containing a polyQ extension and intermediate length of polyQ extensions increases the risk of Amyotrophic Lateral Sclerosis (ALS). Down-regulation of Ataxin-2 has been shown to mitigate TDP-43 proteinopathy in ALS models. To identify alternative therapeutic targets that can mitigate TDP-43 toxicity, we examined the interaction between Ataxin-2 and TDP-43. Co-immunoprecipitation demonstrated that Ataxin-2 and TDP-43 interact, that their interaction is mediated through the RNA recognition motif (RRM) of TDP-43, and knocking down Ataxin-2 or mutating the RRM domains rescued TDP-43 toxicity in an iPSC-derived neuronal model with TDP-43 overexpression. To decipher the Ataxin-2 and TDP-43 interactome, we used co-immunoprecipitation followed by mass spectrometry to identify proteins that interacted with Ataxin-2 and TDP-43 under conditions of endogenous or overexpressed TDP-43 in iPSC-derived neurons. Multiple interactome proteins were differentially regulated by TDP-43 overexpression and toxicity, including those involved in RNA regulation, cell survival, cytoskeleton reorganization, protein modification, and diseases. Interestingly, the RNA-binding protein (RBP), TAF15 which has been implicated in ALS was identified as a strong binder of Ataxin-2 in the condition of TDP-43 overexpression. Together, this study provides a comprehensive annotation of the Ataxin-2 and TDP-43 interactome and identifies potential therapeutic pathways and targets that could be modulated to alleviate Ataxin-2 and TDP-43 interaction-induced toxicity in ALS.}, } @article {pmid39739500, year = {2025}, author = {Saiduzzaman, M and Roy, S and Bhattacharjee, M}, title = {Young Patient with Amyotrophic Lateral Sclerosis Following Suicidal Organophosphorus Compounds Poisoning: A Case Report.}, journal = {Mymensingh medical journal : MMJ}, volume = {34}, number = {1}, pages = {272-275}, pmid = {39739500}, issn = {2408-8757}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Organophosphate Poisoning/complications/therapy/etiology ; Suicide, Attempted ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both upper and lower motor neurons. Its underlying etiology is not well established. But certain risk factors including genetic predilection and exposure to certain environmental toxins like Organophosphorus Compounds (OPC) have been postulated. Here we describe a young male patient presented with progressive weakness of all four limbs immediately following survival from OPC ingestion as a suicidal attempt. He also had slurred, indistinct speech without swallowing difficulty and sensory findings. Neurological examination findings are having mixed upper and lower motor neuron signs. EMG (Electromyography) shows features of denervation and reinnervation suggestive of ALS. ALS following single exposure to OPC is a relatively rare finding. Supportive treatments including physiotherapy and psychotherapy were given. This case may strengthen the etiological link between OPC and ALS.}, } @article {pmid39739450, year = {2025}, author = {Aiello, EN and Poletti, B and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Bella, ED and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Education moderates the association between motor involvement and executive status in ALS.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70027}, pmid = {39739450}, issn = {1468-1331}, support = {//BIBLIOSAN/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; Female ; *Executive Function/physiology ; Middle Aged ; *Educational Status ; Aged ; *Cognitive Reserve/physiology ; Neuropsychological Tests ; Cohort Studies ; }, abstract = {BACKGROUND: This study aimed to determine whether educational attainment-a common proxy of cognitive reserve (CR)-influences the association between motor and cognitive/behavioural outcomes in a large cohort of ALS patients without dementia.

METHODS: N = 726 ALS patients without FTD were assessed for motor (ALSFRS-R), cognitive (Edinburgh Cognitive and Behavioural ALS Screen, ECAS) and behavioural outcomes (ECAS-Carer Interview, ECAS-CI). CR was operationalized via educational attainment (in years). Moderation models were run on each subscale of the cognitive section of the ECAS and on the ECAS-CI by addressing ALSFRS-R as the predictor and education as the moderator.

RESULTS: Education was associated with both the ALSFRS-R and all the cognitive subscales of the ECAS, while not with the ECAS-CI. As to moderation models, a significant Education*ALSFRS-R interaction was detected solely with regard to the ECAS-Executive-with its simple slope-based decomposition revealing that higher ALSFRS-R scores were associated with higher scores on the ECAS-Executive for patients with low (p < 0.001) and average (p = 0.007), while not high, levels of education.

DISCUSSION: Education seems to moderate the association between motor involvement and executive status in ALS patients without dementia, thus possibly exerting a protective role towards both motor function and cognition in this population.}, } @article {pmid39738171, year = {2024}, author = {Jeon, P and Ham, HJ and Choi, H and Park, S and Jang, JW and Park, SW and Cho, DH and Lee, HJ and Song, HK and Komatsu, M and Han, D and Jang, DJ and Lee, JA}, title = {NS1 binding protein regulates stress granule dynamics and clearance by inhibiting p62 ubiquitination.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10925}, pmid = {39738171}, issn = {2041-1723}, support = {2020M3E5D9079911//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; RS-2023-00218515//National Research Foundation of Korea (NRF)/ ; JP19H05706//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP21H004771//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K20044//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 24H00060//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22gm1410004h0003//Japan Agency for Medical Research and Development (AMED)/ ; }, mesh = {Humans ; *Ubiquitination ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Stress Granules/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Sequestosome-1 Protein/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Neurons/metabolism ; HEK293 Cells ; Oxidative Stress ; HeLa Cells ; Autophagy ; Viral Nonstructural Proteins/metabolism/genetics ; Protein Binding ; Cytoplasmic Granules/metabolism ; Apoptosis Regulatory Proteins ; }, abstract = {The NS1 binding protein, known for interacting with the influenza A virus protein, is involved in RNA processing, cancer, and nerve cell growth regulation. However, its role in stress response independent of viral infections remains unclear. This study investigates NS1 binding protein's function in regulating stress granules during oxidative stress through interactions with GABARAP subfamily proteins. We find that NS1 binding protein localizes to stress granules, interacting with core components, GABARAP proteins, and p62, a protein involved in autophagy. In cells lacking NS1 binding protein, stress granule dynamics are altered, and p62 ubiquitination is increased, suggesting impaired stress granule degradation. Overexpression of NS1 binding protein reduces p62 ubiquitination. In amyotrophic lateral sclerosis patient-derived neurons, reduced NS1 binding protein and p62 disrupt stress granule morphology. These findings identify NS1 binding protein as a negative regulator of p62 ubiquitination and a facilitator of GABARAP recruitment to stress granules, implicating it in stress granule regulation and amyotrophic lateral sclerosis pathogenesis.}, } @article {pmid39737952, year = {2024}, author = {Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Comaduran, MF and Verbrugghe, M and Xu, JMS and Minotti, S and Lynch, J and Biswas, J and Wu, T and Durham, HD and Yeo, GW and Vera, M}, title = {Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10796}, pmid = {39737952}, issn = {2041-1723}, support = {RF1 MH126719/MH/NIMH NIH HHS/United States ; 300232//Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)/ ; MH126719//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; HG009889//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; U41 HG009889/HG/NHGRI NIH HHS/United States ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; HG011864//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; PJT-186141//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; HG004659//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; Hudson Translational Team Grant//ALS Society of Canada (ALS Canada)/ ; R01 HG011864/HG/NHGRI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; 2022-ALS Discovery Grant//ALS Society of Canada (ALS Canada)/ ; }, mesh = {*Dendrites/metabolism ; *Proteostasis ; Animals ; Humans ; Mice ; *RNA-Binding Protein FUS/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Motor Neurons/metabolism ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Hippocampus/metabolism/cytology ; Spinal Cord/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Protein Biosynthesis ; Molecular Chaperones/metabolism/genetics ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Microtubules/metabolism ; }, abstract = {Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhances HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites is impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.}, } @article {pmid39737769, year = {2025}, author = {Akyuz, E and Aslan, FS and Hekimoglu, A and Yilmaz, BN}, title = {Insights Into Retinal Pathologies in Neurological Disorders: A Focus on Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Alzheimer's Disease.}, journal = {Journal of neuroscience research}, volume = {103}, number = {1}, pages = {e70006}, doi = {10.1002/jnr.70006}, pmid = {39737769}, issn = {1097-4547}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; *Parkinson Disease/diagnosis/diagnostic imaging/pathology ; *Multiple Sclerosis/pathology/diagnosis/diagnostic imaging ; *Alzheimer Disease/pathology/diagnosis ; *Retina/pathology/diagnostic imaging ; Tomography, Optical Coherence/methods ; Retinal Diseases/diagnosis/pathology/etiology ; Animals ; }, abstract = {Neurological diseases are central nervous system (CNS) disorders affecting the whole body. Early diagnosis of the diseases is difficult due to the lack of disease-specific tests. Adding new biomarkers external to the CNS facilitates the diagnosis of neurological diseases. In this respect, the retina has a common embryologic origin with the CNS. Retinal imaging technologies including optical coherence tomography (OCT) can be used in the understanding and processual monitoring of neurological diseases. Retinal imaging has been recently recognized as a potential source of biomarkers for neurological diseases, increasing the number of studies in this direction. In this review, the association of retinal abnormalities with Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) is explained. Structural and functional abnormalities in retina as a predictive marker may facilitate early diagnosis of diseases. Although not all retinal abnormalities are predictive of neurologic diseases, changes in the retinal layers including retinal pigment epithelium and plexiform layers should suggest the risk of PD, MS, ALS, and AD.}, } @article {pmid39737526, year = {2024}, author = {Nakaya, T}, title = {Release of FUS into the extracellular space is regulated by its amino-terminal prion-like domain.}, journal = {FEBS letters}, volume = {}, number = {}, pages = {}, doi = {10.1002/1873-3468.15086}, pmid = {39737526}, issn = {1873-3468}, support = {22K07374//Japan Society for the Promotion of Science/ ; }, abstract = {Fused in sarcoma (FUS) is a causative factor of amyotrophic lateral sclerosis (ALS) and is believed to propagate pathologically by transmission from cell to cell. However, the mechanism underlying FUS release from cells, which is a critical step for the propagation system, remains poorly understood. This study conducted an analysis of the release of human and mouse FUS from neurons, revealing that human FUS is significantly released into the media compared to its mouse counterpart. Further study using chimeric FUS proteins identified the amino-terminal region of human FUS as essential for its release. These findings indicate that human FUS is released directly from neurons and underscore the novel functional role of its amino-terminal region in this process.}, } @article {pmid39736981, year = {2024}, author = {Zhang, Y and Li, N and Ge, Z and Li, F}, title = {Blood component therapy for dry eye disease: a systematic review and network meta-analysis.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1500160}, pmid = {39736981}, issn = {2296-858X}, abstract = {OBJECTIVE: Blood component therapy has shown promising potential as an emerging treatment for dry eye disease; however, it remains unclear which specific blood component is the most effective. This study aims to compare the efficacy of different blood components in the treatment of dry eye disease through a network meta-analysis, with the goal of providing the latest and most reliable evidence for clinical practice.

METHODS: We conducted a systematic search of the PubMed, Web of Science, Cochrane, Embase, and Scopus databases, with the search concluding on June 1, 2024. Two independent researchers performed literature screening, data extraction, and quality assessment.

RESULTS: A total of 16 randomized controlled trials (RCTs) involving 898 patients with dry eye disease were included. Six different blood components were utilized in treating dry eye disease, with platelet-rich plasma (PRP) being the most widely used. The results of the network meta-analysis indicated that platelet-rich plasma eye drops (PRPD) significantly outperformed artificial tears (AT) in improving the corneal fluorescein staining score (CFSS), while autologous serum (ALS) and umbilical cord serum (UCS) also demonstrated significantly better effects than AT in enhancing tear break-up time (TBUT). Additionally, ALS, PRP injection (PRPI), and PRPD showed significantly superior outcomes compared to AT in improving the ocular surface disease index (OSDI). However, no statistically significant differences were found among the various treatment modalities regarding their effects on Schirmer's I value, CFSS, TBUT, and OSDI. SUCRA analysis predicted that UCS was the most effective in improving Schirmer's I value and TBUT, while PRP excelled in enhancing CFSS and OSDI. Limitations such as publication bias and issues related to randomization, allocation concealment, and blinding may affect the reliability of the current findings.

CONCLUSION: Blood component therapy can significantly improve the pathological damage and ocular surface health in patients with dry eye disease. For those with aqueous-deficient dry eye, UCS may represent the optimal treatment option. In contrast, for patients with more severe corneal epithelial damage, PRP may offer a more effective therapeutic approach.

https://www.crd.york.ac.uk/PROSPERO/, CRD42024534091.}, } @article {pmid39736783, year = {2024}, author = {Zeng, J and Luo, C and Jiang, Y and Hu, T and Lin, B and Xie, Y and Lan, J and Miao, J}, title = {Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {205}, pmid = {39736783}, issn = {2051-5960}, support = {YNXM2024062//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; YNXM2024015//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; Animals ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43's crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43's involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein's propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington's disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein's central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions.}, } @article {pmid39735276, year = {2024}, author = {Moyana, TN}, title = {Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options.}, journal = {World journal of gastroenterology}, volume = {30}, number = {48}, pages = {5198-5204}, pmid = {39735276}, issn = {2219-2840}, mesh = {Humans ; *Small Cell Lung Carcinoma/therapy/secondary/pathology/diagnostic imaging ; *Stomach Neoplasms/pathology/therapy/diagnostic imaging ; *Lung Neoplasms/secondary/therapy/pathology/diagnostic imaging ; Prognosis ; Biomarkers, Tumor/analysis/metabolism ; Positron Emission Tomography Computed Tomography/methods ; Immune Checkpoint Inhibitors/therapeutic use ; Immunohistochemistry ; }, abstract = {Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.}, } @article {pmid39735081, year = {2024}, author = {Dost, W and Rasully, MQ and Zaman, MN and Dost, W and Ali, W and Ayobi, SA and Dost, R and Niazi, J and Bakht, K and Iqbal, A and Bokhari, SFH}, title = {Predictive Biomarkers for the Early Detection of Anastomotic Leaks in Colorectal Surgeries: A Systematic Review.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74616}, pmid = {39735081}, issn = {2168-8184}, abstract = {Anastomotic leaks (ALs) remain a serious postoperative complication in colorectal surgery, often resulting in significant morbidity, prolonged hospitalization, and increased mortality risk. This systematic review aims to evaluate the role of predictive biomarkers in the early detection of ALs, focusing on their diagnostic accuracy and clinical utility. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive literature search was conducted across MEDLINE, Scopus, CENTRAL, and Web of Science, identifying studies that examined biomarkers such as C-reactive protein (CRP), procalcitonin (PCT), and white blood cell (WBC) count in the context of AL. A total of 20 studies met the inclusion criteria, with sample sizes ranging from 59 to 2,655 patients undergoing colorectal surgeries with primary anastomosis. CRP emerged as the most widely studied and reliable biomarker, with studies suggesting that elevated CRP levels, particularly on postoperative days 3-4, can effectively indicate AL risk, showing high negative predictive value. PCT has also shown promise as a complementary biomarker, offering enhanced specificity for infectious complications. Although WBC count alone was a limited predictor, it may add diagnostic value when used with other markers. In addition, innovative biomarkers, such as inflammatory indices in peritoneal fluid, demonstrated potential for further improving AL detection accuracy.}, } @article {pmid39731449, year = {2024}, author = {Fabbrizio, P and Baindoor, S and Margotta, C and Su, J and Morrissey, EP and Woods, I and Hogg, MC and Vianello, S and Venø, MT and Kjems, J and Sorarù, G and Bendotti, C and Prehn, JHM and Nardo, G}, title = {Protective role of Angiogenin in muscle regeneration in amyotrophic lateral sclerosis: Diagnostic and therapeutic implications.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {}, number = {}, pages = {e13328}, doi = {10.1111/bpa.13328}, pmid = {39731449}, issn = {1750-3639}, support = {CUP E48I20000000007//Regione Lombardia/ ; 17/JPND/3455/SFI_/Science Foundation Ireland/Ireland ; 20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; 21/RC/10294_P2/SFI_/Science Foundation Ireland/Ireland ; //EU Joint Programme-Neurodegenerative Disease Research/ ; SG-2018-12366226//Ministero della Salute, Italy/ ; MUSALS-AChR//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 18/CRT/6214//Science Foundation Ireland CRT in Genomics Data Science/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease with no effective treatments, in part caused by variations in progression and the absence of biomarkers. Mice carrying the SOD1G93A transgene with different genetic backgrounds show variable disease rates, reflecting the diversity of patients. While extensive research has been done on the involvement of the central nervous system, the role of skeletal muscle remains underexplored. We examined the impact of angiogenin, including its RNase activity, in skeletal muscles of ALS mouse models and in biopsies from ALS patients. Elevated levels of angiogenin were found in slowly progressing mice but not in rapidly progressing mice, correlating with increased muscle regeneration and vascularisation. In patients, higher levels of angiogenin in skeletal muscles correlated with milder disease. Mechanistically, angiogenin promotes muscle regeneration and vascularisation through satellite cell-endothelial interactions during myogenesis and angiogenesis. Furthermore, specific angiogenin-derived tiRNAs were upregulated in slowly progressing mice, suggesting their role in mediating the effects of angiogenin. These findings highlight angiogenin and its tiRNAs as potential prognostic markers and therapeutic targets for ALS, offering avenues for patient stratification and interventions to mitigate disease progression by promoting muscle regeneration.}, } @article {pmid39731185, year = {2024}, author = {Itou, T and Fujita, K and Okuzono, Y and Warude, D and Miyakawa, S and Mihara, Y and Matsui, N and Morino, H and Kikukawa, Y and Izumi, Y}, title = {Th17 and effector CD8 T cells relate to disease progression in amyotrophic lateral sclerosis: a case control study.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {331}, pmid = {39731185}, issn = {1742-2094}, support = {NA//Takeda Pharmaceutical Company/ ; JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology ; Humans ; *Disease Progression ; Female ; *CD8-Positive T-Lymphocytes/immunology ; Middle Aged ; Male ; *Th17 Cells/immunology/metabolism ; Case-Control Studies ; Aged ; Adult ; }, abstract = {The immune system has garnered attention due to its association with disease progression in amyotrophic lateral sclerosis (ALS). However, the role of peripheral immune cells in this context remains controversial. Here, we conducted single-cell RNA-sequencing of peripheral blood mononuclear cells to comprehensively profile immune cells concerning the rate of disease progression in patients with ALS. Our analysis revealed increased frequencies of T helper 17 cells (Th17) relative to regulatory T cells, effector CD8 T cells relative to naïve CD8 T cells, and CD16[high]CD56[low] mature natural killer cells relative to CD16[low]CD56[high] naïve natural killer cells in patients with rapidly progressive ALS. Additionally, we employed serum proteomics through a proximity extension assay combined with next-generation sequencing to identify inflammation-related proteins associated with rapid disease progression. Among these proteins, interleukin-17 A correlated with the frequency of Th17, while killer cell lectin-like receptor D1 (CD94) correlated with the frequency of effector CD8 T cells. These findings further support the active roles played by these specific immune cell types in the progression of ALS.}, } @article {pmid39730482, year = {2024}, author = {Mitsi, E and Votsi, C and Koutsou, P and Georghiou, A and Christodoulou, CC and Kleopa, K and Zamba-Papanicolaou, E and Christodoulou, K and Nicolaou, P}, title = {Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30781}, pmid = {39730482}, issn = {2045-2322}, support = {73234//Telethon Cyprus/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Cyprus/epidemiology ; Female ; Middle Aged ; Aged ; *C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Genetic Predisposition to Disease ; Molecular Epidemiology ; DNA-Binding Proteins/genetics ; Adult ; RNA-Binding Protein FUS/genetics ; High-Throughput Nucleotide Sequencing ; Mutation ; Cohort Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. More than fifty genes carrying causative or disease-modifying variants have been identified since the 1990s, when the first ALS-associated variant in the gene SOD1 was discovered. The most commonly mutated ALS genes in the European populations include the C9orf72, SOD1, TARDBP and FUS. Understanding the genetic causes of ALS within a population is becoming more significant, especially in light of the possible development of personalized medicine. Here, we provide clinical and genetic data on familial and sporadic ALS patients in a Greek-Cypriot population-based cohort. Eighty-nine ALS patients, including 21 familial ALS (fALS) (23.6%) and 68 sporadic ALS (sALS) (76.4%), provided the cohort for variant screening of the most common ALS-associated genes. Moreover, next-generation sequencing (NGS) was also performed to identify rare ALS variants, and in silico prediction tools were applied to predict the downstream effect of the variants detected in our study. The pathogenic hexanucleotide G4C2 repeat expansion in C9orf72 was the predominant genetic cause (22.47%) of ALS in our population, while variants in six additional ALS-associated genes were identified, including ALS2, TARDBP, FIG4, TBK1, GLT8D1, and BICD2.}, } @article {pmid39729643, year = {2024}, author = {Meiling, JB and Caress, JB and Cartwright, MS}, title = {Ultra High-Frequency Ultrasound of Median Nerve Fascicles at the Wrist in Amyotrophic Lateral Sclerosis: An Exploratory Study.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {}, number = {}, pages = {}, doi = {10.1097/WNP.0000000000001136}, pmid = {39729643}, issn = {1537-1603}, abstract = {PURPOSE: High-frequency ultrasound (HFUS) of muscle and nerve has the potential to be a reliable, responsive, and informative biomarker of disease progression for individuals with amyotrophic lateral sclerosis (ALS). High-frequency ultrasound is not able to visualize median nerve fascicles to the same extent as ultra-high-frequency ultrasound (UHFUS). Evaluating the number and size of fascicles within a nerve may facilitate a better understanding of nerve diseases. This exploratory study aims to image median nerve fascicles at the wrist in individuals with ALS using UHFUS and compare these findings with those from previously observed controls.

METHODS: Fifteen individuals with ALS underwent sonographic examination of the median nerves on each upper limb using UHFUS with a 48-MHz linear array transducer. Fascicle count and density in each examined nerve were determined by a single rater. Demographic and sonographic data from 20 previously studied controls were compared.

RESULTS: In individuals with ALS, the average fascicle number was 22.4 (SD 5.2) and average fascicle density 1.7 (SD 0.5). There was no significant difference in fascicle counts between individuals with ALS and controls.

CONCLUSIONS: Fascicular quantification using UHFUS is possible in individuals with ALS. Given the lack of appreciable difference between fascicle counts in individuals with ALS and controls, UHFUS of the median nerve at the wrist may not be a responsive biomarker for ALS disease progression.}, } @article {pmid39728809, year = {2024}, author = {Al Haffar, M and Fajloun, Z and Azar, S and Sabatier, JM and Abi Khattar, Z}, title = {Lesser-Known Cyanotoxins: A Comprehensive Review of Their Health and Environmental Impacts.}, journal = {Toxins}, volume = {16}, number = {12}, pages = {}, pmid = {39728809}, issn = {2072-6651}, mesh = {Humans ; *Cyanobacteria/metabolism ; *Bacterial Toxins/toxicity ; Animals ; Harmful Algal Bloom ; Cyanobacteria Toxins ; Microcystins/toxicity ; }, abstract = {Cyanobacteria, also known as blue-green algae, are a diverse phylum of photosynthetic, Gram-negative bacteria and one of the largest microbial taxa. These organisms produce cyanotoxins, which are secondary metabolites that can have significant impacts on both human health and the environment. While toxins like Microcystins and Cylindrospermopsins are well-documented and have been extensively studied, other cyanotoxins, including those produced by Lyngbya and Nostoc, remain underexplored. These lesser-known toxins can cause various health issues in humans, including neurotoxicity, hepatotoxicity, and dermatotoxicity, each through distinct mechanisms. Moreover, recent studies have shown that cyanobacteria can be aerosolized and transmitted through the air over long distances, providing an additional route for human exposure to their harmful effects. However, it remains an area that requires much more investigation to accurately assess the health risks and develop appropriate public health guidelines. In addition to direct exposure to toxins, cyanobacteria can lead to harmful algal blooms, which pose further risks to human and wildlife health, and are a global concern. There is limited knowledge about these lesser-known cyanotoxins, highlighting the need for further research to understand their clinical manifestations and improve society's preparedness for the associated health risks. This work aims to review the existing literature on these underexplored cyanotoxins, which are associated with human intoxication, elucidate their clinical relevance, address significant challenges in cyanobacterial research, and provide guidance on mitigating their adverse effects.}, } @article {pmid39728753, year = {2024}, author = {Boziki, M and Theotokis, P and Kesidou, E and Nella, M and Bakirtzis, C and Karafoulidou, E and Tzitiridou-Chatzopoulou, M and Doulberis, M and Kazakos, E and Deretzi, G and Grigoriadis, N and Kountouras, J}, title = {Impact of Mast Cell Activation on Neurodegeneration: A Potential Role for Gut-Brain Axis and Helicobacter pylori Infection.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1750-1778}, pmid = {39728753}, issn = {2035-8385}, abstract = {BACKGROUND: The innate immune response aims to prevent pathogens from entering the organism and/or to facilitate pathogen clearance. Innate immune cells, such as macrophages, mast cells (MCs), natural killer cells and neutrophils, bear pattern recognition receptors and are thus able to recognize common molecular patterns, such as pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), the later occurring in the context of neuroinflammation. An inflammatory component in the pathology of otherwise "primary cerebrovascular and neurodegenerative" disease has recently been recognized and targeted as a means of therapeutic intervention. Activated MCs are multifunctional effector cells generated from hematopoietic stem cells that, together with dendritic cells, represent first-line immune defense mechanisms against pathogens and/or tissue destruction.

METHODS: This review aims to summarize evidence of MC implication in the pathogenesis of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis.

RESULTS: In view of recent evidence that the gut-brain axis may be implicated in the pathogenesis of neurodegenerative diseases and the characterization of the neuroinflammatory component in the pathology of these diseases, this review also focuses on MCs as potential mediators in the gut-brain axis bi-directional communication and the possible role of Helicobacter pylori, a gastric pathogen known to alter the gut-brain axis homeostasis towards local and systemic pro-inflammatory responses.

CONCLUSION: As MCs and Helicobacter pylori infection may offer targets of intervention with potential therapeutic implications for neurodegenerative disease, more clinical and translational evidence is needed to elucidate this field.}, } @article {pmid39728018, year = {2024}, author = {Jeyarajan, S and Ranjith, S and Veerapandian, R and Natarajaseenivasan, K and Chidambaram, P and Kumarasamy, A}, title = {Antibiofilm Activity of Epinecidin-1 and Its Variants Against Drug-Resistant Candida krusei and Candida tropicalis Isolates from Vaginal Candidiasis Patients.}, journal = {Infectious disease reports}, volume = {16}, number = {6}, pages = {1214-1229}, pmid = {39728018}, issn = {2036-7430}, support = {BT/PR2071/BBE/117/241/2016//Department of Biotechnology, India/ ; 311/RUSA(2.0)/2018//RUSA 2.0 Biological Sciences/ ; 01706/P6/2021//Tamil Nadu State Council for Higher Education (TANSCHE)/ ; ICMR-NET- 61754/2010//Indian Council of Medical Research/ ; }, abstract = {Background/Objective: Indwelling intrauterine contraceptive devices (IUDs) have surfaces that facilitate the attachment of Candida spp., creating a suitable environment for biofilm formation. Due to this, vulvovaginal candidiasis (VVC) is frequently linked to IUD usage, necessitating the prompt removal of these devices for effective treatment. In this study, we evaluated the susceptibility of antimicrobial peptides in vitro against biofilm forming, Amphotericin B (MIC50 > 2 mg L[-1]) resistant Candida krusei and Candida tropicalis isolated from IUD users who had signs of vaginal candidiasis (hemorrhage, pelvic pain, inflammation, itching, and vaginal discharge). Three antimicrobial peptides, namely, epinecidin-1 (epi-1) and its two variants, namely, variant-1 (Var-1) and variant-2 (Var-2), which were reported to have enhanced antibacterial activity were tested against IUD isolates (C. krusei and C. tropicalis) with pathogenic form of Candida albicans as control. Variants of epi-1, namely, Var-1 and Var-2 were created by substituting lysine in the place of histidine and alanine. Methods: The antimicrobial activity was measured using the microbroth dilution method to determine the minimum inhibitory concentration (MIC) of peptides against C. albicans, C. krusei and C. tropicalis. The MIC of each peptide was used for biofilm assay by Crystal violet staining, Scanning Electron Microscopy, and Reactive Oxygen Species (ROS) assay. To find the possible mechanism of anti-biofilm activity by the peptides, their ability to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2 were determined through PatchDock. Results: The MIC values of peptides: epi-1, var-1 and var-2 against C. albicans are 128 μg mL[-1], 64 μg mL[-1] and 32 μg mL[-1], C. tropicalis are 256 μg mL[-1], 64 μg mL[-1,] and 32 μg mL[-1] and C. krusei are 128 µg mL[-1], 128 µg mL[-1] and 64 µg mL[-1], respectively. Both the variants outperformed epi-1. Specifically for tested Candida spp., var-1 showed two- to four-fold enhancements and var-2 showed two- to eight-fold enhancements compared to epi-1. Electron microscopy confirmed that the mechanism of action involves pore formation thus inducing reactive oxygen species in Candida spp. cell membrane. Computational analysis showed that the peptides have a high tendency to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2, thereby preventing biofilm formation. Conclusions: The in vitro evidence supports the potential use of epi-1 and its variants to be used as an anti-biofilm agent to coat IUDs in the future for therapeutic purposes.}, } @article {pmid39727843, year = {2024}, author = {An, J and Gopalakrishnan, L and Ortega, V and Saul, J and Kadali, R and Bowser, R}, title = {Development of a Sensitive and Reliable Meso Scale Discovery-Based Electrochemiluminescence Immunoassay to Quantify TDP-43 in Human Biofluids.}, journal = {Biosensors}, volume = {14}, number = {12}, pages = {}, pmid = {39727843}, issn = {2079-6374}, support = {Development of TDP-43 Immunoassays//Target ALS/ ; }, mesh = {Humans ; Immunoassay ; *DNA-Binding Proteins/metabolism ; Amyotrophic Lateral Sclerosis/diagnosis ; Luminescent Measurements ; Biomarkers/blood ; Reproducibility of Results ; Electrochemical Techniques ; Biosensing Techniques ; Limit of Detection ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) is a major component of pathological inclusions in various neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The detection of TDP-43 in biofluids is crucial for the development of diagnostic and prognostic indicators of disease and therapeutic development for TDP-43-related proteinopathies. Despite its potential as a biomarker for numerous neurological disorders, the lack of a sensitive and reproducible TDP-43 assay hinders progress in TDP-43-based therapy development, underscoring the need for an effective and standardized method for accurate quantification. Addressing the limitations of sensitivity and reproducibility in existing assays, in this study, we developed and validated a highly sensitive electrochemiluminescence immunoassay on the Meso Scale Discovery platform. The assay demonstrated the detection of full-length TDP-43 in human biofluids with a limit of detection of 4pg/mL, a working range of 4-20,000 pg/mL, and a total assay time of 16 h. In this study, we developed and validated a sensitive immunoassay for the detection of full-length TDP-43 in human biofluids using the Meso Scale Discovery platform. We used this immunoassay to quantify TDP-43 levels in the plasma and serum of healthy controls and ALS patients. Our results indicate a reduction in full-length TDP-43 in the blood of ALS patients compared to healthy controls.}, } @article {pmid39726289, year = {2024}, author = {Kollstrøm, AM and Christiansen, N and Sandvig, A and Sandvig, I}, title = {Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons.}, journal = {American journal of physiology. Cell physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajpcell.00725.2024}, pmid = {39726289}, issn = {1522-1563}, support = {//Alf Harborgs fund/ ; //Olav Thon Stiftelsen (Olav Thon Foundation)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper and lower motor neurons. Several studies have identified structural and functional alterations in the motor neurons before the manifestation of symptoms, yet the underlying cause of such alterations and how they contribute to the progressive degeneration of affected motor neuron networks remain unclear. Importantly, the short and long-term spatiotemporal dynamics of neuronal network activity make it challenging to discern how ALS-related network reconfigurations emerge and evolve. To address this, we systematically monitored the structural and functional dynamics of motor neuron networks with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived motor neurons display time-dependent neural network dysfunction, specifically reduced firing rate and spike amplitude, impaired bursting, but higher overall synchrony in network activity. These changes coincided with altered neurite outgrowth and branching within the networks. Moreover, transcriptional analyses revealed dysregulation of molecular pathways involved in synaptic development and maintenance, neurite outgrowth and cell adhesion, suggesting impaired synaptic stabilization. This study identifies early synaptic dysfunction as a contributing mechanism resulting in network-wide structural and functional compensation, which may over time render the networks vulnerable to neurodegeneration.}, } @article {pmid39725771, year = {2024}, author = {Pagliari, E and Taiana, M and Manzini, P and Sali, L and Quetti, L and Bertolasi, L and Oldoni, S and Melzi, V and Comi, G and Corti, S and Nizzardo, M and Rizzo, F}, title = {Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {29}, pmid = {39725771}, issn = {1420-9071}, support = {Craiplo Grant 2020-3623//Fondazione Cariplo/ ; 22739//SMA Europe Grant/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Muscular Atrophy, Spinal/therapy/genetics/pathology/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Neuromuscular Junction/metabolism/pathology ; Neuroprotection ; Dependovirus/genetics ; Genetic Therapy/methods ; }, abstract = {The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment.}, } @article {pmid39724103, year = {2024}, author = {Garcia-Toscano, L and Currey, HN and Hincks, JC and Stair, JG and Lehrbach, NJ and Liachko, NF}, title = {Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011518}, pmid = {39724103}, issn = {1553-7404}, support = {I01 BX004044/BX/BLRD VA/United States ; P40 OD010440/OD/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *HSP90 Heat-Shock Proteins/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Humans ; Phosphorylation ; Mutation ; Heat-Shock Response/genetics ; TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.}, } @article {pmid39722698, year = {2024}, author = {Jiao, L and Yang, J and Wang, W and Liu, X and Fu, Y and Fan, D}, title = {sTREM2 cerebrospinal fluid levels are a potential biomarker in amyotrophic lateral sclerosis and associate with UMN burden.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1515252}, pmid = {39722698}, issn = {1664-2295}, abstract = {OBJECTIVES: The aims of this study were to investigate whether CSF sTREM2 may be a potential marker of disease monitoring for amyotrophic lateral sclerosis (ALS).

METHODS: We investigated whether CSF sTREM2 levels are altered in ALS patients and are correlated with upper motor neuron (UMN) burden and disease progression.

RESULTS: CSF sTREM2 was greater in the ALS patients than in the controls (p = 0.002). Elevated CSF sTREM2 was associated with the UMN score (r = 0.38, p = 0.009), ΔFS (r = 0.30, p = 0.04) and serum NFL (lg) (r = 0.35, p = 0.015). As the motor band sign (MBS) score increased, the CSF sTREM2 level increased (p-trend = 0.014). Furthermore, the correlations became stronger (UMN score (r = 0.50, p = 0.01) ΔFRS (r = 0.52, p = 0.008) and serum NFL (lg) (r = 0.55, p = 0.004) when estimated only among patients with a disease duration >12 months.

CONCLUSION: We found that CSF sTREM2 is elevated in ALS patients and may be a novel marker, probably reflecting upper motor unit severity and prognosis.}, } @article {pmid39722495, year = {2024}, author = {García-Ramírez, Y and Cayuela-Fuentes, JM and Mira-Escolano, MP and Maceda-Roldán, LA and Mikulasova, E and Oliva-López, C and Sánchez-Escámez, A and Ciller-Montoya, P and Palomar-Rodríguez, JA}, title = {Characterization, epidemiology, and factors associated with evolution and survival in patients with amyotrophic lateral sclerosis in southeastern Spain, 2008-2021: a population-based study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2024.2439454}, pmid = {39722495}, issn = {2167-9223}, abstract = {OBJECTIVE: To describe the epidemiology, characteristics, and factors associated with the evolution and survival in patients with amyotrophic lateral sclerosis (ALS) in a region of southeastern Spain.

METHODS: An observational study was carried out in people with a diagnosis of ALS in the period 2008-2021 who were registered in the Information System of Rare Diseases of the Region of Murcia (SIER). We calculated crude and standardized incidence rate (SIR) using European Standard Population of 2013 and point prevalence. The Kaplan-Meier method and the log-rank test were used to estimate and compare survival curves.

RESULTS: We identified 374 cases. The mean age at diagnosis was 66.5 ± 11.7 and 50.3% persons were spinal onset. Mean time from the onset of symptoms to diagnosis was 0.9 ± 1.0 years. The global SIR was 1.95/100,000 person-years (95%CI: 1.77-2.12), which was higher in men (ratio 1.34), and the point prevalence in 2021 was 4.57 per 100,000 (95% CI: 4.46-4.68). There were 297 deaths with a mean age of 69.8 ± 10.8. The median survival from clinical onset was 2 years (95%CI: 1.0-3.0). Factors associated with lower survival were bulbar onset (p < 0.001), older age at the onset of symptoms (p < 0.001), and the absence of riluzole treatment (p = 0.003).

CONCLUSIONS: This study is one of few to evaluate the epidemiological, characteristics, and prognostic factors of ALS in Spain, with findings similar to previous population studies. The use of population-based registries offers reliable information on the magnitude, or evolution in these patients.}, } @article {pmid39722149, year = {2024}, author = {Simão, S and Naumann, LL and de Carvalho, M and Santos, MO and Martins, IP}, title = {Adaptation and Validation of Version B of the Edinburgh Cognitive and Behavioural ALS Screen for the Portuguese Population.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {}, number = {}, pages = {}, doi = {10.1093/arclin/acae118}, pmid = {39722149}, issn = {1873-5843}, support = {GA101017598//European Union's Horizon 2020/ ; }, abstract = {OBJECTIVE: This study aims to adapt and provide psychometric support for the validation of version B of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) for the Portuguese population, addressing the need for consistent cognitive evaluations in amyotrophic lateral sclerosis (ALS). A second culturally adapted ECAS screen facilitates the accurate characterization of ALS progression, mitigates learning effects, and supports tailored care management.

METHODS: The adaptation process included forward-backward translation, cultural adaptation, and cognitive debriefing on a prospective sample of 193 ALS patients and 106 controls. A multiple regression analysis identified predictors relevant for establishing ECAS cut-off scores. Psychometric evaluations, including reliability assessments and tests of convergent, construct, and criterion validity, were conducted. Additionally, version A's psychometric properties were reevaluated with complementary analyses and a larger sample.

RESULTS: Version B demonstrated good internal consistency with Cronbach's alpha of 0.802, comparable to the previously established version A. Moderate inter-item correlations further supported reliability, reflecting internal coherence. Equivalence testing between the Portuguese versions supported convergent validity, confirming version B's alignment with version A's theoretical framework. Exploratory factor analysis provided preliminary support for construct validity, and receiver operating characteristic analyses established cut-off values for both versions, revealing moderate sensitivity with a tendency toward false negatives, and higher specificity.

CONCLUSIONS: This study provided evidence for the cultural suitability, reliability, and validity of the Portuguese ECAS B. As evidence supports the equivalence of the Portuguese ECAS versions, they can be used for flexible screenings and applied with the calculated cut-off values to enhance diagnostic accuracy.}, } @article {pmid39722074, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {203}, pmid = {39722074}, issn = {2051-5960}, support = {R35 NS132179/NS/NINDS NIH HHS/United States ; R01 5R35NS132179/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Mice ; *Mice, Transgenic ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Dependovirus/genetics ; Humans ; Male ; Behavior, Animal/physiology ; Mice, Inbred C57BL ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39721808, year = {2024}, author = {Almukhlifi, Y and Crowfoot, G and Hutton, A}, title = {Barriers and Facilitators Toward Disaster Knowledge, Skills, and Preparedness among Emergency Medical Services in Saudi Arabia.}, journal = {Prehospital and disaster medicine}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/S1049023X24000670}, pmid = {39721808}, issn = {1945-1938}, abstract = {INTRODUCTION: Disasters pose significant challenges globally, affecting millions of people annually. In Saudi Arabia, floods constitute a prevalent natural disaster, underscoring the necessity for effective disaster preparedness among Emergency Medical Services (EMS) workers. Despite their critical role in disaster response, research on disaster preparedness among EMS workers in Saudi Arabia is limited.

STUDY OBJECTIVE/METHODS: The study aimed to explore the disaster preparedness among EMS workers in Saudi Arabia. This study applied an explanatory sequential mixed-methods design to explore disaster preparedness among EMS workers in Saudi Arabia, focusing on the qualitative phase. Semi-structured interviews were conducted with 15 EMS workers from National Guard Health Affairs (NGHA) and Ministry of Health (MOH) facilities in Riyadh, Dammam, and Jeddah. Thematic analysis was conducted following Braun and Clarke's six-step process, ensuring data rigor through Schwandt, et al's criteria for trustworthiness.

FINDINGS: The demographic characteristics of participants revealed a predominantly young, male workforce with varying levels of experience and educational backgrounds. Thematic analysis identified three key themes: (1) Newly/developed profession, highlighting the challenges faced by young EMS workers in acquiring disaster preparedness; (2) Access to opportunities and workplace resources (government versus military), indicating discrepancies in disaster preparedness support between government and military hospitals; and (3) Workplace policies and procedures, highlighting the need for clearer disaster policies, training opportunities, and role clarity among EMS workers.

CONCLUSION: The study underscores the importance of addressing the unique challenges faced by EMS workers in Saudi Arabia to enhance disaster preparedness. Recommendations include targeted support for young EMS professionals, standardization of disaster training across health care facilities, and improved communication of disaster policies and procedures. These findings have implications for policy and practice in disaster management and EMS training in Saudi Arabia.}, } @article {pmid39720511, year = {2024}, author = {Terao, SI and Nosaki, Y and Murao, A and Torii, R and Ogawa, N and Miura, N and Sasaki, Y and Sobue, G}, title = {Onset of age, site and respiratory symptoms are strongly associated with respiratory decline in sporadic amyotrophic lateral sclerosis: a long-term longitudinal study.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000829}, pmid = {39720511}, issn = {2632-6140}, abstract = {OBJECTIVE: The objective of this study is to identify factors influencing progression of respiratory decline from the onset of neurological symptoms to respiratory failure in patients with amyotrophic lateral sclerosis (ALS).

METHODS: In 100 patients with sporadic ALS, %vital capacity (%VC) was continuously measured from the first visit to the respiratory endpoint (REP). Cox proportional hazards model identified factors influencing the duration from onset of ALS to REP (Onset-REP). We performed Kaplan-Meier survival curve analysis for onset-REP according to identified factors.

RESULTS: Onset sites were the upper limb (U-ALS), lower limb (L-ALS), bulbar paralysis (B-ALS) and respiratory paralysis (R-ALS) in 37, 19, 32 and 12 patients, respectively. Duration from the onset of ALS to the onset of respiratory symptoms (Onset-Rp) and REP (Onset-REP) was 16.1 (SD 12.1) and 24.9 months (SD 14.6), respectively. Multivariate analysis revealed that age at onset, site of onset, Onset-Rp and %VC decline rate significantly influenced Onset-REP duration. Elderly patients had a significantly shorter Onset-REP duration. Onset-REP duration did not significantly differ between patients with U-ALS and L-ALS, but was longer in these patients than in those with B-ALS and R-ALS. Onset-REP duration was positively associated with Onset-Rp duration. The average monthly %VC decline rate was -5.6% (SD 3.3). Age at onset, onset site and Onset-Rp duration significantly influenced the %VC decline rate.

CONCLUSIONS: Our findings revealed strong and independent patient-specific factors that influence the Onset-REP duration and the %VC decline rate in patients with ALS. These could inform future clinical trials and interventions considering the respiratory function and natural history of patients with ALS.}, } @article {pmid39720419, year = {2024}, author = {Haikal, C and Weissert, R}, title = {Editorial: Aging, peripheral inflammation, and neurodegeneration.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1529026}, pmid = {39720419}, issn = {1663-4365}, } @article {pmid39719859, year = {2024}, author = {Koumasopoulos, E and Stanitsa, E and Angelopoulou, E and Koros, C and Barbarousi, V and Velonakis, G and Michaletou, C and Alevetsovitis, SK and Constantinides, VC and Kyrozis, A and Stefanis, L and Kroupis, C and Papageorgiou, SG}, title = {Heterozygous p62/SQSTM1 mutation and right temporal variant of frontotemporal dementia: Α case report.}, journal = {Neurocase}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/13554794.2024.2446315}, pmid = {39719859}, issn = {1465-3656}, abstract = {Mutations in sequestosome 1 (SQSTM1) gene have been associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia - ALS (FTD-ALS), and very recently, progressive supranuclear palsy (PSP), paget disease of bone (PDB), distal myopathy with rimmed vacuoles (DMRV), and neurodegenerative disorders in childhood. We present a case of right temporal variant of FTD (rtvFTD) with heterozygous mutation (c.823_824del(p.Ser275Phefs *17)) in SQSTM1 gene.}, } @article {pmid39719601, year = {2024}, author = {Kelani, KM and Hegazy, MA and Hassan, AM and Nadim, AH}, title = {Ecological multivariate assisted spectrophotometric methods for determination of antipyrine and benzocaine HCl in presence of antipyrine official impurity and benzocaine HCl degradant: toward greenness and whiteness.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {250}, pmid = {39719601}, issn = {2661-801X}, abstract = {A simple and green chemometrics-assisted spectrophotometric technique has beendeveloped and validated for the determination of antipyrine (ANT) and benzocaine HCl (BEN) along with the official impurity of ANT, antipyrine impurity A (ANT imp-A), and the degradation product of BEN, p-amino benzoic acid (PABA), in their quaternary mixture. Three models were developed and compared: partial least squares (PLS), artificial neural networks (ANN), and multivariate curve resolution-alternating least squares (MCR-ALS) where the four studied drugs were successfully quantified. The quantitative determination of the studied drugs was assessed using percentage recoveries, standard errors of prediction, and root mean square errors of prediction. The ANN model demonstrated the lowest error and the best correlation making it the most accurate method for analysis. The models were constructed in the ranges of 5.0-9.0 µg mL[-1] for ANT, 1.0-5.0 µg mL[-1] for BEN, 0.5-2.5 µg mL[-1] for ANT imp-A, and 0.25-1.25 µg mL[-1] for PABA. The established models successfully determined ANT, BEN, ANT imp-A, and PABA with detection limits of 0.312, 0.178, 0.093, and 0.042 µg mL[-1] for PLS, 0.185, 0.085, 0.001, and 0.034 µg mL[-1] for ANN; and 0.473, 0.240, 0.073, and 0.069 µg mL[-1] for MCR-ALS, respectively. The greenness and the whiteness of the proposed method were assessed using two green evaluating approaches: analytical Eco-scale, and AGREE, along with one white analytical chemistry evaluating tool, RGB. The three proposed models were successfully applied for determination of ANT and BEN in their pharmaceutically co-formulated dosage forms. They are also recommended for stability assays and purity testing of these drugs in quality control laboratories.}, } @article {pmid39719207, year = {2024}, author = {Jirström, E and Matveeva, A and Baindoor, S and Donovan, P and Ma, Q and Morrissey, EP and Arijs, I and Boeckx, B and Lambrechts, D and Garcia-Munoz, A and Dillon, ET and Wynne, K and Ying, Z and Matallanas, D and Hogg, MC and Prehn, JHM}, title = {Effects of ALS-associated 5'tiRNA[Gly-GCC] on the transcriptomic and proteomic profile of primary neurons in vitro.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115128}, doi = {10.1016/j.expneurol.2024.115128}, pmid = {39719207}, issn = {1090-2430}, abstract = {tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5'tiRNA[Gly-GCC], which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5'tiRNA[Gly-GCC] revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5'tiRNA[Gly-GCC] binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5'tiRNA[Gly-GCC] is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.}, } @article {pmid39718981, year = {2024}, author = {Chen, JQA and McNamara, NB and Engelenburg, HJ and Jongejan, A and Wever, DD and Hopman, K and van Rixel, E and Nijhuis, PJH and de Winter, F and Moerland, PD and Smolders, J and Verhaagen, J and Hamann, J and Huitinga, I}, title = {Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae414}, pmid = {39718981}, issn = {1460-2156}, abstract = {Multiple sclerosis (MS) is a highly heterogeneous disease with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies. To elucidate distinct molecular signatures underlying the potential to remyelinate, we stratified MS donors from the Netherlands Brain Bank cohort (n=239) based on proportions of remyelinated lesions (RLs) into efficiently remyelinating donors (ERDs; n=21) and poorly remyelinating donors (PRDs; n=19). We performed bulk RNA sequencing of RLs, active lesions with ramified and amoeboid microglia/macrophage morphology (ALs non-foamy), active lesions with foamy microglia/macrophage morphology (ALs foamy), and normal-appearing white matter (NAWM) from ERDs and PRDs. We found that ALs non-foamy were positively correlated with remyelination, whereas ALs foamy were not, indicating a role for microglia/macrophage state in influencing remyelination potential. Bioinformatics analyses were performed to identify key pathways and molecules implicated in the remyelination process. We found distinct differences between the donors with differing remyelination potential in comparable MS lesion types. RLs and ALs non-foamy of ERDs versus PRDs showed upregulation of epithelial-mesenchymal transition pathway, while in ALs foamy of PRDs, inflammation and damage-associated pathways (i.e. MTORC1 signaling, TNF signaling and oxidative phosphorylation) were upregulated compared to ALs foamy of ERDs, suggesting that these latter pathways may counteract remyelination. We found genes significantly upregulated in RLs and/or ALs non-foamy of ERDs that have previously been associated with remyelination, including CXCL12, EGF, HGF, IGF2, IL10, PDGFB, PPARG, and TREM2, illustrating the strength of our donor and lesion stratification. TGFB1, TGFB2, EGF, and IGF1 were determined as key upstream regulators of genes upregulated in RLs and ALs non-foamy of ERDs. We further identified potential novel pro-remyelinating molecules, such as BTC, GDF10, GDF15, CCN1, CCN4, FGF5, FGF10, and INHBB. Our study identified both known and novel genes associated with efficient remyelination that may facilitate the development of therapeutic strategies to promote tissue repair and clinical recovery in MS.}, } @article {pmid39718871, year = {2025}, author = {Jiang, W and Hua, L and Chakraborty, S}, title = {Degenerate phase-matching for multi-wavelength nonlinear mixing in aperiodic lattice lasers.}, journal = {Optics letters}, volume = {50}, number = {1}, pages = {133-136}, doi = {10.1364/OL.544664}, pmid = {39718871}, issn = {1539-4794}, abstract = {Holographically designed aperiodic lattices (ALs) have proven to be an exciting engineering technique for achieving electrically switchable single- or multi-frequency emissions in terahertz (THz) semiconductor lasers. Here, we employ the nonlinear transfer matrix modeling method to investigate multi-wavelength nonlinear (sum- or difference-) frequency generation within an integrated THz (idler) laser cavity that also supports optical (pump and signal) waves. The laser cavity includes an aperiodic lattice, which engineers the idler photon lifetimes and effective refractive indices. The key findings are the following: (i) the nonlinear conversion efficiency reveals resonant enhancement at those idler frequencies where the photon lifetime is high; (ii) the resonant phase-matching (PM) process between the pump and idler waves has a one-to-one link with the engineered effective index dispersion; and (iii) in the absence of any other dispersion, the lowest threshold, multi-wavelength defect modes of the aperiodic lattice laser have degenerate phase-matched pump frequencies. This set of results will potentially have a significant impact on the wavelength multiplexing in electronically switchable THz-over-fiber communication systems [U.S. patent application 20,150,248,047A1 (3 September 2015)].}, } @article {pmid39718201, year = {2025}, author = {}, title = {Correction to "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis" J. D. Berry , S. Paganoni , M. B. Harms , et al., "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis," Muscle & Nerve 70, no. 6 (2024): 1140-1150, https://doi.org/10.1002/mus.28244.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {280}, doi = {10.1002/mus.28317}, pmid = {39718201}, issn = {1097-4598}, } @article {pmid39717968, year = {2024}, author = {Vergini, DE and Hadjipavlou-Litina, D}, title = {"A patent review on arachidonic acid lipoxygenase (LOX) inhibitors for the treatment of neurodegenerative diseases (2018-present)".}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2024.2447067}, pmid = {39717968}, issn = {1744-7674}, abstract = {INTRODUCTION: Neuroinflammation is correlated to neurodegenerative diseases like Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington Disease (HD), and Parkinson's disease (PD). A lot of recent research and patents are focused on the design and synthesis of arachidonic acid lipoxygenase (ALOX) inhibitors for the treatment of neurodegenerative diseases.

AREAS COVERED: The survey covers natural products, synthesis, hybrids, and assessments of biological effects in biological studies as ALOX inhibitors. A survey of patent publications from 2018 to present, taken from Google Scholar, Espanet, Web of Science, Drugbank, Scopus, or PubMed is analyzed.

EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability, and drug-likeness, the mechanism of action in different animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic method outbalance in the discovery and production of ALOX inhibitors with greater selectivity. Several ALOX inhibitors show promising results for the treatment of neurological disorders. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action and their bioavailability are well defined can be used as lead compounds for the treatment of neurodegenerative diseases.}, } @article {pmid39717315, year = {2024}, author = {Alhayali, M}, title = {Concomitant Amyotrophic Lateral Sclerosis and Rheumatoid Arthritis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74301}, pmid = {39717315}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease that leads to a gradual loss of motor neurons manifesting as progressive weakness, dysarthria, and respiratory decline, with a relatively short life expectancy. Rheumatoid arthritis (RA) is an autoimmune disorder characterized by polyarthritis and affects multiple systems. Motor neuron involvement is rare in rheumatoid arthritis. Here, we report a unique case of a patient with an established diagnosis of ALS who later developed seropositive RA. A 58-year-old male from Baghdad presented to our center with polyarticular joint pain, stiffness, and swelling for about four months, the patient had a history of progressive neurological deficits. The final diagnosis was seropositive rheumatoid arthritis with concomitant amyotrophic lateral sclerosis. While the patient's joint symptoms responded well to methotrexate and prednisolone, he continued to experience a neurological decline. This is one of the few reported cases of concurrent ALS and RA, highlighting the complexity of managing overlapping neurodegenerative and autoimmune conditions.}, } @article {pmid39715603, year = {2024}, author = {Dibling, M and Ortholand, J and Salachas, F and Hesters, A and Tezenas du Montcel, S}, title = {Care pathway heterogeneity in Amyotrophic Lateral Sclerosis: effects of gender, age and onset.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-22}, doi = {10.1159/000542300}, pmid = {39715603}, issn = {1423-0208}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration resulting in loss of muscle function. Care management is restricted to symptomatic and palliative strategies, while clinical manifestations are heterogeneous. However, assessing the timing and benefits of ALS major clinical interventions remains challenging, with varying and nonspecific time-to-events estimates reported in the literature. Consequently, we proposed a retrospective cohort study leveraging healthcare system data to investigate ALS patients care pathway stratified by gender, age class and onset site to describe strategies diversity and temporality.

METHODS: We developed an algorithm to identify incident ALS patients in the French hospitalization registry and assessed its quality through comparison with literature. We described 7 states, encompassing patient status regarding clinical intervention history, considered 15 transitions and stratified the analysis depending on 12 different patient profiles, defined according to gender, the presence of symptoms indicative of disease onset site and age class, to model profile-specific care pathway trajectories. Alongside analysis of median time before transition, we compared acceleration factors resulting from Accelerated Failure Time (AFT) and time-inhomogeneous models.

RESULTS: We identified 21,153 incident patients with ALS between 2013 and 2022 with a mean age of 67.7±13.1 years at time of in-registry detection, male/female and spinal/bulbar ratios of 1.2 and 1.9, respectively. Non-invasive ventilation (NIV), gastrostomy, tracheostomy or death at hospital was recorded for 55.24% of the study population. We identified significant variations in utilization based on gender, age class, and onset site. Notably, older age and bulbar onset site accelerated gastrostomy use and spinal onset site was associated with delayed NIV initiation while tracheostomy, mainly considered for younger patients (<64 years), is rarely indicated in ALS care management. Alongside investigation of time-to-event speed, we report extensively the patient profile-specific estimated median delay before clinical event start.

CONCLUSION: Leveraging real-world data from hospital registries provides a large sample size to investigate low prevalence diseases. In conjunction with multi-state models such data enables a comprehensive analysis of care pathways which revealed variations in ALS management strategies based on patient profiles. By identifying these disparities, our study contributes to enhancing the foreseeability of support strategies for ALS patients.}, } @article {pmid39715100, year = {2024}, author = {Wu, Y and Tian, X and Ma, J and Lin, Y and Ye, J and Wang, Y and Lu, J and Yin, W}, title = {Label-free discrimination analysis of breast cancer tumor and adjacent tissues of patients after neoadjuvant treatment using Raman spectroscopy: a diagnostic study.}, journal = {International journal of surgery (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/JS9.0000000000002201}, pmid = {39715100}, issn = {1743-9159}, abstract = {BACKGROUND AND OBJECTIVE: Breast-conserving surgery (BCS) plays a crucial role in breast cancer treatment, with a primary focus on ensuring cancer-free surgical margins, particularly for patients undergoing neoadjuvant treatment. After neoadjuvant treatment, tumor regression can complicate the differentiation between breast cancer and adjacent tissues. Raman spectroscopy, as a rapid and non-invasive optical technique, offers the advantage of providing detailed biochemical information and molecular signatures of internal molecular components in tissue samples. Despite its potential, there is currently no research on using label-free Raman spectroscopy to distinguish between breast cancer tumors and adjacent tissues after neoadjuvant treatment. This study intends to distinguish between cancer and adjacent tissues after neoadjuvant treatment in breast cancer through label-free Raman spectroscopy.

METHODS: In this study, the intraoperative frozen samples of breast cancer tumor and adjacent tissue were collected from patients who underwent neoadjuvant treatment during surgery. The samples were examined using Raman confocal microscopy, and Raman spectra were collected by LabSpec6 software. Spectra were preprocessed by Savitz-Golay filter, adaptive iterative reweighted penalized least squares and MinMax normalization method. The differences in Raman spectra between breast cancer tumor and adjacent tissues after neoadjuvant treatment were analyzed by Wilcoxon rank-sum test, with a Bonferroni correction for multiple comparisons. Based on the support vector machine (SVM) method in machine learning, a predictive model for classification was established in the total group and subgroups of different hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status and Ki-67 expression level. The independent test set was used to evaluate the performance of the model, and the area under curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy of different models were obtained.

RESULT: This study comprised 4260 Raman spectra of breast cancer tumor and adjacent frozen tissue samples from 142 breast cancer patients treated with neoadjuvant treatment. The Raman peaks associated with nucleotides and their metabolites in the Raman spectra of breast cancer tumor tissues were higher in intensities than those of adjacent tissues after neoadjuvant therapy (676 cm-1: Bonferroni adjusted P < 0.0001; 724 cm-1: P < 0.0001; 754 cm-1: P < 0.0001), and the Raman peaks from amide III bands were more intense (1271 cm-1: P < 0.01). Multivariate curve resolution- alternating least squares (MCR-ALS) decomposition of Raman spectra revealed reduced lipid content and increased collagen and nucleic acid content in breast cancer tumor tissues compared to adjacent tissues following neoadjuvant therapy. The predictive model based on the Raman spectral signature of breast cancer tumor and adjacent tissues after neoadjuvant treatment achieved an AUC of 0.98, with accuracy, sensitivity, and specificity values of 0.89, 0.97, and 0.83, respectively. The AUC of subgroup analysis according to different status of molecular pathological biomarkers was stably around 99%.

CONCLUSION: This study demonstrated that label-free Raman spectroscopy can differentiate cancer and adjacent tissues of breast cancer patients treated with neoadjuvant therapy thorough getting the panoramic perspective of the biochemical compounds for the first time. Our study provided a novel technique for determining the margin status in BCS in breast cancer following neoadjuvant treatment rapidly and precisely.}, } @article {pmid39715090, year = {2025}, author = {Huggon, L and Clayton, EL}, title = {Beginning from the end: the presynaptic terminal as a pathomechanism hub in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3217-3218}, doi = {10.4103/NRR.NRR-D-24-00639}, pmid = {39715090}, issn = {1673-5374}, } @article {pmid39714593, year = {2024}, author = {Eldeeb, MA and Hohman, G and Shahid, M}, title = {Novel Approaches in Targeting Cell Surface and Secreted Proteins for Lysosomal Degradation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {e202400887}, doi = {10.1002/cbic.202400887}, pmid = {39714593}, issn = {1439-7633}, abstract = {Protein degradation is pivotal for all biochemical aspects of cellular function. In mammalian cells, protein degradation is mediated mainly by the ubiquitin proteasome system (UPS) and the autophagic-lysosomal system (ALS). Over the last two decades, different types of targeted protein degradation approaches have been developed including proteolysis targeting chimeras (PROTACs) and lysosome targeting chimeras (LYTACs), which employ the UPS to degrade intracellular proteins and the ALS to degrade extracellular and membrane proteins respectively. Nevertheless, Current targeted membrane protein degradation approaches face some inherent challenges including limited target protein degradation efficacy and cell type specific applicability. Herein, we highlight some recent developments of novel targeted membrane protein degradation modalities that exhibit wide-applicability and high protein degradation efficiency. These novel membrane protein degraders hold tremendous promise as new pharmacological and biochemical tools in targeting membrane and secretory proteins for lysosomal degradation.}, } @article {pmid39713159, year = {2024}, author = {Wang, YB and Jin, CZ}, title = {Roles of traditional Chinese medicine extracts in hyperuricemia and gout treatment: Mechanisms and clinical applications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {47}, pages = {5076-5080}, pmid = {39713159}, issn = {2219-2840}, mesh = {*Hyperuricemia/drug therapy/blood ; Humans ; *Gout/drug therapy ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Uric Acid/blood/metabolism ; Gout Suppressants/therapeutic use ; Animals ; }, abstract = {In this manuscript, we comment on the article by Liu et al published in the recent issue of the journal. Hyperuricemia (HUA) has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout. This discussion focuses on the targets and clinical application value of traditional Chinese medicine (TCM) extracts in the treatment of HUA and gout, emphasizing the role of gut microbiota. Liu et al's study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms, including inhibition of uric acid (UA) reabsorption, promotion of UA excretion, repair of intestinal barrier function, and regulation of gut microbiota and metabolome. Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat, which have clear and single targets, many TCMs have multi-target effects. However, the active components and mechanisms of TCMs are not fully understood, limiting their clinical application in the treatment of HUA and gout. Additionally, the role of gut microbiota in UA metabolic homeostasis needs to be further explored.}, } @article {pmid39712644, year = {2024}, author = {Yusuf, IO and Camille, W and Thompson, PR and Xu, Z}, title = {Protein Citrullination in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.}, journal = {Journal of experimental neurology}, volume = {5}, number = {4}, pages = {183-191}, pmid = {39712644}, issn = {2692-2819}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; R35 GM118112/GM/NIGMS NIH HHS/United States ; }, abstract = {Protein citrullination (PC) is a posttranslational modification (PTM) that converts a peptidyl arginine into a peptidyl citrulline. Aberrant PC is a hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, prion disease, and multiple sclerosis. Common among these diseases is a dramatic increase of PC in reactive astrocytes. Some citrullinated proteins have been identified. The most prominent are astrocytic cytoskeletal proteins such as GFAP and vimentin, and myelin protein MBP. Recent investigation in ALS has revealed new changes, including a decreased PC in neurons and an association of PC with myelin protein aggregates. These findings suggest that PC contributes to protein aggregation, neuronal dysfunction, neuroinflammation, and axonal degeneration. However, how PC impact neurodegeneration remains to be understood. Further studies are needed to understand a range of questions, from how PC modulates individual protein functions to its impact on diseases. Because of the PC's robust changes in neurodegenerative diseases, there are also prospects that this PTM may be harnessed as biomarkers, and modulation of this PTM may be an avenue for therapy. In this review, we summarize the current understanding of PC in ALS and other neurodegenerative diseases, the investigative methods for PC, and PC's potential as a biomarker and a therapeutic target.}, } @article {pmid39711523, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV- C9ORF72 (G 4 C 2) 66 mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39711523}, issn = {2693-5015}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39709547, year = {2024}, author = {Bakshi, B and Yerraguntla, S and Armon, C and Barkhaus, P and Bertorini, T and Bowser, R and Breevoort, S and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Fullam, T and Greene, M and Heiman-Patterson, T and Jackson, C and Jhooty, S and Mallon, E and Cadavid, JM and Mcdermott, CJ and Pattee, G and Pierce, K and Ratner, D and Sun, Y and Wang, O and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #77: Psilocybin.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2441274}, pmid = {39709547}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternate and off-label treatments prompted by patient interest. Here, we review psilocybin, a chemical derived from mushrooms and belonging in the category of drugs known as psychedelics. Psilocybin has plausible mechanisms for slowing ALS progression because of its ability to cross the blood brain barrier and effect neurogenesis and inflammation. Currently, there are no pre-clinical ALS models, case reports, or trials for psilocybin and ALS in the context of disease modifying therapy. Depending on dosing, there can be a high risk of psychological side effects including hallucinations and physical harm. Based on the above information, we do not currently support the use of psilocybin as a means to slow ALS progression.}, } @article {pmid39709476, year = {2024}, author = {Udine, E and Finch, NA and DeJesus-Hernandez, M and Jackson, JL and Baker, MC and Saravanaperumal, SA and Wieben, E and Ebbert, MTW and Shah, J and Petrucelli, L and Rademakers, R and Oskarsson, B and van Blitterswijk, M}, title = {Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {99}, pmid = {39709476}, issn = {1750-1326}, support = {ALS Association//ALS Association/ ; R21 NS099631/NS/NINDS NIH HHS/United States ; Muscular Dystrophy Association//Muscular Dystrophy Association/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; Robert Packard Center for ALS Research, Johns Hopkins University//Robert Packard Center for ALS Research, Johns Hopkins University/ ; RF1 NS123052/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *DNA Methylation/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Aged ; Frontotemporal Dementia/genetics ; Sequence Analysis, DNA/methods ; }, abstract = {BACKGROUND: The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels.

METHODS: We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method. Our primary goal was to determine the presence and subsequent quantification of observed methylation in the C9orf72 repeat expansion. In addition, we measured the repeat length and purity of the expansion. To do this, we sequenced DNA extracted from blood for 27 individuals with an expanded C9orf72 repeat.

RESULTS: For these individuals, we obtained a total of 7,765 on-target reads, including 1,612 fully covering the expanded allele. Our in-depth analysis revealed that the expansion itself is methylated, with great variability in total methylation levels observed, as represented by the proportion of methylated CpGs (13 to 66%). Interestingly, we demonstrated that the expanded allele is more highly methylated than the wild-type allele (P-Value = 2.76E-05) and that increased methylation levels are observed in longer repeat expansions (P-Value = 1.18E-04). Furthermore, methylation levels correlate with age at collection (P-Value = 3.25E-04) as well as age at disease onset (P-Value = 0.020). Additionally, we detected repeat lengths up to 4,088 repeats (~ 25 kb) and found that the expansion contains few interruptions in the blood.

CONCLUSIONS: Taken together, our study demonstrates robust ability to quantify methylation of the expanded C9orf72 repeat, capturing differences between individuals harboring this expansion and revealing clinical associations.}, } @article {pmid39709457, year = {2024}, author = {Keeley, O and Mendoza, E and Menon, D and Coyne, AN}, title = {CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {199}, pmid = {39709457}, issn = {2051-5960}, support = {R01NS132836/NS/NINDS NIH HHS/United States ; R00NS123242//National Institute of Aging/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Nuclear Pore/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Neurons/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent "activation" is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.}, } @article {pmid39708835, year = {2024}, author = {Davalos, L and Kushlaf, H}, title = {Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders.}, journal = {Seminars in respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2463-3385}, pmid = {39708835}, issn = {1098-9048}, abstract = {Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.}, } @article {pmid39707523, year = {2024}, author = {Straczkiewicz, M and Burke, KM and Calcagno, N and Premasiri, A and Vieira, FG and Onnela, JP and Berry, JD}, title = {Free-living monitoring of ALS progression in upper limbs using wearable accelerometers.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {223}, pmid = {39707523}, issn = {1743-0003}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; *Disease Progression ; Middle Aged ; *Wearable Electronic Devices ; *Accelerometry/instrumentation ; *Upper Extremity/physiopathology ; Aged ; Adult ; Wrist ; Movement/physiology ; }, abstract = {BACKGROUND: Wearable technology offers objective and remote quantification of disease progression in neurological diseases such as amyotrophic lateral sclerosis (ALS). Large population studies are needed to determine generalization and reproducibility of findings from pilot studies.

METHODS: A large cohort of patients with ALS (N = 202) wore wearable accelerometers on their dominant and non-dominant wrists for a week every two to four weeks and self-entered the ALS Functional Rating Scale-Revised (ALSFRS-RSE) in similar time intervals. Wearable device data were processed to quantify digital biomarkers on four upper limb movements: flexion, extension, supination, and pronation using previously developed and validated open-source methodology. In this study, we determined the association between digital biomarkers and disease progression, studied the impact of study design in terms of required sensor wear-time and sensor position, and determined the impact of self-reported disease onset location on upper limb movements.

RESULTS: The main investigation considered data from a sensor placed on the non-dominant wrist. Participants with higher ALSFRS-RSE scores performed more frequent and faster upper limb movements compared to participants with more advanced disease status. Digital biomarkers exhibited statistically significant change over time while their rate of change was more profound compared to survey responses. Using data from the dominant wrist and changing data inclusion criteria did not alter our findings. ALS disease onset location significantly impacted use of upper limbs. Results presented here were comparable to an earlier study on twenty patients with ALS.

DISCUSSION: Digital health technologies provide sensitive and objective means to quantify ALS disease progression. Interpretable approaches, such as the one used in this paper, can improve patient evaluation and hasten therapeutic development.}, } @article {pmid39706636, year = {2025}, author = {Benatar, M and Robertson, J and Andersen, PM}, title = {Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {77-86}, doi = {10.1016/S1474-4422(24)00479-4}, pmid = {39706636}, issn = {1474-4465}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/prevention & control ; Disease Models, Animal ; Genetic Therapy/methods ; *Superoxide Dismutase-1/genetics ; }, abstract = {Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.}, } @article {pmid39706627, year = {2025}, author = {Andersen, PM and Benatar, M}, title = {Patrikios syndrome and SOD1 ALS.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {27}, doi = {10.1016/S1474-4422(24)00491-5}, pmid = {39706627}, issn = {1474-4465}, } @article {pmid39706377, year = {2024}, author = {Rush, CL and Lyons, C and Gittle, J and Seward, M and Scalia, J and Ho, D and Babu, S and Garret, MA and Brizzi, K and Berry, JD and Fava, M and Lindenberger, E and Vranceanu, AM and , }, title = {Clinician Perspectives Highlight the Need for Early Dyadic Coping Skills for People Living With Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2024.12.010}, pmid = {39706377}, issn = {1873-6513}, abstract = {CONTEXT: A diagnosis of ALS can be challenging, and many people find ways to adapt. At the same time, emotional distress can arise early after an ALS diagnosis even when high quality multidisciplinary care is provided. When emotional distress occurs, it can become chronic over time, and can affect both the person living with ALS and their care-partner (together called a dyad).

OBJECTIVES: We set out to understand ALS multidisciplinary clinicians' perception of the challenges experienced by people with ALS and care-partners who experience emotional distress after diagnosis and potential benefits of a coping skills program to help these patients and their care-partners, Resilient Together-ALS (RT-ALS).

METHODS: We conducted semi-structured focus groups and individual interviews with 17 clinicians at the Sean M. Healey & AMG Center for ALS at MGH (N = 2 focus groups and five interviews) to elicit feedback on four domains: 1) Psychosocial Needs of ALS Dyads seen in the clinic; 2) Clinic Flow and Referral System to RT-ALS; 3) Clinic Partnership Approach in Support of RT-ALS; 4) RT-ALS Program Content and Manual Format. We conducted rapid data analyses for a time-efficient hybrid inductive-deductive thematic approach.

RESULTS: Clinicians noted that dyadic distress (distress experienced by both patient and their care-partner individually and as a unit), though not universal, is often present early after diagnosis. The response to the proposed program content (dyadic and individual coping skills) and structure (6 weekly virtual sessions delivered within about 2 months after diagnosis) was positive. Multidisciplinary clinicians emphasized the importance of a skills-based program for dyads experiencing elevated early emotional distress for which referral can be easily integrated within clinic flow so as not to not increase provider and dyad burden.

CONCLUSION: RT-ALS program content and structure is acceptable to clinicians. It is imperative to next seek further input from dyads about whether this type of program would be of interest and if yes, to pilot and refine the program for feasibility testing and then efficacy.}, } @article {pmid39706179, year = {2024}, author = {Setsu, S and Morimoto, S and Nakamura, S and Ozawa, F and Utami, KH and Nishiyama, A and Suzuki, N and Aoki, M and Takeshita, Y and Tomari, Y and Okano, H}, title = {Swift induction of human spinal lower motor neurons and robust ALS cell screening via single-cell imaging.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102377}, doi = {10.1016/j.stemcr.2024.11.007}, pmid = {39706179}, issn = {2213-6711}, abstract = {This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons.}, } @article {pmid39705668, year = {2024}, author = {Khandia, R and Gurjar, P and Priyanka, and Romashchenko, V and Al-Hussain, SA and Zaki, MEA}, title = {Recent advances in stem cell therapy: efficacy, ethics, safety concerns, and future directions focusing on neurodegenerative disorders - a review.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {10}, pages = {6367-6381}, pmid = {39705668}, issn = {1743-9159}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegeneration refers to the gradual loss of neurons and extensive changes in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behavior. Common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxia (SCA), and supranuclear palsy. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF), and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and amyloid beta (Aβ) production has been observed in Alzheimer's patients. A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.}, } @article {pmid39705453, year = {2024}, author = {Jeong, J and Song, KJ and Lee, JC and Shin, SD and Kim, YJ}, title = {Optimal wearable camera mount locations for medical supervision during simulated out-of-hospital cardiopulmonary resuscitation.}, journal = {Medicine}, volume = {103}, number = {51}, pages = {e40973}, pmid = {39705453}, issn = {1536-5964}, support = {2020R1F1A1076561//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/instrumentation/methods ; Prospective Studies ; *Video Recording ; *Out-of-Hospital Cardiac Arrest/therapy ; *Wearable Electronic Devices ; Male ; Female ; Emergency Medical Technicians/education ; Emergency Medical Services/methods ; Adult ; Simulation Training/methods ; }, abstract = {The quality of the visual information transmitted from a scene is crucial for effective medical supervision in prehospital settings. This study investigated the influence of wearable camera mount locations on visibility during simulated out-of-hospital cardiopulmonary resuscitation. A prospective, observational, non-randomized simulation study was conducted to replicate a cardiac arrest scenario adhering to an advanced life support (ALS) protocol. Seven advanced emergency medical technicians (AEMTs) participated, and 5 camera mount locations were tested: the sternum, forehead, lateral side of the eyelid, mid-nasal, and glabella. Video recordings were captured from the Airway, Intravenous (IV), and Leading providers. Five experienced medical directors independently evaluated visibility scores (1-5) for each procedure with optimal visibility defined as a score of 4 to 5. Glabella mount demonstrated the highest median visibility score and interquartile range (5 [4-5]) and proportion of optimal visibility (77.5%) for most procedures across provider positions. Mixed models revealed significant estimates for the lateral side of the eyelid, mid-nasal, and glabella mounts compared to the sternum, with glabella having the largest effect size (estimate = 1.62). Generalized linear mixed models showed that the glabella mount had the highest odds ratio (OR = 8.07, 95% confidence interval [CI]: 3.01-21.6) to achieve optimal visibility. Wearable camera mount location significantly affected visibility during simulated resuscitation. Mounting cameras closer to eye level provided the most accurate visual data. Further research using objective measures, such as artificial intelligence, and evaluating the visibility of wearable cameras in real-world situations is warranted to optimize simulation-based training for prehospital care.}, } @article {pmid39705326, year = {2025}, author = {}, title = {Correction to Supporting Information for Le et al., Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {2}, pages = {e2424914121}, doi = {10.1073/pnas.2424914121}, pmid = {39705326}, issn = {1091-6490}, } @article {pmid39705260, year = {2024}, author = {Lima, TBWE and Fonseca, JDMD and Silva, AAMD and Vieira, RGDS and Montemezzo, D and Otto-Yáñez, M and Torres-Castro, R and Júnior, METD and Resqueti, VR and Fregonezi, GAF}, title = {Methods to normalize surface electromyography in respiratory muscles: Is it similar between amyotrophic lateral sclerosis and healthy people?.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0315846}, pmid = {39705260}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Electromyography/methods ; Male ; Female ; *Respiratory Muscles/physiopathology ; Middle Aged ; Adult ; Cross-Sectional Studies ; Aged ; Case-Control Studies ; Isometric Contraction/physiology ; }, abstract = {The normalization process is important to determine the best approach for normalizing electromyographic signals from respiratory muscles in healthy subjects and those with ALS. The aim of this study is to compare different methods of normalizing the sEMG signal of respiratory muscles in both healthy subjects and those with Amyotrophic Lateral Sclerosis (ALS). This cross-sectional study was conducted in 67 subjects (50 healthy and 17 with ALS). The electrical activity of the sternocleidomastoid (SCM), scalene (ESC), diaphragm (DIA), parasternal (PS), external intercostal (EI), external oblique (EO), and rectus abdominal (RA) muscles were analyzed during maximal inspiratory pressure maneuvers (MIP), maximal nasal inspiratory pressure (SNIP), maximal expiratory pressure (MEP), and maximal voluntary isometric contraction of SCM and ESC (MVICSCM/ESC) and RA (MVICRA) using surface electromyography (sEMG). In the healthy group, inspiratory and expiratory muscles displayed higher electrical activity during MVICSCM/ESC and MIVCRA maneuvers, respectively (p<0.05). In the ALS group, inspiratory muscle activity was higher during the SNIP maneuver, while expiratory muscles showed higher activity during MVICRA (p<0.05). Based on the findings, it can be concluded that the MVIC resulted in greater inspiratory muscle activity, being the ideal method of normalization for inspiratory and expiratory muscles in healthy subjects. In ALS patients, the SNIP maneuver resulted in greater inspiratory muscle activity, while MVIC resulted in greater muscle activity in expiratory muscles.}, } @article {pmid39703667, year = {2024}, author = {Lewis, RD and Keilholz, AN and Smith, CL and Burd, EA and Nichols, NL}, title = {Spinal TNF-α receptor 1 is differentially required for phrenic long-term facilitation (pLTF) over the course of motor neuron death in adult rats.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1488951}, pmid = {39703667}, issn = {1664-042X}, support = {T32 OD011126/OD/NIH HHS/United States ; }, abstract = {INTRODUCTION: Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) result in selective respiratory (e.g., phrenic) motor neuron death and mimics aspects of motor neuron disease [(e.g., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)], such as breathing deficits. This rodent model allows us to study the impact motor neuron death has on the output of surviving phrenic motor neurons as well as the compensatory mechanisms that are recruited. Microglial density in the phrenic motor nucleus as well as cervical gene expression of markers associated with inflammation (e.g., tumor necrosis factor α; TNF-α) are increased following CTB-SAP-induced phrenic motor neuron death, and ketoprofen (nonsteroidal anti-inflammatory drug) delivery attenuated phrenic long-term facilitation (pLTF) in 7 day (d) CTB-SAP rats but enhanced pLTF in 28d CTB-SAP rats.

METHODS: Here, we worked to determine the impact of TNF-α in the phrenic motor nucleus by: 1) quantifying TNFR1 (a high affinity transmembrane receptor for TNF-α) expression; 2) investigating astrocytes (glial cells known to release TNF-α) by performing a morphological analysis in the phrenic motor nucleus; and 3) determining whether acute TNFR1 inhibition differentially affects phrenic plasticity over the course of CTB-SAP-induced motor neuron loss by delivering an inhibitor for TNF-α receptor 1 (sTNFR1i) in 7d and 28d male CTB-SAP and control rats.

RESULTS: Results revealed that TNFR1 expression was increased on phrenic motor neurons of 28d CTB-SAP rats (p < 0.05), and that astrocytes were increased and exhibited reactive morphology (consistent with an activated phenotype; p < 0.05) in the phrenic motor nucleus of CTB-SAP rats. Additionally, we found that pLTF was attenuated in 7d CTB-SAP rats but enhanced in 28d CTB-SAP rats (p < 0.05) following intrathecal sTNFR1i delivery.

CONCLUSION: This work suggests that we could harness TNFR1 as a potential therapeutic agent in CTB-SAP rats and patients with respiratory motor neuron disease by increasing compensatory plasticity in surviving neurons to improve phrenic motor neuron function and breathing as well as quality of life. Future studies will focus on microglial and astrocytic cytokine release, the role they play in the differential mechanisms of pLTF utilized by 7d and 28d CTB-SAP rats, and potential therapies that target them.}, } @article {pmid39703459, year = {2024}, author = {Oliveira, D and Nishimura, AL}, title = {Editorial: Mechanisms of neurodegeneration in amyotrophic lateral sclerosis and related disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1531449}, doi = {10.3389/fncel.2024.1531449}, pmid = {39703459}, issn = {1662-5102}, } @article {pmid39703273, year = {2024}, author = {Solano, J and Eni, G and Viswanath, A and Enany, B}, title = {Successful Rescue of Ventricular Fibrillation Electrical Storm Secondary to Acute Myocardial Infarction in a Patient Presenting to a District General Hospital: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73959}, pmid = {39703273}, issn = {2168-8184}, abstract = {Ventricular arrhythmia is a critical and challenging cardiovascular complication of myocardial infarction (MI). An electrical storm (ES), characterised by three or more episodes of sustained ventricular arrhythmia within 24 hours, poses a significant life-threatening risk. Standard management includes advanced life support (ALS) protocols and specialised pharmacological interventions. We present the case of a 43-year-old female who presented to the emergency department (ED) following an out-of-hospital ventricular fibrillation (OOHVF) arrest, with the return of spontaneous circulation (ROSC) achieved after multiple defibrillation shocks. Electrocardiography (ECG) revealed anterior ST-segment elevation MI (STEMI) involving the left anterior descending (LAD) artery. During her ED stay, she experienced recurrent ventricular fibrillation (VF) arrests requiring repeated defibrillation, adrenaline, amiodarone, and thrombolysis with alteplase. She was subsequently intubated and transferred to a primary percutaneous coronary intervention (PPCI) centre with intensive care support. Angiography confirmed a 100% occlusion of the LAD, which was successfully treated with stenting. The patient was admitted to the intensive care unit (ICU) and later discharged with full neurological recovery, on secondary prevention and heart failure therapy, with follow-up planned. This case underscores the complexity of managing electrical storms in MI, particularly in non-PPCI centres. It emphasises the importance of thrombolysis as an early reperfusion strategy in STEMI, especially when PPCI is not immediately available.}, } @article {pmid39703094, year = {2024}, author = {De Decker, M and Zelina, P and Moens, TG and Beckers, J and Contardo, M and Dittlau, KS and Van Schoor, E and Ronisz, A and Eggermont, K and Moisse, M and Chandran, S and Veldink, JH and Thal, DR and Van Den Bosch, L and Pasterkamp, RJ and Van Damme, P}, title = {C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae331}, pmid = {39703094}, issn = {1460-2156}, support = {C1-C14-17-107//KU Leuven/ ; //Opening the Future Fund (KU Leuven)/ ; 150031//Agency for Innovation by Science and Technology/ ; //ALS Liga België/ ; //National Lottery of Belgium/ ; //European E-Rare-3 project INTEGRALS/ ; //European E-Rare-3 project MAXOMOD/ ; //Stichting ALS Nederland/ ; //Vlaanderen/ ; 772376/ERC_/European Research Council/International ; }, abstract = {Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length. We report that C21ORF2 is located at the basal body of the primary cilium, and mutations associated with ALS alter this localization. Furthermore, we show that a reduction of C21ORF2 levels in cell lines and motor neurons is sufficient to cause fewer primary cilia and reduced cilial length. This ciliary dysfunction leads to defective downstream sonic hedgehog signalling and reduces the expression of cellular retinoic acid binding protein 1 (CRABP1), a protein involved in motor neuron maintenance and survival. In a compartmentalized co-culture system of motor neurons and muscle cells, these ciliary defects were associated with a reduced ability of neuromuscular junction formation. Interestingly, these cilia defects are seemingly not restricted to C21ORF2 ALS, as we also observed perturbed primary cilia in cultured motor neurons and post-mortem motor cortex from patients with the most common genetic subtype of ALS caused by repeat expansions in the C9ORF72 gene. Finally, overexpression of C21ORF2 in mutant C21ORF2 motor neurons rescued the ciliary frequency and length, CRAPBP1 expression and neuromuscular junction formation, confirming the importance of primary cilia for motor neuron function. These results point towards primary cilia dysfunction contributing to motor neuron degeneration in ALS and open new avenues for further research and interventions for this as yet untreatable disease.}, } @article {pmid39702138, year = {2024}, author = {Chen, C and Meng, J and Cheng, K and Kang, C and Zhou, L and Guo, H and Zhu, X}, title = {Spatial and morphologic features of lenses with different axial lengths in cataract patients: a swept-source optical coherence tomography-based study.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {542}, pmid = {39702138}, issn = {1471-2415}, support = {82122017, 82271069, 81870642, 82371040, 81970780, 81470613 and 81670835//National Natural Science Foundation of China/ ; 23Y11909800 and 21S31904900//Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission/ ; SHDC12020111//Clinical Research Plan of Shanghai Shenkang Hospital Development Center/ ; shslczdzk01901//Shanghai Municipal Key Clinical Specialty Program/ ; }, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Female ; Male ; *Cataract/pathology ; *Axial Length, Eye/pathology/diagnostic imaging ; Aged ; Middle Aged ; *Lens, Crystalline/diagnostic imaging/pathology ; Visual Acuity/physiology ; Myopia/physiopathology ; Retrospective Studies ; Aged, 80 and over ; Cataract Extraction ; }, abstract = {BACKGROUND: To investigate the spatial and morphologic features of lenses with different axial length (ALs) in cataract patients using swept-source optical coherence tomography (SS-OCT).

METHODS: Totally 105 eyes of 105 patients scheduled to have cataract surgery were included. Eyes were divided into the control (AL < 24.5 mm), moderate myopia (MM, 24.5 ≤ AL < 26 mm) and high myopia (HM, AL ≥ 26 mm) groups. Spatial features including lens vault (LV) and iris-to-lens distance (ILD), and morphologic features including radii of curvature of anterior and posterior surface (Ra, Rp), lens diameter (LD) and lens thickness (LT) were measured in eight directions by SS-OCT.

RESULTS: Spatially, the HM group had larger LV and ILD than the control group (both P < .05). LV and ILD were negatively correlated with AL, respectively (LV: r = -.484, P < .0001; ILD: r = -.656, P < .0001). Morphologically, both MM and HM groups had greater Ra and Rp than the control group. Ra was positively correlated with AL (r = .622, P < .0001), while the relationship between Rp and AL was non-linear. Moreover, the MM and HM groups had larger LD than the control group (both P < .001). Anterior LT was thinner in the HM than in the MM group (P = .026), while posterior LT between these two groups was similar. When compared in eight directions, similar trends were seen in Ra, Rp and LD, and the HM group showed a greater difference in Ra between horizontal and vertical directions.

CONCLUSIONS: This SS-OCT-based study showed that longer axial length is associated with a flatter lens, which was mainly attributed to the increase of Ra and LD. Longitudinal studies would be necessary to establish a causal relationship and temporal progression.}, } @article {pmid39701414, year = {2024}, author = {Tantoco, AM and Peterson, R and Corbin, B and Coyne, F and Herbst, B and Hunt, S and Levoy, E and Luttrell, H and Shanske, S and Sunyal, S and Dwyer-Matzky, K and Jenkins, AM}, title = {Pediatric to Adult Care Transition in the Hospital Context (PATCH) Tool: A Novel Tool to Assess Pediatric Institutional Guidelines for Inpatient Care of Adults.}, journal = {Academic pediatrics}, volume = {}, number = {}, pages = {102625}, doi = {10.1016/j.acap.2024.102625}, pmid = {39701414}, issn = {1876-2867}, abstract = {OBJECTIVE: The growing number of adults with childhood onset chronic conditions (COCC) is reflected in the increase of adult-aged admissions to pediatric institutions. Despite national bodies advising pediatric institutions to have a pediatric to adult healthcare transition (HCT) policy, little guidance is available on if or how to include inpatient care. We sought to create a framework-based Pediatric to Adult Transitional Care in the Hospital Context (PATCH) tool to assess how inpatient care of adults is addressed in pediatric institutional guidelines or policies (hereafter guidelines) as a first step towards informing future PATCH guideline development.

METHODS: We used convenience and snowball sampling to obtain 11 pediatric institutional guidelines. Combining the GotTransition® core elements with Coller et al's inpatient transition conceptual model through iterative consensus building, we developed the PATCH tool. Interrater reliability was assessed by using mean percent agreement amongst raters. A three-phase content validity process utilizing existing guidelines refined the finalized tool.

RESULTS: The PATCH tool included 42 items within nine domains. There was a high degree of agreeability amongst reviewers, and qualitative analysis revealed no missing items. Twenty-five (59%) of our 42 PATCH tool items were present in at least one of the reviewed guidelines, with age being present in all.

CONCLUSION: We developed the PATCH tool as a guide for pediatric institutions regarding the care of adolescent and adult patients. The PATCH tool, embedded in multidisciplinary stakeholder discussion and patient- and system-specific knowledge, may help institutions incorporate HCT into processes for adolescent and adult patients with COCCs.}, } @article {pmid39701395, year = {2024}, author = {Force, E and Alvarez, C and Fuentes, A and Maria, A and Bozzolan, F and Debernard, S}, title = {Diet influence on male sexual maturation through interplay between insulin signaling and juvenile hormone in insects.}, journal = {Insect biochemistry and molecular biology}, volume = {177}, number = {}, pages = {104252}, doi = {10.1016/j.ibmb.2024.104252}, pmid = {39701395}, issn = {1879-0240}, abstract = {In animals, sexual maturation coincides with the development of sexual behaviors and reproductive system. These developmental events are influenced by diet and governed by endocrine signals. Here, for the first time in insects, we explored functional links between nutrition and juvenile hormone (JH) in the male reproductive physiology through the insulin signaling pathway (ISP) acting as a transducer of nutritional signals. We turned to the male moth Agrotis ipsilon for which sexual maturation, including accessory sex glands (ASGs) development concomitantly with antennal lobes (ALs) maturation for female sex pheromone processing and display of sexual behavior, is known to be JH- and diet-dependent. Indeed, a diet rich in sugars with sodium was previously shown to accelerate sexual maturation, which was achieved from the third day of adult life. In this study, we demonstrated that such a diet raised i) the expression of JH signaling actors (Methoprene-tolerant, Taiman, and Krüppel homolog 1) in ALs and ASGs, ii) the biosynthesis and circulating levels of JH, and iii) the expression of both insulin receptor (InR) and insulin-like peptides (ILPs) in corpora allata (CAs) and brain respectively. Insulin injection raised JH biosynthesis following increased HMG-CoA reductase expression in CAs; opposite effects were induced in InR-deficient males. Thus, we highlighted that promoting effects of a diet composed of sugars with sodium on male sexual maturation results from an early induction of ISP causing an increase in JH biosynthesis followed by a potentiation of JH actions on the development of ASGs and ALs in A. ipsilon.}, } @article {pmid39700696, year = {2024}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Current evidence of arterial spin labeling in amyotrophic lateral sclerosis: A systematic review.}, journal = {Clinical neurology and neurosurgery}, volume = {249}, number = {}, pages = {108691}, doi = {10.1016/j.clineuro.2024.108691}, pmid = {39700696}, issn = {1872-6968}, abstract = {OBJECTIVE: This study aimed to evaluate the utility of arterial spin labeling (ASL) in assessing cerebral blood flow (CBF) changes in amyotrophic lateral sclerosis (ALS), and its potential as a biomarker for early diagnosis.

METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies that employed ASL to compare CBF between ALS patients and healthy controls were included.

RESULTS: Seven studies were included. A consistent finding across these studies was hypoperfusion in both the motor and non-motor regions, particularly in the frontotemporal cortex. Hypoperfusion in motor regions was correlated with functional impairment and was observed prior to structural changes, suggesting its potential as an early biomarker. There is limited evidence to suggest that monitoring changes in CBF patterns in the brain. Besides, limited findings showed initial hyperperfusion in regions not yet involved in the pathological process, and progressing hypoperfusion in regions with increasing pathological burden.

CONCLUSIONS: This review highlights the potential of ASL as a valuable tool for understanding the neurovascular dysfunction in ALS. Further research is required to validate its clinical utility for diagnosing ALS and monitoring disease progression.}, } @article {pmid39698283, year = {2024}, author = {Kos, JA and Langiu, M and Hellyer, SD and Gregory, KJ}, title = {Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {12}, pages = {3671-3690}, pmid = {39698283}, issn = {2575-9108}, abstract = {Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu5) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified. mGlu5 negative allosteric modulators (NAMs) are promising novel therapeutics for developmental, neuropsychiatric and neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, autism spectrum disorders, substance use disorders, stroke, anxiety and depression) and show promise in ameliorating adverse effects induced by other medications (e.g., L-dopa induced dyskinesia in Parkinson's Disease). However, despite preclinical success, mGlu5 NAMs are yet to reach the market due to poor safety and efficacy profiles in clinical trials. Herein, we review the physiology and signal transduction of mGlu5. We provide a comprehensive critique of therapeutic options with respect to mGlu5 inhibitors, spanning from orthosteric antagonists to NAMs. Finally, we address the challenges associated with drug development and highlight future directions to guide rational drug discovery of safe and effective novel therapeutics.}, } @article {pmid39697625, year = {2024}, author = {Zhao, X and Huang, S}, title = {Plasma extracellular vesicle: a novel biomarker for neurodegenerative disease diagnosis.}, journal = {Extracellular vesicles and circulating nucleic acids}, volume = {5}, number = {3}, pages = {569-573}, pmid = {39697625}, issn = {2767-6641}, abstract = {Extracellular vesicles (EVs) are membrane-bound structures that carry proteins, lipids, RNA, and DNA, playing key roles in cell communication and material transport. Recent research highlights their potential as disease biomarkers due to their stability in bodily fluids. This study explores using tau and TDP-43 proteins in plasma EVs as diagnostic biomarkers for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Analyzing plasma EVs from clinical cohorts, the study found that the 3R/4R tau ratio and TDP-43 levels effectively differentiate between diagnostic groups with high accuracy. Notably, plasma EV biomarkers demonstrate higher diagnostic accuracy and stability compared to direct plasma testing, providing new insights and approaches for future research and clinical practice. Further research is needed to validate these biomarkers in diverse populations and to establish standardized protocols. Future studies should continue to explore the potential of EV biomarkers in a broader range of neurodegenerative diseases and delve deeper into the mechanisms of EV secretion and sorting to enhance their diagnostic utility.}, } @article {pmid39697444, year = {2024}, author = {He, SY and Cai, WC and Su, WM and Duan, QQ and Jiang, Z and Yin, KF and Gu, XJ and Chen, YP and Cao, B}, title = {Quantifying the split-elbow sign: a comprehensive study in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1499668}, pmid = {39697444}, issn = {1664-2295}, abstract = {PURPOSE: The split-elbow sign (SES), characterized by preferential dysfunction of the biceps brachii compared to the triceps, is a clinical feature observed in amyotrophic lateral sclerosis (ALS). However, the quantified SES index has not been extensively investigated, and its role in diagnosing ALS remains unknown. Therefore, this study aimed to investigate the split-elbow index (SEI) derived from compound muscle action potential (CMAP), motor unit number index (MUNIX), and echo intensity (EI) in ALS.

METHODS: A cohort comprising 70 individuals diagnosed with ALS, along with 41 disease controls and 40 healthy controls, was recruited for the study. The SEI was calculated by dividing the recorded values of CMAP, MUNIX, and EI obtained over the biceps brachii by the corresponding value measured in the triceps, resulting in SEICMAP, SEIMUNIX, and SEIEI, respectively. Receiver operating characteristic (ROC) curves of the three methods were used for comparison. Statistical analyses were performed using SPSS V.26.0 and R software.

RESULTS: Both SEICMAP and SEIMUNIX exhibited significant reductions in ALS patients compared to that in controls (PSEICMAp  < 0.0001, PSEIMUNIX < 0.0001), while SEIEI showed an elevation (P < 0.0001). Furthermore, there was a notable decrease in SEIMUNIX values as the disease progressed (p < 0.001). Moreover, ROC for SEIMUNIX exhibited superior diagnostic performance (AUC = 0.846), and a comprehensive diagnostic approach combining SEICMAP, SEIMUNIX, and SEIEI resulted in AUC (0.90) on the ROC curve.

CONCLUSION: Our study suggested that SES has emerged as a significant clinical characteristic in ALS and indicated the potential of SES indicators as biomarkers for both diagnosis and assessment of disease progression in ALS.}, } @article {pmid39696694, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Baulch, JE and Ng, DQ and Du, M and Johnston, KG and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {190}, pmid = {39696694}, issn = {2051-5960}, support = {R01 CA276212/CA/NCI NIH HHS/United States ; P30CA062203//National Institutes of Health (UC Irvine Comprehensive Cancer Center)/ ; P30 CA062203/CA/NCI NIH HHS/United States ; UL1TR001414//National Institutes of Health (UC Irvine and National Center for Advancing Translational Sciences, NCATS)/ ; UL1 TR001414/TR/NCATS NIH HHS/United States ; R01CA276212/NH/NIH HHS/United States ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; *Cognitive Dysfunction/etiology/metabolism ; *Cranial Irradiation/adverse effects ; Mice ; Male ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Neurodegenerative Diseases/radiotherapy ; Hippocampus/metabolism/radiation effects/drug effects ; Female ; }, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, } @article {pmid39696212, year = {2024}, author = {Giusti, A and Pukrittayakamee, P and Wannarit, K and Thongchot, L and Janwanishstaporn, S and Nkhoma, K and Venkatapuram, S and Harding, R}, title = {How to deliver person-centred care for people living with heart failure: a multi stakeholder interview study with patients, caregivers and healthcare professionals in Thailand.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {1570}, pmid = {39696212}, issn = {1472-6963}, support = {GHRU 16/136/54//National Institute of Health Research (NIHR) Global Health Research Unit on Health System Strengthening in Sub-Saharan Africa, King's College London/ ; GA-00937//Funds for Graduate Women (FfGW)/ ; }, mesh = {Humans ; *Heart Failure/therapy/psychology ; Thailand ; *Caregivers/psychology ; Male ; *Patient-Centered Care ; Cross-Sectional Studies ; Female ; Middle Aged ; *Qualitative Research ; *Health Personnel/psychology ; Aged ; Adult ; Interviews as Topic ; }, abstract = {CONTEXT: Heart failure has high, growing global prevalence, morbidity and mortality, and is a leading cause of death with serious health-related suffering in low- and middle-income countries. Person-centred care (PCC) is a critical component of high-quality healthcare and is particularly vital in the context of a serious illness such as heart failure. However, there are limited data exploring PCC in this population in low- and middle-income settings.

AIM: The aim of this study was to explore how clinical services could respond to the PCC needs of individuals living with heart failure in Thailand, with potential for adaptation in other settings. The specific objectives were (i) to understand the experiences and needs of persons living with heart failure, their caregivers and HCPs; (ii) to explore specific practical actions that can help deliver PCC for heart failure patients in this setting.

METHODS: Cross-sectional qualitative study. In depth, semi-structured interviews were conducted in Thailand with heart failure patients (n = 14), their caregivers (n = 10) and healthcare professionals (n = 12). Framework analysis was conducted with deductive coding to populate an a priori coding frame based on Santana et al's PCC model (2018) and Giusti et al's systematic review (2020), with further inductive coding of novel findings to expand the frame. The study is reported in accordance with the consolidated criteria for reporting qualitative research guidelines (COREQ).

RESULTS: The findings reveal specific practice actions that deliver PCC for persons living with heart failure in Thailand, such as (i) compassionate communication by healthcare professionals; (ii) effective teamwork amongst multidisciplinary healthcare professionals; (iii) proactive responses to physical, psychosocial, relational and information needs of patients and caregivers; (iv) engaging patients and families in symptom management; (v) providing opportunities for patients to be cared for in the community; and (vi) responding to the social determinants of health, illness and healthcare access.

CONCLUSION: Person-centred healthcare systems must aim to address the social determinants of illness and place focus on community- and home-based care. Heart failure patients and caregivers must be supported to self-manage, including how to recognise symptoms and take appropriate action. Delivering PCC in such a way has the potential to improve outcomes for patients, enhance patients' sense of agency and experiences of care, improve health equity, and reduce hospital admissions, relieving pressure on the hospital system and reducing overall costs of care.}, } @article {pmid39694549, year = {2024}, author = {Ma, YL and Qiu, T and Xu, XL and Wang, LX and Zhuang, PY}, title = {[Analysis of clinical characteristics of amyotrophic lateral sclerosis patients initially diagnosed with abnormal laryngeal function].}, journal = {Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery}, volume = {59}, number = {12}, pages = {1293-1298}, doi = {10.3760/cma.j.cn115330-20240630-00388}, pmid = {39694549}, issn = {1673-0860}, support = {82271155//National Natural Science Foundation of China/ ; 2020J011212//Fujian Provincial Natural Science Foundation/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Larynx/physiopathology ; }, abstract = {Objective: To study the laryngeal functional characteristics of patients with amyotrophic lateral sclerosis (ALS)disease diagnosed at the voice clinic. Methods: A retrospective analysis(case series study) was conducted on the laryngeal functional characteristics of 7 patients [2 males, 5 females, age ranged from 43 to 76(60.85±13.18)]with motor neuron disease who visited the voice clinic and were ultimately diagnosed by neurologists. The data included laryngostroboscopy, fiberoptic endoscopic examination of swallowing(FEES), acoustic analysis and laryngeal electromyography(LEMG). Descriptive methods were used for analysis. Results: ①There were 2 males and 5 females, with an average age of (60.85±13.18) years. They had previously visited the otolaryngology department more than twice, visit frequency with an average of 3.57 and an average diagnosis time of 12.28 months. The main complaints of the patient at the time of treatment were voice change, dysphagia or vocal fatigue. ②LEMG: Among 7 cases, 4 cases demonstrated neurogenic damage, all of which were bilateral, and 3 cases showed normal findings on examination. Spontaneous potentials (SP) were present in three cases for more than 6 months, with the longest duration being 24 months. Three cases exhibited the coexistence of spontaneous potential and reinnervated motor unit potentials (MUPs), and two cases showed bundle tremor potential.③Laryngostroboscopy revealed bilateral vocal fold asymmetry and glottic insufficiency in 7 cases, and decreased vocal cord movement in 4 cases, and vocal cord atrophy in 5 cases. FEES showed that 7 patients presented with mild to severe swallowing dysfunction, 3 cases had soft palate insufficiency and mild to severe food residues in the epiglottic valley and pyriform fossa. 1 case showed leakage and 1 case showed aspiration. Conclusions: Patients presenting with initial symptoms of abnormal laryngeal function should be vigilant for the possibility of motor neuron disease, especially when laryngostroboscopy reveals abnormal vocal fold movement and swallowing dysfunction. LEMG examination reveals bilateral neurogenic damage, prolonged spontaneous potential, coexistence of spontaneous potential and reinnervated MUPs, and the appearance of bundle tremor potential, which is beneficial for early detection of motor neuron disease.}, } @article {pmid39694468, year = {2024}, author = {Cornell, PY and Gadkari, G and Hua, CL and Smith, L and Johnson, A and Schwartz, L and Rahman, M and Thomas, KS}, title = {Risk of Hospitalization Among Assisted Living Residents Dually Enrolled in Medicare and Medicaid.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {2}, pages = {105421}, doi = {10.1016/j.jamda.2024.105421}, pmid = {39694468}, issn = {1538-9375}, abstract = {OBJECTIVES: To examine how risk of hospitalization among assisted living (AL) residents differs by dual enrollment in Medicare and Medicaid and by the percent of dually enrolled individuals in an AL community.

DESIGN: Retrospective cohort study.

SETTING AND PARTICIPANTS: We used Medicare data from 2008 to 2018 and a national directory of licensed AL communities to identify Medicare beneficiaries with a change in their ZIP+4 code suggesting a new residence in an AL.

METHODS: We estimated linear regression models of hospitalization onto interactions of residents' dual enrollment status and categories of the AL community's percentage of dually enrolled residents. In the models, we adjusted for person-level clinical and demographic characteristics, year-fixed effects, and fixed effects for the AL residents' prior ZIP code.

RESULTS: Among 620,542 Medicare beneficiaries who moved to an AL community, the 1-year risk of hospitalization was higher for dually enrolled residents compared with Medicare-only residents. In adjusted models, dually enrolled residents in high-dual AL communities (>50% dually enrolled) had an 7.4% higher risk of hospital admission compared with dually enrolled residents in low-dual AL communities. Medicare-only beneficiaries in high-dual AL communities had a 9.4% higher risk of hospitalization than Medicare-only beneficiaries in low-dual ALs.

CONCLUSIONS AND IMPLICATIONS: The proportion of residents in an AL community who were dually enrolled was associated with residents' risk of hospitalization, regardless of their dual enrollment status. Additional research is needed to understand whether differences observed in residents' risk of hospitalization are due to differences in the types of services provided, unmeasured resident acuity, or the quality of care delivered in these settings.}, } @article {pmid39693933, year = {2025}, author = {Taisei Ito, and Ohuchi, K and Kurita, H and Murakami, T and Takizawa, S and Fujimaki, A and Murata, J and Oida, Y and Hozumi, I and Kitaichi, K and Inden, M}, title = {Neuroprotective effects of activated fibroblast growth factor receptor 1 via the suppression of p53 accumulation against poly-PR-mediated toxicity.}, journal = {Biochemical and biophysical research communications}, volume = {743}, number = {}, pages = {151181}, doi = {10.1016/j.bbrc.2024.151181}, pmid = {39693933}, issn = {1090-2104}, mesh = {*Tumor Suppressor Protein p53/metabolism/genetics ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism/genetics/antagonists & inhibitors ; Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Cell Line ; Proto-Oncogene Proteins c-mdm2/metabolism/genetics ; Cell Survival/drug effects ; Motor Neurons/metabolism/drug effects ; Humans ; }, abstract = {A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. Nevertheless, there has been no previous report of its neuroprotective effects against poly-PR toxicity. The objective of this study was to investigate the neuroprotective effects of FGFR1 activation in poly-PR-expressing NSC34 motor neuron-like cells. RT-qPCR analysis in NSC34 cells showed that Fgfr1 was the most highly expressed member of the Fgfr family in NSC34 cells. The activation of FGFR1 by FGF2, a common ligand for all FGFRs, exerted neuroprotective effects against the toxicity of poly-PR. Additionally, FGFR1 activation was observed to enhance cell viability through the PI3K-AKT pathway, while the contribution of the MEK-ERK pathway was found to be limited. Furthermore, FGFR1 activation suppressed the accumulation of p53 protein and promoted its degradation through increased murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets p53. The neuroprotective effects were attenuated by PD173074, a selective FGFR1 inhibitor or Nutlin-3a, an inhibitor of the p53-MDM2 interaction. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity. Consequently, this study suggests the potential utility of FGFR1 activation as a therapeutic strategy for ALS.}, } @article {pmid39693632, year = {2024}, author = {Hausmann, F and Caldi Gomes, L and Hänzelmann, S and Khatri, R and Oller, S and Gebelin, M and Parvaz, M and Tzeplaeff, L and Pasetto, L and Zhou, Q and Zelina, P and Edbauer, D and Pasterkamp, RJ and Rehrauer, H and Schlapbach, R and Carapito, C and Bonetto, V and Bonn, S and Lingor, P}, title = {A dataset profiling the multiomic landscape of the prefrontal cortex in amyotrophic lateral sclerosis.}, journal = {GigaScience}, volume = {13}, number = {}, pages = {}, pmid = {39693632}, issn = {2047-217X}, support = {01GM1917A//Bundesministerium für Bildung und Forschung/ ; CRC1192//DFG/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Prefrontal Cortex/metabolism/pathology ; Humans ; Female ; Mice ; Male ; Animals ; Mice, Transgenic ; Transcriptome ; Proteome ; Disease Models, Animal ; Aged ; Gene Expression Profiling/methods ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, which still lacks effective disease-modifying therapies. Similar to other neurodegenerative disorders, such as Alzheimer and Parkinson disease, ALS pathology is presumed to propagate over time, originating from the motor cortex and spreading to other cortical regions. Exploring early disease stages is crucial to understand the causative molecular changes underlying the pathology. For this, we sampled human postmortem prefrontal cortex (PFC) tissue from Brodmann area 6, an area that exhibits only moderate pathology at the time of death, and performed a multiomic analysis of 51 patients with sporadic ALS and 50 control subjects. To compare sporadic disease to genetic ALS, we additionally analyzed PFC tissue from 4 transgenic ALS mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS) using the same methods. This multiomic data resource includes transcriptome, small RNAome, and proteome data from female and male samples, aimed at elucidating early and sex-specific ALS mechanisms, biomarkers, and drug targets.}, } @article {pmid39691755, year = {2025}, author = {Sood, A and Mishra, GV and Kar, P and Khandelwal, S and Gaur, S and Manuja, N}, title = {Amyotrophic lateral sclerosis in a tricenarian female.}, journal = {Radiology case reports}, volume = {20}, number = {2}, pages = {1121-1123}, pmid = {39691755}, issn = {1930-0433}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by the progressive degeneration of the upper and lower motor neurons. This disease is mostly observed in patients of the 6th decade or above, and it is extremely rare to observe this pathology in patients less than 50 years of age. This manuscript depicts the magnetic resonance imaging findings of ALS showing a wine glass sign in a 31-year-old female from a rural area with complaints of progressive limb weakness and muscle wasting.}, } @article {pmid39691422, year = {2024}, author = {Fang, K}, title = {Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases.}, journal = {Ibrain}, volume = {10}, number = {4}, pages = {462-476}, pmid = {39691422}, issn = {2769-2795}, abstract = {The immune response in the central nervous system (CNS) is a highly specialized and tightly regulated process essential for maintaining neural health and protecting against pathogens and injuries. The primary immune cells within the CNS include microglia, astrocytes, T cells, and B cells. They work together, continuously monitor the CNS environment for signs of infection, injury, or disease, and respond by phagocytosing debris, releasing cytokines, and recruiting other immune cells. In addition to providing neuroprotection, these immune responses must be carefully balanced to prevent excessive inflammation that can lead to neuronal damage and contribute to neurodegenerative diseases. Dysregulated immune responses in the CNS are implicated in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Wnt signaling is a crucial pathway in the CNS that regulates various cellular processes critical for brain development, function, and maintenance. Despite enhancing immune responses in the health CNS, dysregulated Wnt signaling exacerbates neuroinflammation in the neurodegenerative brains. This review summarized the role of Wnt signaling in regulating immune response under different conditions. We then examined the role of immune response in healthy brains and during the development of neurodegenerative diseases. We also discussed therapeutic intervention in various neurodegenerative diseases through the modulation of the Wnt signaling pathway and neuroinflammation and highlighted challenges and limitations in current clinical trials.}, } @article {pmid39690447, year = {2025}, author = {Koch, R and Nagoshi, E}, title = {Examining the potential involvement of NONO in TDP-43 proteinopathy in Drosophila.}, journal = {The European journal of neuroscience}, volume = {61}, number = {1}, pages = {e16632}, pmid = {39690447}, issn = {1460-9568}, support = {310030_189169//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; 310030_189169//The Swiss National Science Foundation/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *Drosophila Proteins/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Drosophila ; Neurons/metabolism ; Longevity ; Cell Nucleus/metabolism ; }, abstract = {The misfolding and aggregation of TAR DNA binding protein-43 (TDP-43), leading to the formation of cytoplasmic inclusions, emerge as a key pathological feature in a spectrum of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). TDP-43 shuttles between the nucleus and cytoplasm but forms nuclear bodies (NBs) in response to stress. These NBs partially colocalise with nuclear speckles and paraspeckles that sequester RNAs and proteins, thereby regulating many cellular functions. The laboratory of Steven Brown has recently found that the non-POU domain-containing octamer-binding protein (NONO), a component of paraspeckles, forms novel nuclear speckle-like structures in mouse cortical neurons in response to stress and sleep deprivation. These findings suggest the possibility of a functional link between NONO and TDP-43, potentially contributing to TDP-43 proteinopathy. Here, we demonstrate that pathological phenotypes caused by TDP-43 gain of function-locomotor defects and life span shortening-are exacerbated by silencing the Drosophila homolog of NONO, no on or off transient A (NonA). Additionally, NonA silencing results in an increase in nuclear TDP-43 NBs. These results provide supporting evidence for the functional link between NONO and TDP-43 and lay the foundation for dissecting underlying mechanisms.}, } @article {pmid39690343, year = {2024}, author = {Lamichhane, S and Seo, JE and Jeong, JH and Lee, S and Lee, S}, title = {Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges.}, journal = {Archives of pharmacal research}, volume = {}, number = {}, pages = {}, pmid = {39690343}, issn = {1976-3786}, support = {Research grant 2024//Chung-Ang University/ ; NRF-2016R1A6A1A03011325//Ministry of Education/ ; }, abstract = {Neurological disorders, encompassing conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), pose a significant global health challenge, affecting millions worldwide. With an aging population and increased life expectancy, the prevalence of these disorders is escalating rapidly, leading to substantial economic burdens exceeding trillions of dollars annually. Animal models play a crucial role in understanding the underlying mechanisms of these disorders and developing effective treatments. Various species, including rodents, non-human primates, and fruit flies, are utilized to replicate specific aspects of human neurological conditions. However, selecting the ideal animal model requires careful consideration of its proximity to human disease conditions and its ability to mimic disease pathobiology and pharmacological responses. An Animal Model Quality Assessment (AMQA) tool has been developed to facilitate this selection process, focusing on assessing models based on their similarity to human conditions and disease pathobiology. Therefore, integrating intrinsic and extrinsic factors linked to the disease into the study's objectives aids in constructing a biological information matrix for comparing disease progression between the animal model and human disease. Ultimately, selecting an ideal animal disease model depends on its predictive, face, and construct validity, ensuring relevance and reliability in translational research efforts.}, } @article {pmid39689069, year = {2024}, author = {Junedahl, E and Lundgren, P and Andersson, E and Gupta, V and Råmunddal, T and Rawshani, A and Rawshani, A and Riva, G and Arnetorp, I and Hessulf, F and Herlitz, J and Djärv, T}, title = {The evidence supporting AHA guidelines on adult cardiopulmonary resuscitation (CPR).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0309241}, pmid = {39689069}, issn = {1932-6203}, mesh = {Humans ; *Cardiopulmonary Resuscitation/standards/methods ; *American Heart Association ; Adult ; *Practice Guidelines as Topic ; United States ; *Heart Arrest/therapy ; Evidence-Based Medicine/standards ; }, abstract = {BACKGROUND: Guidelines for the management of cardiac arrest play a crucial role in guiding clinical decisions and care. We examined the strength and quality of evidence underlying these recommendations in order to elucidate strengths and gaps in knowledge.

METHODS: Using the 2020 American Heart Association (AHA) Guidelines for Adult CPR, we subdivided all recommendations into advanced life support (ALS), basic life support (BLS), and recovery after cardiac arrest, as well as a more granular categorization by topic (i.e. the intervention or evaluation recommended). The Class of Recommendation (COR) and Level of Evidence (LOE) for each were reviewed. Additionally, we reviewed the 2023 guidelines to ensure the inclusion of the most recent updates.

RESULTS: We noted 254 recommendations, of which 181 were ALS, 69 were BLS, and 4 were recovery after resuscitation. In total, only 2 (1%) had the most robust evidence (LOE A), while 23% were at LOE B-NR (Non-Randomized), 15% at LOE B-R (Randomized), 50% at LOE C-LD (Limited Data), and 12% relied on expert opinion LOE C-EO (Expert Opinion). Despite the strength of ALS recommendations (Class 1, 2a, or 2b), none had LOE A. In BLS, no recommendations were supported by LOE A. For BLS, 7% of recommendations had LOE C (C-LD or C-EO). The evidence for specific BLS topics, such as airway management, was notably low. Among ALS topics, neurological prognostication had relatively stronger evidence.

CONCLUSIONS: Only 26 out of the 81 COR 1 recommendations (32%) were supported by LOE A or B, indicating a strong discrepancy between the strength of recommendation and the underlying evidence in cardiac arrest guidelines. The findings underscore a pressing need for more rigorous research, particularly randomized trials.}, } @article {pmid39688956, year = {2024}, author = {Spargo, TP and Gilchrist, L and Hunt, GP and Dobson, RJB and Proitsi, P and Al-Chalabi, A and Pain, O and Iacoangeli, A}, title = {Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39688956}, issn = {2050-084X}, support = {DRIVE-Health Centre for Doctoral Training//King's College London/ ; 772376-EScORIAL//Horizon 2020/ ; ES/L008238/1//Economic and Social Research Council/ ; 633413//Horizon 2020/ ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; 259867//European Community's Health Seventh Framework Programme/ ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; 10.35802/222811/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Genome-Wide Association Study ; Genetic Predisposition to Disease ; Mental Disorders/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Schizophrenia/genetics ; Genetic Loci ; Parkinson Disease/genetics ; Alzheimer Disease/genetics ; }, abstract = {Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant 'local' genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation. We explored the utility of a genome-wide local genetic correlation analysis approach for identifying genetic overlaps between the candidate neuropsychiatric disorders, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson's disease, and schizophrenia. The correlation analysis identified several associations between traits, the majority of which were loci in the human leukocyte antigen region. Colocalisation analysis suggested that disease-implicated variants in these loci often differ between traits and, in one locus, indicated a shared causal variant between ALS and AD. Our study identified candidate loci that might play a role in multiple neuropsychiatric diseases and suggested the role of distinct mechanisms across diseases despite shared loci. The fine-mapping and colocalisation analysis protocol designed for this study has been implemented in a flexible analysis pipeline that produces HTML reports and is available at: https://github.com/ThomasPSpargo/COLOC-reporter.}, } @article {pmid39688717, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Batouli, SAH}, title = {Involvement of the left uncinate fasciculus in the amyotrophic lateral sclerosis: an exploratory longitudinal multi-modal neuroimaging and neuropsychological study.}, journal = {Brain structure & function}, volume = {230}, number = {1}, pages = {8}, pmid = {39688717}, issn = {1863-2661}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; Female ; Male ; Middle Aged ; *Diffusion Tensor Imaging/methods ; Longitudinal Studies ; *Magnetic Resonance Imaging ; Aged ; Neuropsychological Tests ; Adult ; Neural Pathways/diagnostic imaging/physiopathology/pathology ; White Matter/diagnostic imaging/pathology ; Neuroimaging/methods ; Multimodal Imaging ; }, abstract = {To investigate the microstructural integrity, tract volume analysis, and functional connectivity (FC) alterations of the left uncinate fasciculus (UF) in patients with amyotrophic lateral sclerosis (ALS) compared to healthy controls (HCs). Fourteen limb-onset ALS patients were recruited at baseline and ten at follow-up, along with 14 HCs. All participants underwent 3D T1-weighted, diffusion tensor imaging and kurtosis imaging (DTI/DKI), and resting-state functional MRI (rs-fMRI) using a 3 Tesla scanner with 64-channel coils. Eight metrics of diffusion, rs-FC of the left UF, and graph theory analyses were extracted. Statistical group comparisons and correlation analysis for significant diffusion metrics were also conducted. Significantly lower radial kurtosis (RK), mean kurtosis (MK), and higher DTI diffusivity metrics were observed in the left UF of ALS patients than in HCs. RK and MK were correlated with various cognitive scores, particularly executive function and visuospatial ability. The volume of the left UF was positively correlated only with RK and MK at follow-up. While rs-FC analysis did not reveal group differences, a negative functional link between the left UF and cerebellum was observed in HCs but not in patients. Graph theory analysis suggested decreased connectivity in baseline patients and potential compensatory effects during the follow-up. Our study reveals microstructural abnormalities and potential network changes in left UF. DKI metrics, especially RK and MK, may be more sensitive biomarkers than DTI metrics, particularly longitudinally. Diffusion changes appear to precede volume and functional connectivity alterations, suggesting diffusion as a potential early biomarker.}, } @article {pmid39688317, year = {2024}, author = {Tseriotis, VS and Eleftheriadou, K and Mavridis, T and Konstantis, G and Falkenburger, B and Arnaoutoglou, M}, title = {Is the Swallow Tail Sign a Useful Imaging Biomarker in Clinical Neurology? A Systematic Review.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.14304}, pmid = {39688317}, issn = {2330-1619}, support = {//Hellenic Academic Libraries Link/ ; }, abstract = {BACKGROUND: Loss of dorsolateral nigral hyperintensity (DNH) in iron-sensitive sequences of Magnetic Resonance Imaging (MRI), also described as "swallow tail sign" (STS) loss, has shown promising diagnostic value in Parkinson's Disease (PD) and Atypical Parkinsonian Syndromes (APS).

OBJECTIVE: To conduct a bibliometric analysis on substantia nigra MRI and a systematic review on the clinical utility of STS visual assessment on Susceptibility-Weighted Imaging in various clinical entities.

METHODS: VOSviewer's keyword co-occurrence network was employed using Web of Science (WOS). Complying with the PRISMA statement, we searched MEDLINE, WOS, SCOPUS, ProQuest and Google Scholar for peer-reviewed studies conducted in vivo, excluding quantitative imaging techniques.

RESULTS: DNH is a relatively novel parameter in substantia nigra MRI literature. Our SWI-focused review included 42 studies (3281 patients). Diagnostic accuracy of STS loss for PD/APS differentiation from controls and for Lewy Body Dementia differentiation from other dementias was 47.8-98.5% and 76-90%, respectively, with poorer capacity, however, in delineating PD from APS. STS evaluation in idiopathic REM sleep behavior disorder, a sign of prodromal PD, was typically concordant with nuclear scans, identifying subjects with high conversion risk. Iron deposition can affect STS in Multiple Sclerosis and STS loss in Amyotrophic Lateral Sclerosis is linked with multisystem degeneration, with poorer prognosis. In healthy individuals iron-induced microvessel changes are suspected for false positive results.

CONCLUSION: STS assessment exhibits potential in different settings, with a possibly intermediate role in the diagnostic work-up of various conditions. Its clinical utility should be explored further, through standardized MRI protocols on larger cohorts.}, } @article {pmid39687363, year = {2024}, author = {Stal, C and Covătaru, C and De Wolf, Q and Ignat, T and Pecheniuk, D and Lazăr, C}, title = {Towards a spatial data repository for archaeological research in the Romanian Mostiștea Basin and Danube Valley.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {111119}, doi = {10.1016/j.dib.2024.111119}, pmid = {39687363}, issn = {2352-3409}, abstract = {Spatial data are crucial in archaeological research, where orthophotos, digital elevation models, and 3D models are widely used for mapping, documenting, and monitoring archaeological sites. The introduction of affordable and compact unmanned aerial vehicles (UAVs) has significantly advanced the use of UAV-based photogrammetry in the past 20 years. Recently, compact airborne systems have also enabled the capture of thermal, multispectral, and aerial laser scanning data. This paper presents the data acquired with different platforms and sensors at Chalcolithic archaeological sites in Romania's Mostiștea Basin and Danube Valley. Since laser scanning and photogrammetry generate large data volumes, data storage and dissemination must also be carefully considered. Based on a thorough study of system performance, data acquisition and processing methods, and data outputs, a workflow for the systematic mapping and documentation of sites has been proposed. Given the experience obtained in the last 5 summer campaigns (2018-2023), 19 sites have been accurately mapped, of which 5 sites are mapped using airborne laser scanning. 18 sites are documented using multispectral photogrammetry, and for 17 sites, interactive image-based 3D models are acquired using true-color photogrammetry. All data are stored on a publicly accessible website for visualization, as well as on an open-data platform for data exchange. For the multispectral data, a raster tile service has been implemented, allowing the use of the data in a GIS environment.}, } @article {pmid39687198, year = {2024}, author = {Pappalardo, XG and Jansen, G and Amaradio, M and Costanza, J and Umeton, R and Guarino, F and De Pinto, V and Oliver, SG and Messina, A and Nicosia, G}, title = {Inferring gene regulatory networks of ALS from blood transcriptome profiles.}, journal = {Heliyon}, volume = {10}, number = {23}, pages = {e40696}, pmid = {39687198}, issn = {2405-8440}, abstract = {One of the most robust approaches to the prediction of causal driver genes of complex diseases is to apply reverse engineering methods to infer a gene regulatory network (GRN) from gene expression profiles (GEPs). In this work, we analysed 794 GEPs of 1117 human whole-blood samples from Amyotrophic Lateral Sclerosis (ALS) patients and healthy subjects reported in the GSE112681 dataset. GRNs for ALS and healthy individuals were reconstructed by ARACNe-AP (Algorithm for the Reconstruction of Accurate Cellular Networks - Adaptive Partitioning). In order to examine phenotypic differences in the ALS population surveyed, several datasets were built by arranging GEPs according to sex, spinal or bulbar onset, and survival time. The designed reverse engineering methodology identified a significant number of potential ALS-promoting mechanisms and putative transcriptional biomarkers that were previously unknown. In particular, the characterization of ALS phenotypic networks by pathway enrichment analysis has identified a gender-specific disease signature, namely network activation related to the radiation damage response, reported in the networks of bulbar and female ALS patients. Also, focusing on a smaller interaction network, we selected some hub genes to investigate their inferred pathological and healthy subnetworks. The inferred GRNs revealed the interconnection of the four selected hub genes (TP53, SOD1, ALS2, VDAC3) with p53-mediated pathways, suggesting the potential neurovascular response to ALS neuroinflammation. In addition to being well consistent with literature data, our results provide a novel integrated view of ALS transcriptional regulators, expanding information on the possible mechanisms underlying ALS and also offering important insights for diagnostic purposes and for developing possible therapies for a disease yet incurable.}, } @article {pmid39686920, year = {2025}, author = {Sodagari, S and Sodagari, N}, title = {Examining vaccination-related adverse events in frequent neurodegenerative diseases.}, journal = {Brain, behavior, & immunity - health}, volume = {43}, number = {}, pages = {100902}, pmid = {39686920}, issn = {2666-3546}, abstract = {This study investigates adverse events following vaccination in patients with four neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Multiple Sclerosis (MS), and Parkinson's disease. We applied advanced data processing techniques to analyze symptom patterns and severity scores across these disease groups. Patients were identified through filtering, and symptom clusters were extracted to group similar symptoms into distinct clusters, and severity scores were computed based on hospitalization and death reports. A chi-squared test was performed to assess the statistical significance of adverse event distributions among the diseases for different vaccines. The results reveal that ALS patients exhibit severe respiratory symptoms post-vaccination, while Alzheimer's patients report significant respiratory and gastrointestinal issues. MS patients commonly experience general symptoms such as fatigue, while Parkinson's patients face exacerbated motor symptoms. Notably, our analysis showed no significant difference in adverse event reporting rates between COVID-19 and pneumococcal vaccines across these disease groups. This research provides new insights into disease-specific responses to vaccines, emphasizing the importance of personalized monitoring and treatment strategies to mitigate risks and improve clinical outcomes in these vulnerable populations.}, } @article {pmid39684507, year = {2024}, author = {Tournezy, J and Léger, C and Klonjkowski, B and Gonzalez-Dunia, D and Szelechowski, M and Garenne, A and Mathis, S and Chevallier, S and Le Masson, G}, title = {The Neuroprotective Effect of the X Protein of Orthobornavirus Bornaense Type 1 in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684507}, issn = {1422-0067}, support = {Evaluation of the therapeutic potential of the Borna virus X protein and X-derived peptides in ALS//Association pour la recherche sur la Sclérose Latérale Amyotrophique/ ; Award Fabrice Le Mouaher 2020//Fondation pour la Recherche Médicale/ ; trampoline grant 20219//Association Francaise contre les Myopathies/ ; X protein and ALS//Rotary Club of Bergerac/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Motor Neurons/metabolism/pathology ; Mice ; *Neuroprotective Agents/pharmacology ; *Disease Models, Animal ; Adenosine Triphosphate/metabolism ; Viral Proteins/metabolism/genetics ; Mice, Transgenic ; Humans ; }, abstract = {In amyotrophic lateral sclerosis (ALS), early mitochondrial dysfunction may contribute to progressive motor neuron loss. Remarkably, the ectopic expression of the Orthobornavirus bornaense type 1 (BoDV-1) X protein in mitochondria blocks apoptosis and protects neurons from degeneration. Therefore, this study examines the neuroprotective effects of X protein in an ALS mouse model. We first tested in vitro the effect of the X-derived peptide (PX3) on motoneurons primary cultures of SOD1[G93A] mice. The total intracellular adenosine triphosphate (ATP) content was measured after incubation of the peptide. We next tested in vivo the intramuscular injection of X protein using a canine viral vector (CAV2-X) and PX3 intranasal administrations in SOD1[G93A] mice. Disease onset and progression were assessed through rotarod performance, functional motor unit analysis via electrophysiology, and motor neuron survival by immunohistochemistry. The results showed that in vitro PX3 restored the ATP level in SOD1[G93A] motor neurons. In vivo, treated mice demonstrated better motor performance, preserved motor units, and higher motor neuron survival. Although life expectancy was not extended in this severe mouse model of motor neuron degeneration, the present findings clearly demonstrate the neuroprotective potential of X protein in a model of ALS. We are convinced that further studies may improve the therapeutic impact of X protein with optimized administration methods.}, } @article {pmid39684324, year = {2024}, author = {Toader, C and Tataru, CP and Munteanu, O and Serban, M and Covache-Busuioc, RA and Ciurea, AV and Enyedi, M}, title = {Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684324}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Parkinson Disease/therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; Neurodegenerative Diseases/therapy/metabolism/genetics ; Drug Delivery Systems ; Gene Editing ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.}, } @article {pmid39684308, year = {2024}, author = {Ścibior, A and Llopis, J and Dobrakowski, PP and Męcik-Kronenberg, T}, title = {Magnesium (Mg) and Neurodegeneration: A Comprehensive Overview of Studies on Mg Levels in Biological Specimens in Humans Affected Some Neurodegenerative Disorders with an Update on Therapy and Clinical Trials Supplemented with Selected Animal Studies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684308}, issn = {1422-0067}, mesh = {Humans ; *Magnesium/therapeutic use ; Animals ; *Neurodegenerative Diseases/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Neuroprotective Agents/therapeutic use/pharmacology ; Parkinson Disease/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Neurodegenerative diseases, characterized by neuron loss, are a group of neurological disorders that adversely affect the lives of millions of people worldwide. Although several medicines have been approved for managing neurodegenerative diseases, new therapies allowing for a significant slowdown in the progression of neurodegenerative syndromes are constantly being sought. Magnesium (Mg), a crucial mineral necessary for the functioning of organisms, is important to normal central nervous system (CNS) activity. Although the effects of this bioelement on the CNS are relatively well recognized, its role in the pathophysiology of neurological disorders in humans is not yet well characterized. Therefore, the main goal of this review is to collect data about a possible association between Mg and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's Disease (PD), and Amyotrophic lateral sclerosis (ALS) in humans. Hence, the levels of Mg in blood, cerebrospinal fluid (CSF), urine, and hair from subjects with AD, PD, and ALS are compiled to detect possible variations in the levels of this mineral in the biological specimens of people with neurodegenerative illnesses. Additionally, the findings from an animal model are summarized to offer the reader a deeper insight into studies on Mg in the context of neuroprotection and neurodegeneration. Data provided in the present review indicate that Mg, due to its neuroprotective, antioxidant, anti-inflammatory, and mitochondrial-supportive properties, could be a potential therapeutic agent for AD, PD, and ALS. However, more epidemiological studies with standardized methods of dietary assessment and Mg measurement are necessary to recognize its exact role in neurodegenerative disorders. Moreover, extensive well-designed clinical trials are also needed to establish definitive therapeutic protocols and optimal dosages, and to ensure long-term safety of this mineral supplementation in AD, PD, and ALS patients.}, } @article {pmid39684197, year = {2024}, author = {García-González, N and Gonçalves-Sánchez, J and Gómez-Nieto, R and Gonçalves-Estella, JM and López, DE}, title = {Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684197}, issn = {1422-0067}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; Amyotrophic Lateral Sclerosis/therapy/genetics ; }, abstract = {This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.}, } @article {pmid39682764, year = {2024}, author = {Huang, R and Xia, H and Lin, W and Wang, Z and Li, L and Deng, J and Ye, T and Li, Z and Yang, Y and Huang, Y}, title = {Riluzole Reverses Blood-Testis Barrier Loss to Rescue Chemotherapy-Induced Male Infertility by Binding to TRPC.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682764}, issn = {2073-4409}, support = {No. U22A20277, 32170865, and 82071634//National Natural Science Foundation of China/ ; No. 2022A1515012178//Natural Science Foundation of Guangdong Province/ ; No. 202103030003//Guangzhou Key R&D Program/ ; No.2022B1111080007//Kea-Area Research and Development Program of Guangdong Province/ ; }, mesh = {Male ; *Riluzole/pharmacology/therapeutic use ; Animals ; *Blood-Testis Barrier/drug effects/metabolism ; *Infertility, Male/chemically induced/drug therapy/pathology ; Mice ; TRPC Cation Channels/metabolism ; Busulfan/pharmacology/adverse effects ; Antineoplastic Agents/pharmacology/adverse effects ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Protein Binding/drug effects ; }, abstract = {Cancer treatments, including cytotoxic therapy, often result in male infertility, necessitating the development of safe and effective strategies to preserve male reproductive potential during chemotherapy. Notably, our study uncovers the potential of repurposing riluzole, an FDA-approved drug for amyotrophic lateral sclerosis (ALS), in enhancing spermatogenesis. Hence, this research aims to explore the feasibility of utilizing riluzole to alleviate male infertility induced by busulfan (BSF), a commonly used chemotherapy drug. We established a BSF-induced oligospermia model in 4-week-old male mice and found that riluzole could effectively counter the detrimental effects of BSF on sperm production in mice with oligospermia. By restoring blood-testis barrier (BTB) functionality, riluzole improves sperm quality and reduces testicular atrophy. Through transcriptomic and molecular docking analyses, we identify transient receptor potential canonical subfamily member 5 (TRPC5) as a potential target for riluzole-mediated regulation of blood-testis barrier function. These findings propose riluzole as a promising therapeutic option for chemotherapy-induced male infertility, thereby addressing the fertility challenges associated with cancer treatments. Moreover, repurposing riluzole could streamline the drug development process, providing a cost-effective approach with reduced risk compared to developing entirely new drugs.}, } @article {pmid39681722, year = {2024}, author = {Weiner, HL}, title = {Immune mechanisms and shared immune targets in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {39681722}, issn = {1759-4766}, abstract = {The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.}, } @article {pmid39681698, year = {2024}, author = {Aschemacher, NA and Siano, ÁS and Teglia, CM and Goicoechea, HC}, title = {Development, optimization and comparison of solid-liquid and liquid-liquid microextraction for the determination of four flavonols in Schinus molle L. using high-performance liquid chromatography coupled with second-order data modeling.}, journal = {Analytical and bioanalytical chemistry}, volume = {}, number = {}, pages = {}, pmid = {39681698}, issn = {1618-2650}, support = {PICT 2020-0304//Fondo para la Investigación Científica y Tecnológica/ ; }, abstract = {Flavonoids are particularly interesting because they have a broad spectrum of biological effects, including antioxidant and free radical scavenging activities. In this work, solid-liquid microextraction and dispersive liquid-liquid microextraction enhanced by ultrasound were developed and compared with the conventional method (Soxhlet extraction) to optimize the extraction of four flavonoids: rutin, quercitrin, quercetin, and myricetin in samples of Schinus molle (Aguaribay). During the development of the analytical method, different chemometric tools were used to optimize the microextraction procedure. In addition, an analytical method based on high-performance liquid chromatography with diode array detector (HPLC-DAD) and second order calibration using multivariate curve resolution-alternating least square (MCR-ALS) is presented to quantify the flavonoids with limits of quantification between 0.011 and 0.082 µg mL[-1]. Finally, solid-liquid microextraction using 4.00 mL water/ethanol (54.3:45.7%), 14 s vortex, and 45 min was selected as the most suitable method due to its high recovery rate and environmental friendliness (with a greenness score of 0.78). After the optimization step, the concentrations found in the plant samples were 1825.3, 632.6, 110.2, and 18.9 µg g[-1] for rutin, quercitrin, quercetin, and myricetin, respectively. The present work is the first achievement of simultaneously determining these four analytes with exceptional sensitivity, demonstrating lower LOQs compared to previous reports.}, } @article {pmid39680524, year = {2024}, author = {Rocha, PS and Bento, N and Folgado, D and Carreiro, AV and Santos, MO and de Carvalho, M and Miranda, B}, title = {Evaluation of smartphone-based cough data in amyotrophic lateral sclerosis as a potential predictor of functional disability.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301734}, pmid = {39680524}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Cough/physiopathology ; Male ; Female ; *Smartphone ; Middle Aged ; Case-Control Studies ; Aged ; Cross-Sectional Studies ; Support Vector Machine ; Adult ; }, abstract = {OBJECTIVES: Cough dysfunction is a feature of patients with amyotrophic lateral sclerosis (ALS). The cough sounds carry information about the respiratory system and bulbar involvement. Our goal was to explore the association between cough sound characteristics and the respiratory and bulbar functions in ALS.

METHODS: This was a single-center, cross-sectional, and case-control study. On-demand coughs from ALS patients and healthy controls were collected with a smartphone. A total of 31 sound features were extracted for each cough recording using time-frequency signal processing analysis. Logistic regression was applied to test the differences between patients and controls, and in patients with bulbar and respiratory impairment. Support vector machines (SVM) were employed to estimate the accuracy of classifying between patients and controls and between patients with bulbar and respiratory impairment. Multiple linear regressions were applied to examine correlations between cough sound features and clinical variables.

RESULTS: Sixty ALS patients (28 with bulbar dysfunction, and 25 with respiratory dysfunction) and forty age- and gender-matched controls were recruited. Our results revealed clear differences between patients and controls, particularly within the frequency-related group of features (AUC 0.85, CI 0.79-0.91). Similar results were observed when comparing patients with and without bulbar dysfunction. Sound features related to intensity displayed the strongest correlation with disease severity, and were the most significant in distinguishing patients with and without respiratory dysfunction.

DISCUSSION: We found a good relationship between specific cough sound features and clinical variables related to ALS functional disability. The findings relate well with some expected impact from ALS on both respiratory and bulbar contributions to the physiology of cough. Finally, our approach could be relevant for clinical practice, and it also facilitates home-based data collection.}, } @article {pmid39680215, year = {2024}, author = {Wu, H and Erenay, FS and Özaltın, OY and Dalgıç, ÖO and Sır, MY and He, QM and Crum, BA and Pasupathy, KS and , }, title = {Prognostic factors affecting ALS progression through disease tollgates.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {69}, pmid = {39680215}, issn = {1432-1459}, support = {2018-06596//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; 2017-04001//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Disease Progression ; Male ; Female ; Prognosis ; Middle Aged ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Understanding factors affecting the timing of critical clinical events in ALS progression.

METHODS: We captured ALS progression based on the timing of critical events (tollgates), by augmenting 6366 patients' data from the PRO-ACT database with tollgate-passed information using classification. Time trajectories of passing ALS tollgates after the first visit were derived using Kaplan-Meier analyses. The significant prognostic factors were found using log-rank tests. Decision-tree-based classifications identified significant ALS phenotypes characterized by the list of body segments involved at the first visit.

RESULTS: Standard (e.g., gender and onset type) and tollgate-related (phenotype and initial tollgate level) prognostic factors affect the timing of ALS tollgates. For instance, by the third year after the first visit, 80-100% of bulbar-onset patients vs. 43-48% of limb-onset patients, and 65-73% of females vs. 42-49% of males lost the ability to talk and started using a feeding tube. Compared to the standard factors, tollgate-related factors had a stronger effect on ALS progression. The initial impairment level significantly impacted subsequent ALS progression in a segment while affected segment combinations further characterized progression speed. For instance, patients with normal speech (Tollgate Level 0) at the first visit had less than a 10% likelihood of losing speech within a year, while for patients with Tollgate Level 1 (affected speech), this likelihood varied between 23 and 53% based on additional segment (leg) involvement.

CONCLUSIONS: Tollgate- and phenotype-related factors have a strong effect on the timing of ALS tollgates. All factors should be jointly considered to better characterize patient groups with different progression aggressiveness.}, } @article {pmid39679928, year = {2024}, author = {Bhattacharjee, T and Vengalil, S and Belur, Y and Atchayaram, N and Ghosh, PK}, title = {Inter-speaker acoustic differences of sustained vowels at varied dysarthria severities for amyotrophic lateral sclerosis.}, journal = {JASA express letters}, volume = {4}, number = {12}, pages = {}, doi = {10.1121/10.0034613}, pmid = {39679928}, issn = {2691-1191}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Dysarthria/etiology/physiopathology ; *Speech Acoustics ; Male ; Female ; Middle Aged ; Aged ; Severity of Illness Index ; Phonetics ; }, abstract = {We study inter-speaker acoustic differences during sustained vowel utterances at varied severities of Amyotrophic Lateral Sclerosis-induced dysarthria. Among source attributes, jitter and standard deviation of fundamental frequency exhibit enhanced inter-speaker differences among patients than healthy controls (HCs) at all severity levels. Though inter-speaker differences in vocal tract filter attributes at most severity levels are higher than those among HCs for close vowels /i/ and /u/, these are comparable with or lower than those among HCs for the relatively more open vowels /a/ and /o/. The differences typically increase with severity except for a few parameters for /a/ and /i/.}, } @article {pmid39679063, year = {2024}, author = {Kodavati, M and Hegde, ML}, title = {A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS.}, journal = {Neuroscience insights}, volume = {19}, number = {}, pages = {26331055241305151}, pmid = {39679063}, issn = {2633-1055}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.}, } @article {pmid39678608, year = {2024}, author = {Dong, F}, title = {Bioinformatic materials science reconsidered.}, journal = {American journal of translational research}, volume = {16}, number = {11}, pages = {7200-7204}, pmid = {39678608}, issn = {1943-8141}, abstract = {Bioinformatic materials science integrates medical science, materials science, informatics, and other disciplines, aiming to maintain the balance of tissues and organs in the human body. This paper explores the relationship between structural information and the structures synthesized through regulated gene expression. Specifically, it describes the transformation of information into substances via biological structural systems, using mathematical formulas to develop bioinformatic materials. These materials have applications in medical treatments, functional foods for preventive healthcare, and cosmetic products for health maintenance. Notably, bioinformatic materials have been applied in treating acromegaly, a rare and life-threatening disease of unknown etiology, and have improved the neurofilament light chain (NFL) index and typical symptoms of Amyotrophic Lateral Sclerosis (ALS). In summary, bioinformatic materials science holds potential for enhancing human health and contributing to advances in medicine.}, } @article {pmid39678458, year = {2024}, author = {Sulek, A}, title = {Secretome - the role of extracellular vesicles in the pathogenesis and therapy of neurodegenerative diseases.}, journal = {Postepy psychiatrii neurologii}, volume = {33}, number = {3}, pages = {147-162}, pmid = {39678458}, issn = {2720-5371}, abstract = {PURPOSE: Extracellular vesicles are the subject of many studies in various medical specialties. Their role in neurodegenerative diseases is increasing and they worth introducing in more detail.

METHODS: This review was performed following an electronic search of the database PubMed/Medline and Web of Science for English-language articles between 2010 and 2024 in the fields of medicine, molecular biology, and biochemistry. Keywords searches included combinations of the following terms: "extracellular vesicles" OR "exosomes" AND "neurodeg*" AND "microRNA" OR "miRNA" AND "AD" OR "PD" OR "ALS" OR "HD". Articles had to be original work or reviews.

RESULTS: The classification of extracellular vesicles is based on their size or origin. Their content is of key importance in communication between cells and can be treated as a physiological determinant of the normal or pathological condition of a body. The cargo transported in the extracellular space and over longer distances in various body fluids is diversified and may be nucleic acids (DNA, RNA, miRNA) as well as proteins and lipids, and, in the case of apoptotic bodies also a cell's organelles. Exosomes are the most thoroughly studied extracellular vesicles and the most often considered for therapeutic applications. Vesicles carrying biological substances in the body perform three basic functions: participation in a pathological mechanism, a biomarker role that also has diagnostic and prognostic functions, and a role in therapeutic activities. In the case of neurodegenerative diseases, it appears that extracellular vesicles can transport misfolded proteins, initiating pathological processes in previously normal cells.

CONCLUSIONS: The transport of various substances enclosed in vesicles seems to be very promising in therapeutic prospects in various diseases, and the possibility of their crossing the blood-brain barrier particularly indicates diseases of the central nervous system. Despite many years of research on extracellular vesicles in the context of neurodegenerative diseases, their practical use is currently limited to studies on animal and cellular models, and their practical application in clinical trials in neurodegenerative diseases is to date extremely rare.}, } @article {pmid39678223, year = {2025}, author = {Banos, M and Preuilh, A and Pradat, PF and Lackmy-Vallée, A and Marchand-Pauvert, V}, title = {Exercises and Brain Stimulation to Preserve Function in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {1}, pages = {e200408}, pmid = {39678223}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to the loss of motor function and muscle strength. Nonpharmacologic neuromodulative therapeutic approaches such as active exercise may contribute to preserve motor functions in ALS, but this hypothesis remains debated. The present meta-analysis first aimed to evaluate the effect of active exercise on function and muscle strength preservation. Moreover, since the responsiveness to induced neuroplasticity of patients with ALS is being discussed, the second objective was to review the analogous effects of noninvasive brain stimulation (NIBS).

METHODS: Following PRISMA guidelines, we systematically reviewed PubMed, CENTRAL, NIH PMC, PEDro, ScienceDirect, and Web of Science databases from the period between January 10 and July 1, 2023. Criteria limited inclusion to randomized controlled trials comparing active exercise (aerobic or resistance) with usual care or NIBS with sham. The primary outcome was assessed based on functional assessment scores reported on validated clinical scales, and the secondary outcome analysis included muscle strength and neurophysiologic changes. Methodologic quality of the selected studies was assessed using the Physiotherapy Evidence-Based (PEDro) scale. Relative risk (RR) and heterogeneity (I[2]) were calculated with Revman software, and evidence quality was estimated by the GRADE quality scale.

RESULTS: Thirteen studies were included. Analysis involved 393 patients among whom 164 underwent active exercise and 155 received usual care, 41 received NIBS and 33 underwent sham stimulations. The nature of active exercise was consistent across studies but varied in frequency. NIBS parameters were consistent for stimulation sites and session frequency. Function was significantly preserved in 5 of 9 studies on active exercise and 2 of 4 NIBS trials. Meta-analysis on functional scales indicated a moderate quality of evidence for the effectiveness of active exercises (RR = 0.61 [0.18, 1.04] with I[2] = 69%) compared with usual care and very low quality of evidence for NIBS (RR = -1.41 [-0.44, 3.26] with I[2] = 89%). Only 1 NIBS study revealed neuroplastic changes in the brain.

DISCUSSION: Active exercise likely slows functional loss in ALS, but the effects of NIBS need further investigation to support their neuroprotective effectiveness. Moreover, both interventions require further neurophysiologic investigation to elucidate ALS neuroplasticity.

This review has been registered in PROSPERO (CRD42023408121).}, } @article {pmid39678056, year = {2024}, author = {Baslo, SA and Şirin, NG and Orhan, EK and Baslo, MB and Öge, AE}, title = {Selective Muscle Involvement in Amyotrophic Lateral Sclerosis: Evidence Inferred from the Point of Motor Unit Firing Rates.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {296-305}, pmid = {39678056}, issn = {1300-0667}, abstract = {INTRODUCTION: The aim of the study is to determine the role of upper motor neuron (UMN) or lower motor neuron (LMN) dysfunction as the primary initiator of distal-proximal and lateral-medial gradients of muscle involvement in amyotrophic lateral sclerosis (ALS).

METHODS: Concentric needle electromyography recordings were performed in deltoid, abductor digiti minimi, and first dorsal interosseous (FDI) muscles in patients with ALS and controls during slight voluntary contraction needed to activate two motor units (MU). Five motor unit potential (MUP) pairs were recorded from each muscle. Motor unit potential analyses were performed offline using Multi-MUP analysis program. Quantitative MUP parameters, MU firing rate (FR), FR variability (FRV), and mean consecutive difference (MCD) were calculated. Motor-evoked potentials and the triple stimulation technique (TST) were performed to evaluate UMN involvement.

RESULTS: Twenty patients with ALS along with 20 age and sex-matched healthy volunteers were enrolled. Quantitative MUP parameters compatible with denervation and reinnervation were found in patients with ALS, who also showed higher FR, FRV, and MCD values, most prominently in FDI. First dorsal interosseous FRV was lower in patients with abnormal central motor conduction time (CMCT). Firing rate and FRV were negatively correlated with CMCT, but not with TST.

CONCLUSION: Distal limb muscles, particularly FDI, revealed more prominent FR abnormalities in patients with ALS in parallel with the distal-proximal and lateral-medial gradients of the selective muscle involvement pattern which seems predominantly to be correlated with LMN dysfunction. Reduced FRV may be associated with the presence of UMN dysfunction in ALS.}, } @article {pmid39678053, year = {2024}, author = {Finsterer, J and Mehri, S}, title = {The Causality Spectrum of Dropped Head Syndrome is Broad and Includes Myopathy, Neurodegenerative Disorders, and Varia.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {382-383}, pmid = {39678053}, issn = {1300-0667}, abstract = {Dropped head syndrome is a common complication of various neurological disorders. Most commonly, dropped head syndrome is due to primary or secondary myopathy. However, neurodegenerative diseases and various other conditions can also be complicated by dropped head syndrome. Among the primary myopathies, dropped head occurs most commonly in association with mitochondrial disorders, congenital myasthenic syndrome, and axial myopathies. Among the secondary myopathies, dropped occurs most commonly in association with inflammatory myopathies. Myasthenia is the most common transmission disorder associated with dropped head syndrome. The neurodegenerative disorder most commonly associated with dropped head syndrome is Parkinson syndrome. The diagnosis and treatment of dropped head syndrome from any cause requires a multidisciplinary approach. Outcome varies considerably but early diagnosis and early treatment are associated with a more favourable outcome.}, } @article {pmid39677679, year = {2024}, author = {Chen, L and Smith, M and Roe, DR and Miranda-Quintana, RA}, title = {Extended Quality (eQual): Radial threshold clustering based on n-ary similarity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677679}, issn = {2692-8205}, support = {R35 GM150620/GM/NIGMS NIH HHS/United States ; }, abstract = {We are transforming Radial Threshold Clustering (RTC), an O (N 2) algorithm, into Extended Quality Clustering, an O (N) algorithm with several novel features. Daura et al's RTC algorithm is a partitioning clustering algorithm that groups similar frames together based on their similarity to the seed configuration. Two current issues with RTC is that it scales as O (N 2) making it inefficient at high frame counts, and the clustering results are dependent on the order of the input frames. To address the first issue, we have increased the speed of the seed selection by using k -means++ to select the seeds of the available frames. To address the second issue and make the results invariant with respect to frame ordering, whenever there is a tie in the most populated cluster, the densest and most compact cluster is chosen using the extended similarity indices. The new algorithm is able to cluster in linear time and produce more compact and separate clusters.}, } @article {pmid39677629, year = {2024}, author = {Park, S and Park, SK and Liebman, SW}, title = {A model of inborn metabolism errors associated with adenine amyloid-like fiber formation reduces TDP-43 aggregation and toxicity in yeast.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.03.626668}, pmid = {39677629}, issn = {2692-8205}, abstract = {TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1Δ aah1Δ yeast model of disorders of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from a liquid-like, toward a more amyloid-like, state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like and not amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1Δ aah1Δ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine/TDP-43 fiber interactions as seen for other heterologous fibers. The work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.}, } @article {pmid39677625, year = {2024}, author = {Li, A and Dong, L and Li, X and Yi, J and Ma, J and Zhou, J}, title = {ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677625}, issn = {2692-8205}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, abstract = {Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression and exploring the underlying molecular nature may deliver great therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis and ALDH3A1 is an inactivation-resistant intracellular detoxifier of 4-HNE protecting eyes against UV-induced oxidative stress. Here we detected prominently higher levels of ALDH3A1 in mouse EOMs than other muscles under normal physiological conditions. In an ALS mouse model (hSOD1[G93A]) reaching end-stage, ALDH3A1 expression was sustained at high level in EOMs, whereas substantial upregulation of ALDH3A1 occurred in soleus and diaphragm. The upregulation was less pronounced in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling as demonstrated by unparalleled upregulation of a denervation marker ANKRD1 expression. Interestingly, sciatic nerve transection in wildtype mice induced ALDH3A1 and ANKRD1 expression in an inverse manner over muscle type and time. Adeno-associated virus enforced overexpression of ALDH3A1 protected myotubes from 4-HNE-induced DNA fragmentation, plasma membrane leakage and restored MG53-mediated membrane repair. Our data indicate that ALDH3A1 may contribute to distinct muscle resistance to ALS through detoxifying reactive aldehydes.}, } @article {pmid39676614, year = {2024}, author = {Roscoe, S and Allen, SP and McDermott, C and Stavroulakis, T}, title = {Exploring the role of anthropometric measurements to assess nutritional status in amyotrophic lateral sclerosis: a longitudinal prospective cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/21678421.2024.2434176}, pmid = {39676614}, issn = {2167-9223}, abstract = {OBJECTIVE: To observe longitudinal correlations between limb anthropometry against weight, BMI and functional decline in patients with amyotrophic lateral sclerosis.

METHODS: A longitudinal, prospective, cohort study was undertaken. Four consecutive measurements of weight, height, triceps skinfold thickness (TSF), mid-upper arm (MUAC) and calf circumferences were collected at three-monthly intervals. Fat- and lean body mass were estimated using measurements of TSF and derivations of arm muscle area, respectively. Correlation analyses indicated associations between anthropometric assessments and functional decline (ALSFRS-R). Longitudinal changes were assessed using repeated measures analyses.

RESULTS: Data from 18 participants was analyzed. At enrollment, weight positively correlated with MUAC (n = 17, p = 0.0001), arm muscle area (n = 17, p = 0.04) and calf circumference (n = 17, p < 0.0001). The ALSFRS-R score negatively correlated with weight (n = 17, p = 0.03), MUAC (n = 18, p = 0.01), TSF (n = 18, p = 0.04), and calf circumference (n = 18, p = 0.003). Function significantly declined by a difference of 6.3 points per month (p = 0.009). A positive correlation was observed between the changes in weight and calf circumference over nine months (r = 0.70, p = 0.02, n = 10).

CONCLUSION: Limb anthropometric measurements may be surrogate indicators of weight and BMI; TSF may be a practical, reliable indicator of fat mass, whilst changes in calf circumference may be alternatively used to monitor changes in nutritional status in the clinic.}, } @article {pmid39674407, year = {2024}, author = {Xue, S and Bao, W and Lyu, J and Wang, C and Zhang, Y and Li, H and Chen, D and Lu, Y}, title = {In vitro nephrotoxicity and structure-toxicity relationships of eight natural aristolactams.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {254}, number = {}, pages = {108214}, doi = {10.1016/j.toxicon.2024.108214}, pmid = {39674407}, issn = {1879-3150}, abstract = {The structural similarity between aristolactams (ALs) and aristolochic acids (AAs) raises constant concerns about the safety of ALs-containing plants. Natural ALs are distributed more extensively than AAs, leading to a higher risk of ALs exposure in daily consumption. This study aimed to evaluate and compare the in vitro nephrotoxicity on human renal tubular epithelial cells (HK-2 cells) of eight natural ALs with different substituents on the phenanthrene ring and amide ring, including aristolactam Ⅰ (AL Ⅰ), AL BⅡ, velutinam, AL AⅡ, sauristolactam, AL AⅠa, AL FⅠ and N-methyl piperolactam A. Their IC50 values of cell viability were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of kidney injury molecule-1 (KIM-1), transforming growth factor-β1 (TGF-β1) and fibronectin (FN). The reactive oxygen species (ROS) assay was used to detect the intracellular oxidative stress level. The results showed that the eight ALs all had specific nephrotoxicity on HK-2 cells. Particularly, AL Ⅰ, AL BⅡ and velutinam exhibited more potent cytotoxicity on HK-2 cells (IC50 = 2.49-2.78 μM) than the other five ALs (IC50 = 12.33-43.84 μM). The structure-toxicity relationships indicated that both methylenedioxy (-OCH2O-) and methoxy (-OCH3) were positively contributing functional groups of ALs on nephrotoxicity, while the hydroxy group (-OH) and methyl substitution on nitrogen (N-CH3) accounted for a detrimental effect conversely. Consistent with this structure-toxicity relationship, the eight ALs increased KIM-1 levels in the same trend as their cytotoxicity at the same concentration of 2.5 μg/mL, associating with different levels of ROS generation. And the four most toxic ALs, AL Ⅰ, AL BⅡ, velutinam and AL AⅡ, could also induce fibrosis by increasing TGF-β1 and FN levels.}, } @article {pmid39674307, year = {2024}, author = {Pistolesi, A and Ranieri, G and Calvani, M and Guasti, D and Chiarugi, A and Buonvicino, D}, title = {Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115095}, doi = {10.1016/j.expneurol.2024.115095}, pmid = {39674307}, issn = {1090-2430}, abstract = {Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.}, } @article {pmid39657109, year = {2024}, author = {Benatar, M and McDermott, C and Turner, MR and van Eijk, RPA}, title = {Rethinking phase 2 trials in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae396}, pmid = {39657109}, issn = {1460-2156}, abstract = {There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on Phase 2 data, which then fail in Phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected. Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to Phase 2 go/no-go decisions. Over-interpretation of Phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritisation for the investment needed for definitive Phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to Phase 2 design and implementation.}, } @article {pmid39656857, year = {2024}, author = {Alvarado, M and Gómez-Navajas, JA and Blázquez-Muñoz, MT and Gómez-Molero, E and Fernández-Sánchez, S and Eraso, E and Munro, CA and Valentín, E and Mateo, E and de Groot, PWJ}, title = {The good, the bad, and the hazardous: comparative genomic analysis unveils cell wall features in the pathogen Candidozyma auris typical for both baker's yeast and Candida.}, journal = {FEMS yeast research}, volume = {24}, number = {}, pages = {}, pmid = {39656857}, issn = {1567-1364}, support = {PID2020-117983RB-I00//Agencia Estatal de Investigación/ ; SBPLY/23/180225/000029//UCLM/ ; //European Regional Development Fund/ ; JDC2023-051226-I//European Social Fund Plus/ ; }, mesh = {*Cell Wall/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Computational Biology ; Genomics ; Candida auris/genetics/metabolism/drug effects ; beta-Glucans/metabolism ; Genome, Fungal ; Fungal Proteins/genetics/metabolism ; Glycosylphosphatidylinositols/metabolism/genetics ; Candida albicans/genetics/pathogenicity ; Candida/genetics/metabolism/pathogenicity ; }, abstract = {The drug-resistant pathogenic yeast Candidozyma auris (formerly named Candida auris) is considered a critical health problem of global importance. As the cell wall plays a crucial role in pathobiology, here we performed a detailed bioinformatic analysis of its biosynthesis in C. auris and related Candidozyma haemuli complex species using Candida albicans and Saccharomyces cerevisiae as references. Our data indicate that the cell wall architecture described for these reference yeasts is largely conserved in Candidozyma spp.; however, expansions or reductions in gene families point to subtle alterations, particularly with respect to β--1,3--glucan synthesis and remodeling, phosphomannosylation, β-mannosylation, and glycosylphosphatidylinositol (GPI) proteins. In several aspects, C. auris holds a position in between C. albicans and S. cerevisiae, consistent with being classified in a separate genus. Strikingly, among the identified putative GPI proteins in C. auris are adhesins typical for both Candida (Als and Hyr/Iff) and Saccharomyces (Flo11 and Flo5-like flocculins). Further, 26 putative C. auris GPI proteins lack homologs in Candida genus species. Phenotypic analysis of one such gene, QG37_05701, showed mild phenotypes implicating a role associated with cell wall β-1,3-glucan. Altogether, our study uncovered a wealth of information relevant for the pathogenicity of C. auris as well as targets for follow-up studies.}, } @article {pmid39656589, year = {2024}, author = {Nascimento, F and Özyurt, MG and Halablab, K and Bhumbra, GS and Caron, G and Bączyk, M and Zytnicki, D and Manuel, M and Roselli, F and Brownstone, R and Beato, M}, title = {Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115046}, doi = {10.1016/j.celrep.2024.115046}, pmid = {39656589}, issn = {2211-1247}, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; Mice ; *Homeostasis ; *Disease Models, Animal ; *Spinal Cord/pathology/metabolism ; Synaptic Transmission/physiology ; Receptors, Glycine/metabolism ; Nerve Degeneration/pathology ; Mice, Inbred C57BL ; Renshaw Cells/metabolism ; }, abstract = {In many neurological conditions, early-stage neural circuit adaptation preserves relatively normal behavior. In some diseases, spinal motoneurons progressively degenerate yet movement remains initially preserved. This study investigates whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we find that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that, in this motoneuron degenerative condition, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.}, } @article {pmid39673573, year = {2024}, author = {Riaz, S and Steinsland, H and Andersen, AZ and Boysen, A and Hanevik, K}, title = {Proportions of IgA antibodies targeting glycosylated epitopes of secreted Escherichia coli mucinase YghJ in initial plasmablast response differ from salivary and intestinally secreted IgA.}, journal = {Medical microbiology and immunology}, volume = {214}, number = {1}, pages = {2}, pmid = {39673573}, issn = {1432-1831}, support = {234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 7041-00220//Innovation Fund Denmark/ ; 7041-00220//Innovation Fund Denmark/ ; }, mesh = {Humans ; Glycosylation ; *Saliva/immunology ; *Epitopes/immunology ; Enterotoxigenic Escherichia coli/immunology ; Escherichia coli Proteins/immunology ; Antibodies, Bacterial/immunology/blood ; Plasma Cells/immunology ; Immunoglobulin A, Secretory/immunology ; Immunoglobulin A/immunology/blood ; Adult ; Male ; Female ; Escherichia coli Infections/immunology ; Young Adult ; }, abstract = {Mucosal infections normally cause an immune response including activation of antigen-specific B cells in regional mucosa-associated lymphoid tissue. After recirculation of plasmablasts, and maturation at mucosal surfaces or bone marrow, plasma cells produce secretory or systemic IgA. It remains uncertain to what extent secretory and systemic IgA share the same target specificities. For vaccine candidate optimization, it is important to know whether IgA targeting of glycosylated epitopes of a protein antigen vary between mucosal and systemic sites. We evaluated glycosylated epitope specificity of systemic and mucosally secreted IgA against YghJ, a potential vaccine candidate antigen secreted by most pathogenic Escherichia coli. IgA from intestinal lavage, saliva, serum, and blood-derived antibody in lymphocyte supernatants (ALS) were collected from 21 volunteers following experimental infection with enterotoxigenic E. coli. Methods for preparing IgA from saliva and ALS were developed, and multiplex bead flow cytometric immunoassays were used to determine levels of IgA targeting natively glycosylated YghJ and estimating what proportion of these antibodies specifically targeted glycosylated epitopes. Following infection, anti-YghJ IgA levels increased substantially for most volunteers across all four specimen types. Target specificity of ALS IgA correlated well with serum IgA, but not with mucosally secreted IgA. Furthermore, glycosylation-specific proportion of salivary IgA was higher than, and did not correlate with, intestinally secreted IgA. These results indicate a new degree of complexity to our understanding of epitope-targeting and tissue specificity of mucosal antibody responses. Our findings also suggest that all features of an intestinal IgA response may not be well reflected in serum, saliva, or ALS, which are commonly used proxy specimens for evaluating intestinal immune responses.}, } @article {pmid39673548, year = {2024}, author = {Alzahrani, AK and Imran, M and Alshrari, AS}, title = {Investigating the impact of SOD1 mutations on amyotrophic lateral sclerosis progression and potential drug repurposing through in silico analysis.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/07391102.2024.2439577}, pmid = {39673548}, issn = {1538-0254}, abstract = {Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for attenuating oxidative stress through its ability to facilitate the dismutation of the superoxide radical into oxygen and hydrogen peroxide. The progressive loss of motor neurons characterize amyotrophic lateral sclerosis (ALS), a crippling neurodegenerative disease that is caused by mutations in the SOD1 gene. In this study, in silico mutational analysis was performed to study the various mutations, the pathogenicity and stability ΔΔG (binding free energy) of the variant of SOD1. x in the protein variant analysis showed a considerable destabilizing effect with a ΔΔG value of -4.2 kcal/mol, signifying a notable impact on protein stability. Molecular dynamics simulations were conducted on both wild-type and C146R mutant SOD1. RMSD profiles indicated that both maintained consistent structural conformation over time. Additionally, virtual screening of 3067 FDA-approved drugs against the mutant SOD1 identified two potential binders, Tucatinib (51039094) and Regorafenib (11167602), which interacted with Leu106, similar to the control drug, Ebselen. Further simulations assessed the dynamic properties of SOD1 in monomeric and dimeric forms while bound to these compounds. 11167602 maintained stable interaction with the monomeric SOD1 mutant, whereas 51039094 and Ebselen dissociated from the monomeric protein's binding site. However, all three compounds were stably bound to the dimeric SOD1. MM/GBSA analysis revealed similar negative binding free energies for 11167602 and 51039094, identifying them as strong binders due to their interaction with Cys111. Experimental validation, including in vitro, cell-based, and in vivo assays are essential to confirm these candidates before advancing to clinical trials.}, } @article {pmid39672239, year = {2024}, author = {Cocozza, G and Busdraghi, LM and Chece, G and Menini, A and Ceccanti, M and Libonati, L and Cambieri, C and Fiorentino, F and Rotili, D and Scavizzi, F and Raspa, M and Aronica, E and Inghilleri, M and Garofalo, S and Limatola, C}, title = {GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {124}, number = {}, pages = {280-293}, doi = {10.1016/j.bbi.2024.12.010}, pmid = {39672239}, issn = {1090-2139}, abstract = {Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1[G93A] mouse model and that GFRAL is upregulated in the brainstem of hSOD1[G93A] mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1[G93A] mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.}, } @article {pmid39672208, year = {2024}, author = {Liu, Y and Wu, L and Peng, W and Mao, X}, title = {Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102638}, doi = {10.1016/j.arr.2024.102638}, pmid = {39672208}, issn = {1872-9649}, abstract = {Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.}, } @article {pmid39671529, year = {2024}, author = {Katzman, D and Kalman, G and Almog, O and Fogel, I}, title = {Deployment of Physician Resources and Innovative Medical Strategies in the 2023-2024 Israel-Hamas War: Israel's Strategy to Deliver Advanced Life Support and Whole Blood Transfusion to the Battlefield via Forward Medical Teams and the Impact on the Case Fatality Rate.}, journal = {Military medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/milmed/usae553}, pmid = {39671529}, issn = {1930-613X}, abstract = {The 2023-2024 Israel-Hamas War, which began following a Hamas attack on Israel on October 7, 2023, has seen a case fatality rate (CFR) among the lowest in the history of warfare. In resultant ground maneuvers, the Israel Defense Forces Medical Corps (IDF-MC) doctrine for the delivery of combat casualty care has been battle tested. We suggest the decreased CFR in part reflects a paradigm shift in combat deployment of medical resources, so as to introduce life-saving strategies not previously seen on the battlefield in large scale to date. These changes, which began in the 2006 Lebanon war and have been in evolution since, include strategic physician deployment to positions more forward than in previous wars and in teams smaller than the previous standard. These forward medical teams have replaced the battalion aid station in the Gaza theater of operations and serve to increase the availability of Advanced Life Support (ALS) level care at the point of injury, wherever a casualty might be on a multidimensional battlefield. These forward medical teams deploy with advanced medical capabilities, including in some cases the ability to transfuse low titer O whole blood. This article reviews aspects of the IDF-MC combat casualty care doctrine as implemented during the current war, the role and advantages of transfusion-capable ALS forward medical teams, and the apparent impact on the CFR thereof.}, } @article {pmid39671291, year = {2024}, author = {Lin, J and Carman, PJ and Gambogi, CW and Kendsersky, NM and Chuang, E and Gates, SN and Yokom, AL and Rizo, AN and Southworth, DR and Shorter, J}, title = {Design principles to tailor Hsp104 therapeutics.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115005}, doi = {10.1016/j.celrep.2024.115005}, pmid = {39671291}, issn = {2211-1247}, mesh = {Humans ; *Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Adenosine Triphosphate/metabolism ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; HSP40 Heat-Shock Proteins/metabolism/genetics ; HEK293 Cells ; Adenosine Diphosphate/metabolism ; Protein Binding ; }, abstract = {The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated proteins. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can (1) reduce Hsp70 collaboration without enhancing activity, (2) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s, (3) produce Hsp70-independent potentiated variants, or (4) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting an NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS and TDP-43 proteinopathies in human cells. Thus, we establish design principles to tailor Hsp104 therapeutics.}, } @article {pmid39671140, year = {2024}, author = {Ikehata, A}, title = {Extension of the molar absorption coefficient for non-ideal mixtures: an application to aqueous monovalent alcohol solutions.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {}, number = {}, pages = {}, pmid = {39671140}, issn = {1348-2246}, abstract = {The hydration state of the alcohols was investigated using the extended molar absorption coefficient, which redefines the molar absorption coefficient as a differential coefficient of concentration. The extended molar absorption coefficient is a function of the concentration calculated from the difference in absorbance, and is consistent with the conventional molar absorption coefficient, allowing a complete quantitative comparison. The quantitative performance was verified using IR and NIR absorption spectra of aqueous solutions of monovalent alcohols (methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol) that were soluble in water at any mixing ratio. Extended molar absorption coefficient spectra were calculated for the combination bands of water, which were further separated by multivariate curve resolution-alternating least squares (MCR-ALS) into molecular species with different peak wavenumbers: strongly hydrogen-bonded (SHB), weakly hydrogen-bonded (WHB), and free OH species. The number of water species that change when one alcohol molecule increases, i.e., the perturbed hydration number (PHN), was calculated by comparison with the conventional molar absorption coefficient of pure water. The calculated PHN indicates that the numbers of SHB and WHB species are reversed at approximately 20 wt%, and that the free OH species increase at higher alcohol concentrations and are more pronounced for alcohols with bulky alkyl groups. These results provide a quantitative answer to the long-debated question of anomalies in water-alcohol mixing.}, } @article {pmid39670820, year = {2024}, author = {Lagiakos, HR and Zou, Y and Igawa, H and Therrien, E and Lawrenz, M and Kato, M and Svensson, M and Gray, F and Jensen, K and Dahlgren, MK and Pelletier, RD and Dingley, K and Bell, JA and Liu, Z and Jiang, Y and Zhou, H and Skene, RJ and Nie, Z}, title = {In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.4c02074}, pmid = {39670820}, issn = {1520-4804}, abstract = {Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.}, } @article {pmid39670434, year = {2024}, author = {Piga, G and Fadda, L and Borghero, G and Maccabeo, A and Pala, F and Murru, MR and Giglio, S and Puligheddu, M and Floris, G}, title = {Semantic behavioral variant frontotemporal dementia and semantic dementia associated with TARDBP mutations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2439448}, pmid = {39670434}, issn = {2167-9223}, abstract = {Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. TARDBP gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore TARDBP mutations' association with tvFTD, and review related literature. From our FTD cohort of 94 patients, ten fulfilled the criteria for sbvFTD. Therefore, in light of the diagnostic reclassification carried out, we describe the largest series of unrelated patients with TARDBP p.A382T missense mutation, including four new cases of tvFTD: two sbvFTD and two svPPA, exhibiting semantic and behavioral disorders and showing predominant right and left anterior temporal lobe involvement, respectively. We present for the first time two sbvFTD cases carrying the pA382T TARDBP mutation. Comparison with C9orf72 and non-mutated patients revealed lower age at onset (p = 0.006), and a higher prevalence of tvFTD, particularly sbvFTD (p < 0.001), and motor neuron disease in TARDBP carriers (p < 0.001). Our findings along with a review of the literature highlighted TARDBP mutations' association with sbvFTD and semantic dementia, suggesting a genetic role in temporal variants of FTD and emphasizing the need for TARDBP mutation screening in these cases. Reclassifying FTD cohorts, including the sbvFTD phenotype, could aid in better defining the clinical spectrum of tvFTD and guide differential diagnosis across different FTD populations with TARDBP or other FTD-related mutations.}, } @article {pmid39670345, year = {2024}, author = {D'Anna, L and Wragg, D and Mauro, D and Rubino, S and Terenzi, A and Barone, G and Thomas, S and Casini, A and Bonsignore, R and Spinello, A}, title = {Unraveling the molecular basis for G-quadruplex-binders to ALS/FTD-associated G4C2 repeats of the C9orf72 gene.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {e202400974}, doi = {10.1002/cbic.202400974}, pmid = {39670345}, issn = {1439-7633}, abstract = {The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G4C2) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G4C2 repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof of principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing in silico investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related C9orf72 G4-binders. Moreover, we investigated the binding properties of a strong and selective metal-based G4 stabilizer, the AuI bis-N-heterocyclic carbene (NHC) complex - Au(TMX)2 - showing that it moderately stabilizes G4C2 G4 RNA by Förster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX)2 binding mode and the associated free-energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS/FTD neurodegenerative disorders.}, } @article {pmid39670112, year = {2024}, author = {Pinkerton, M and Adler, GL and Ledger, M and Ni, CY and Yang, Y and Tan, RH}, title = {Heterogeneous nuclear ribonucleoprotein D - an understudied subfamily affected in sporadic TDP-43 proteinopathies.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae352}, pmid = {39670112}, issn = {2632-1297}, abstract = {Despite the recognition that heterogeneous nuclear ribonucleoproteins (hnRNPs) modulate TDP-43 and can limit aberrant splicing events to compensate for TDP-43 loss, their role in TDP-43 proteinopathies remains poorly understood and studies in patient tissue are lacking. This study assesses seven heterogeneous nuclear ribonucleoproteins from the A/B, C, D and H subfamilies in two cortical regions implicated in early TDP-43 dysfunction versus late TDP-43 dysfunction in sporadic amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. Our results reveal significant nuclear loss of hnRNPD, hnRNPC and hnRNPA1 in the frontal cortex of frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis but not in the motor cortical neurons or Betz cells of amyotrophic lateral sclerosis cases. Cytoplasmic co-occurrence was observed between hnRNPA1 and hnRNPC but not with phosphorylated TDP-43 (pTDP-43). Interestingly, nuclear hnRNPD loss associated with increasing cytoplasmic pTDP-43, highlighting an understudied subfamily in sporadic TDP-43 proteinopathies. In summary, this study identifies the nuclear loss of hnRNPD, C and A1 in a predilection brain region of TDP-43 in frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis cases without significant pTDP-43 in this region. This highlights the need for further investigation into the involvement of these heterogeneous nuclear ribonucleoproteins in disease pathogenesis and potential to serve as modulatory targets and/or proximal markers of TDP-43 dysfunction in sporadic TDP-43 proteinopathies.}, } @article {pmid39669591, year = {2024}, author = {Beauregard-Lacroix, É and Scott, A and Nguyen, TTM and Wierenga, KJ and Purcarin, G and Karstensen, AB and Carvalho, DR and Alessandri, JL and Payet, F and Girisha, KM and Ferron, M and Campeau, PM}, title = {Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome.}, journal = {Genetics in medicine open}, volume = {2}, number = {}, pages = {101837}, pmid = {39669591}, issn = {2949-7744}, abstract = {PURPOSE: Biallelic variants in FIG4 or VAC14 are associated with Yunis-Varón syndrome (YVS), which is characterized by multisystem involvement including skeletal findings, craniofacial dysmorphisms and central nervous system anomalies. Pathogenic variants in those same genes have also been associated with a predominantly neurological phenotype and with nonsyndromic conditions, such as Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. By describing 5 new cases of FIG4-associated YVS and reviewing the literature, we better delineate the clinical phenotype associated with loss of function of those genes. We also explore osteopenia mechanisms by assessing bone physiologic parameters in a mouse model.

METHODS: Exome sequencing or Sanger sequencing was performed in 5 unrelated individuals. Bone histomorphometry was performed in Fig4 [plt/plt] mice and compared with wild type. Relevant literature from the last 10 years was reviewed.

RESULTS: All individuals presented a phenotype overlapping the typical YVS and the brain anomalies and neurologic syndrome. Clinical features included developmental delay, structural brain malformations, and skeletal anomalies, such as osteopenia. Biallelic FIG4 variants were identified in each individual. In mice, bone histomorphometry parameters suggested that osteopenia might be secondary to reduced bone formation rather than increased bone degradation.

CONCLUSION: This study contributes to a better understanding of the phenotypic variability caused by pathogenic variants in FIG4 or VAC14 and suggests an important overlap between previously described phenotypes. The brain anomalies and neurologic syndrome is likely in the same spectrum as classical YVS. Further studies are still needed to clarify the effects of partial loss-of-function (hypomorphic) variants and to identify genotype-phenotype correlations.}, } @article {pmid39669124, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and McKeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, ŁJ and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 repeat expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {NAR molecular medicine}, volume = {1}, number = {4}, pages = {ugae019}, pmid = {39669124}, issn = {2976-856X}, support = {P50 NS048843/NS/NINDS NIH HHS/United States ; U54 NS048843/NS/NINDS NIH HHS/United States ; }, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown. Here, we show C9orf72Exp in pre-symptomatic and amyotrophic lateral sclerosis-frontotemporal dementia patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb of C9orf72 as highly compacted chromatin embedded in an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72Exp patient contained a highly rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72Exp repeat instability and chromosomal fragility are sensitive to folate deficiency. Age-dependent repeat instability, chromosomal fragility and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72Exp mice, implicating C9orf72Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, } @article {pmid39667814, year = {2025}, author = {Rousseau, JA and Maier, M and Ait-Mohand, S and Dumulon-Perreault, V and Sarrhini, O and Tremblay, S and Rousseau, E and Salzmann, M and Guérin, B}, title = {Antibody-Based PET Imaging of Misfolded Superoxide Dismutase 1 in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {1}, pages = {130-135}, pmid = {39667814}, issn = {1535-5667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Positron-Emission Tomography/methods ; *Disease Models, Animal ; *Zirconium/chemistry ; Protein Folding ; Mice, Transgenic ; Deferoxamine/chemistry ; Antibodies/chemistry ; Radioisotopes ; Tissue Distribution ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron loss in the motor cortex, brain stem, and spinal cord. Mutations in the superoxide dismutase 1 (SOD1) gene, resulting in misfolding of its protein product, are a common cause of ALS. Currently, there is no approved ALS diagnostic tool. Here, we present the development of a PET radiotracer, [[89]Zr]Zr-desferoxamine (DFO)-α-miSOD1, targeting selectively misfolded SOD1 (misSOD1). Methods: DFO-α-miSOD1 was prepared by conjugating α-miSOD1 antibody with DFO and labeled with [89]Zr. A longitudinal imaging study was performed to identify the optimal mouse age and time after administration of [[89]Zr]Zr-DFO-α-miSOD1 for the detection of misSOD1 aggregation in transgenic mice overexpressing misSOD1 and in wild-type mice. Subsets of mice were either coinjected with an excess of α-miSOD1 or imaged with deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 to assess target specificity. The internal radiation dose for [[89]Zr]Zr-DFO-α-miSOD1 was estimated by extrapolating data from mouse biodistribution experiments. Results: Imaging with [[89]Zr]Zr-DFO-α-miSOD1 was optimal in 136-d-old transgenic mice on day 10 after administration. Significant accumulation of [[89]Zr]Zr-DFO-α-miSOD1 was detected in the spinal cord and cartilage of ALS transgenic mice compared with the wild-type mice (P = 0.01). The radiotracer accumulation is selective and blockable with an excess of α-miSOD1. Deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 results in high-contrast detection of misSOD1 but is prone to aggregation. The dosimetry for [[89]Zr]Zr-DFO-α-miSOD1 is comparable to that for other [89]Zr-based tracers currently used in humans. Conclusion: This work thus establishes that [[89]Zr]Zr-DFO-α-miSOD1 PET can detect misSOD1 in transgenic mice, paving the way for application in early diagnosis of ALS and therapeutic monitoring.}, } @article {pmid39667295, year = {2024}, author = {Spencer, PS and Berntsson, SG and Buguet, A and Butterfield, P and Calne, DB and Calne, SM and Giménez-Roldán, S and Hugon, J and Kahlon, S and Kisby, GE and Lagrange, E and Landtblom, AE and Ludolph, AC and Nunn, PB and Palmer, VS and Reis, J and Román, GC and Sipilä, JOT and Spencer, SS and Angues, RV and Vernoux, JP and Yabushita, M}, title = {Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123340}, doi = {10.1016/j.jns.2024.123340}, pmid = {39667295}, issn = {1878-5883}, abstract = {While rising global rates of neurodegenerative disease encourage early diagnosis and therapeutic intervention to block clinical expression (secondary prevention), a more powerful approach is to identify and remove environmental factors that trigger long-latencybrain disease (primary prevention) by acting on a susceptible genotype or acting alone. The latter is illustrated by the post-World War II decline and disappearance of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC), a prototypical often-familial neurodegenerative disease formerly present in very high incidence on the island of Guam. Lessons learned from 75 years of investigation on the etiology of ALS/PDC include: the importance of focusing field research on the disease epicenter and patients with early-onset disease; soliciting exposure history from patients, family, and community to guide multidisciplinary biomedical investigation; recognition that disease phenotype may vary with exposure history, and that familial brain disease may have a primarily environmental origin. Furthermore, removal from exposure to the environmental trigger effects primary disease prevention.}, } @article {pmid39666202, year = {2024}, author = {van Eijk, RPA and van Loon, FT and van Unnik, JWJ and Weemering, DN and Seitidis, G and Mavridis, D and van den Berg, LH and Nikolakopoulos, S}, title = {Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {40}, pmid = {39666202}, issn = {1432-1459}, support = {EVIDENCE//Stichting ALS Nederland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Randomized Controlled Trials as Topic ; Patient Dropouts/statistics & numerical data ; }, abstract = {OBJECTIVES: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.

METHODS: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm. Subsequently, we meta-analyzed attrition rates across studies, evaluated the difference between study arms, and explored the impact of study-level characteristics. Finally, a meta-regression model predicting study discontinuation for future clinical trials was translated into a web application.

RESULTS: In total, 60 randomized placebo-controlled clinical trials were included in the meta-analysis, randomizing 14,493 patients with ALS. Attrition varied significantly between studies, ranging from 3.1% to 75.7% of all randomized patients, with a pooled effect of 32.0% (90% prediction interval 6.1% to 66.3%). Attrition was similar between the intervention and placebo arm (odds ratio 1.08, 95% CI 0.89 to 1.31, p = 0.43). The follow-up duration was identified as the sole study-level predictor (0.032, 95% CI 0.026 to 0.039, p < 0.001), resulting in predicted attrition of 19.3% for 6-month, 36.4% for 12-month, and 55.6% for 18-month clinical trials.

CONCLUSIONS: ALS clinical trials encounter high attrition, which increases with the follow-up duration. These findings underscore the need to refine our strategies to manage attrition, preserving the integrity and generalizability of ALS clinical trials.}, } @article {pmid39666144, year = {2024}, author = {Levison, LS and Blicher, JU and Andersen, H}, title = {Incidence and mortality of ALS: a 42-year population-based nationwide study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {44}, pmid = {39666144}, issn = {1432-1459}, support = {A3520//Health Research Fund of Central Denmark Region/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Male ; Female ; Incidence ; Middle Aged ; Denmark/epidemiology ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND AND AIM: Recent studies have suggested that the incidence rate (IR) and the rate of death (MR) of amyotrophic lateral sclerosis (ALS) are increasing. Still, it remains unclear whether this is due to improved case ascertainment or represents a true increase. We examined the development in the incidence and mortality of ALS in Denmark for 42 years.

METHODS: We retrieved individual-level data of all patients aged above 18 years with first-time ALS diagnosed at any Danish department of neurology. The IR and MR were calculated based on data from 1980 to 2021, stratified by gender and age.

RESULTS: We identified 5,943 patients with ALS and identified a total of 5,069 deaths in the nationwide population. Overall, the IR was 3.4 per 100,000 persons per year (95% CI 3.4-3.5). ALS incidence rose gradually during the study period, and the IR was 2.8 times higher (95% CI 2.4-3.2) when comparing the latest period (2018-2021) with the first (1980-1983). Parallel to the IR, the MR increased over time and was associated with male gender and rose with age at diagnosis, peaking in the 70-79-year age group.

CONCLUSION: In Denmark, the IR and MR of ALS increased threefold from 1980 to 2021, with steadily increasing risk related to male gender and in particular to higher age. Considering our aging societies, the number of elderly patients with ALS can be expected to increase considerably.}, } @article {pmid39666121, year = {2024}, author = {Okubo, S and Naruse, H and Ishiura, H and Sudo, A and Esaki, K and Mitsui, J and Matsukawa, T and Satake, W and Greimel, P and Shingai, N and Oya, Y and Yoshikawa, T and Tsuji, S and Toda, T}, title = {Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {36}, pmid = {39666121}, issn = {1432-1459}, support = {JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; JP23ek0109673//Japan Agency for Medical Research and Development/ ; JP23ek0109617//Japan Agency for Medical Research and Development/ ; JP23ek0109631//Japan Agency for Medical Research and Development/ ; JP24K18698//Japan Society for the Promotion of Science/ ; JP23K27514//Japan Society for the Promotion of Science/ ; 21K07512//Japan Society for the Promotion of Science/ ; Glyco-lipidologue Initiative Program//RIKEN/ ; }, mesh = {Humans ; *Serine C-Palmitoyltransferase/genetics ; Female ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; Male ; Young Adult ; Adult ; Middle Aged ; Aged ; Adolescent ; Pedigree ; Sphingolipids/blood ; Mutation ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1, encoding a subunit of serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), and have recently been associated with juvenile ALS. SPTLC1 variants associated with ALS cause elevated levels of sphinganines and ceramides. Reports on ALS associated with SPTLC1 remain limited. This study aimed to investigate the frequency of SPTLC1 variants in ALS and relevant clinical characteristics.

METHODS: We analyzed whole-exome and whole-genome sequence data from 40 probands with familial ALS and 413 patients with sporadic ALS without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis and droplet digital PCR (ddPCR) were used to assess splicing and mosaicism, respectively. Plasma sphingolipid levels were quantified to analyze biochemical consequences.

RESULTS: The heterozygous c.58G>A, p.Ala20Thr variant was identified in a 21-year-old Japanese female patient presenting with symmetric weakness which slowly progressed over 15 years. RT-PCR analysis showed no splice defects. Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents. ddPCR revealed that the asymptomatic father harbored a mosaic variant with 17% relative mutant allele abundance in peripheral blood leukocytes.

CONCLUSIONS: We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism. Lipid analysis results are consistent with previous findings on SPTLC1-associated ALS. Further studies are necessary to determine the clinical effect of mosaic variants of SPTLC1.}, } @article {pmid39666115, year = {2024}, author = {Psychogios, I and Hu, Y and Seitz, C and Joyce, EE and Lovik, A and Ingre, C and Fang, F}, title = {Exploring clinical chemistry markers in amyotrophic lateral sclerosis: insights into survival and disease trajectories.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {7}, pmid = {39666115}, issn = {1432-1459}, support = {2019-01088//Swedish Research Council/ ; 2023-02428//Swedish Research Council/ ; MegaALS 802091//European Research Council Starting Grant/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; R01TS000324-01-00/CC/CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Biomarkers/blood ; Aged ; *Disease Progression ; Cohort Studies ; Sweden ; Adult ; Prognosis ; }, abstract = {OBJECTIVE: Commonly measured clinical chemistry markers might be indicative of survival and disease progression in amyotrophic lateral sclerosis (ALS).

METHODS: In a cohort study of 270 ALS patients diagnosed from April 2014 to May 2021 in Stockholm, Sweden, we examined the link between 29 clinical chemistry markers at diagnosis and mortality risk at 6 months, 1 year, and 3 years after diagnosis. Summary variables from exploratory factor analysis (EFA) assessed the markers' collective impact on survival. We integrated ALS functional rating scale-revised (ALSFRS-R) scores with survival data using a joint latent class model to identify patterns of functional decline. Multinomial logistic regression determined how the EFA-derived factors predicted the decline trajectories post-diagnosis.

RESULTS: Higher levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and albumin at diagnosis were linked to lower mortality in ALS patients, while increased neurofilament light chain (NfL), leukocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and carbon dioxide (CO2) levels indicated higher mortality. The 'Red blood cell profile' factor, derived from EFA, emerged as a significant predictor of survival, independent of other prognostic indicators. The joint latent class model identified three distinct patient groups based on functional decline, with 'Red blood cell profile' suggesting a lower likelihood of being in the groups with slower progression.

CONCLUSION: Clinical chemistry markers, including NfL, lipids, albumin, leukocyte count, MCV, MCH, CO2, and the 'Red blood cell profile,' were associated with ALS survival. As these markers represent broader bodily functions, integrating them in ALS patient care could improve disease management.}, } @article {pmid39666103, year = {2024}, author = {Zimmermann, M and Mengel, D and Raupach, K and Haack, T and Neumann, M and Synofzik, M}, title = {Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {58}, pmid = {39666103}, issn = {1432-1459}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Female ; *Huntingtin Protein/genetics ; Middle Aged ; Aged ; *Trinucleotide Repeat Expansion/genetics ; Brain/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington's disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions.

METHODS: Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier.

RESULTS: One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03-0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed-in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions-HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration.

CONCLUSIONS: Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which-given the low repeat number-is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS.}, } @article {pmid39666071, year = {2024}, author = {de Boer, EMJ and de Vries, BS and Van Hecke, W and Mühlebner, A and Vincken, KL and Mol, CP and van Rheenen, W and Westeneng, HJ and Veldink, JH and Höglinger, GU and Morris, HR and Litvan, I and Raaphorst, J and Ticozzi, N and Corcia, P and Vandenberghe, W and Pijnenburg, YAL and Seelaar, H and Ingre, C and Van Damme, P and van den Berg, LH and van de Warrenburg, BPC and van Es, MA}, title = {Diagnosing primary lateral sclerosis: a clinico-pathological study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {46}, pmid = {39666071}, issn = {1432-1459}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/genetics ; Autopsy ; Brain/pathology/diagnostic imaging ; Diagnosis, Differential ; *Motor Neuron Disease/diagnosis/pathology ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

METHODS: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires.

RESULTS: Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases.

CONCLUSIONS: This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS. Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.}, } @article {pmid39665821, year = {2025}, author = {Serneels, PJ and De Schutter, JD and De Groef, L and Moons, L and Bergmans, S}, title = {Oligodendroglial heterogeneity in health, disease, and recovery: deeper insights into myelin dynamics.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3179-3192}, doi = {10.4103/NRR.NRR-D-24-00694}, pmid = {39665821}, issn = {1673-5374}, abstract = {Decades of research asserted that the oligodendroglial lineage comprises two cell types: oligodendrocyte precursor cells and oligodendrocytes. However, recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states, prompting a revision of the existing terminology. Going forward, the oligodendroglial lineage should be delineated into five distinct cell states: oligodendrocyte precursor cells, committed oligodendrocyte precursor cells, newly formed oligodendrocytes, myelin-forming oligodendrocytes, and mature oligodendrocytes. This new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological contexts. Adopting this uniform terminology will facilitate comparison and integration of data across studies. This, including the consolidation of findings from various demyelinating models, is essential to better understand the pathogenesis of demyelinating diseases. Additionally, comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination failure. Thus, by standardizing terminology and synthesizing data from diverse studies across different animal models, we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, all of which involve oligodendroglial and myelin dysfunction.}, } @article {pmid39664805, year = {2025}, author = {Xing, H and McGregor, SKM and Batista, BD and Whitefield, C and Stone, ISJ and Murray, CE and Hurst, RM and Liu, Y and Chow, S and Fahrenhorst-Jones, T and Zhao, Q and Houston, SD and Hu, SH and Lonhienne, T and Nouwens, A and Burns, JM and Savage, GP and Walter, GH and Guddat, LW and Rafter, MA and Williams, CM}, title = {In search of herbistasis: COT-metsulfuron methyl displays rare herbistatic properties.}, journal = {Chemical science}, volume = {16}, number = {2}, pages = {649-658}, pmid = {39664805}, issn = {2041-6520}, abstract = {Weed management is an essential intervention for maintaining food security and protecting biodiversity but is heavily reliant on chemical control measures (i.e., herbicides). Concerningly, only one herbicide has been developed with a new mode of action (MOA) since the 1980s. Therefore, alternative strategies for preventing weed growth need to be explored. The lesser-known concept of halting weed growth through herbistasis could be one strategy to alleviate the lack of success in obtaining new MOA leads, but this type of activity has rarely been investigated. Herein reported is a bioisosteric cyclooctatetraene (COT) for phenyl ring replacement tactic, using the commercial acetolactate synthase (ALS) inhibitor metsulfuron methyl, that has unearthed a rare agent displaying herbistatic properties against the weed, Cryptostegia grandiflora (rubber vine).}, } @article {pmid39664295, year = {2024}, author = {Chen, LX and Zhang, MD and Xu, HF and Ye, HQ and Chen, DF and Wang, PS and Bao, ZW and Zou, SM and Lv, YT and Wu, ZY and Li, HF}, title = {Single-Nucleus RNA Sequencing Reveals the Spatiotemporal Dynamics of Disease-Associated Microglia in Amyotrophic Lateral Sclerosis.}, journal = {Research (Washington, D.C.)}, volume = {7}, number = {}, pages = {0548}, pmid = {39664295}, issn = {2639-5274}, abstract = {Disease-associated microglia (DAM) are observed in neurodegenerative diseases, demyelinating disorders, and aging. However, the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis (ALS) remain unclear. Using a mouse model of ALS that expresses a human SOD1 gene mutation, we found that the microglia subtype DAM begins to appear following motor neuron degeneration, primarily in the brain stem and spinal cord. Using reverse transcription quantitative polymerase chain reaction, RNAscope in situ hybridization, and flow cytometry, we found that DAM increased in number as the disease progressed, reaching their peak in the late disease stage. DAM responded to disease progression in both SOD1[G93A] mice and sporadic ALS and C9orf72-mutated patients. Motor neuron loss in SOD1[G93A] mice exhibited 2 accelerated phases: P90 to P110 (early stage) and P130 to P150 (late stage). Some markers were synchronized with the accelerated phase of motor neuron loss, suggesting that these proteins may be particularly responsive to disease progression. Through pseudotime trajectory analysis, we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia. Interestingly, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in SOD1[G93A] mice and observed that DAM survival is independent of CSF1R. An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes. These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS. Inducing the DAM phenotype and enhancing its function during the early phase of disease progression, or the time window between P130 and P150 where motor neuron loss slows, could serve as a neuroprotective strategy for ALS.}, } @article {pmid39663989, year = {2024}, author = {Das, U and Gayan, A and Biswas, R}, title = {A highly sensitive facile plasmonic scheme for assessment of melamine in raw milk.}, journal = {Analytical methods : advancing methods and applications}, volume = {}, number = {}, pages = {}, doi = {10.1039/d4ay01764a}, pmid = {39663989}, issn = {1759-9679}, abstract = {This work presents two novel devices with a microcontroller and two different light sensors, namely, Light Dependent Resistor (LDR) and Ambient Light Sensor (ALS), which can provide a quantitative output from the colorimetric variations of citrate capped borohydride reduced silver nanoparticles (AgNPs) and citrate capped gold nanoparticles (AuNPs) upon addition of melamine adulterated milk. The limit of detection (LOD) of the LDR setup with AgNPs and AuNPs was found to be 1.24 ppm and 1.68 ppm, respectively, and the corresponding recovery rates were 92.86% and 88.57%, respectively. The device fabricated with the ALS with AgNPs displayed a recovery rate of 97.14% with a LOD value of 0.64 ppm.}, } @article {pmid39662855, year = {2025}, author = {Yang, ZF and Jiang, XC and Gao, JQ}, title = {Present insights into the progress in gene therapy delivery systems for central nervous system diseases.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125069}, doi = {10.1016/j.ijpharm.2024.125069}, pmid = {39662855}, issn = {1873-3476}, mesh = {Humans ; *Genetic Therapy/methods ; *Central Nervous System Diseases/therapy ; Animals ; *Gene Transfer Techniques ; *Genetic Vectors/administration & dosage ; Dependovirus/genetics ; }, abstract = {Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases. Despite the remarkable progress in refining and enhancing the structural design of gene therapy agents, substantial obstacles persist in their effective and safe delivery within living systems. To surmount these obstacles, a diverse array of gene delivery systems has been devised and continuously improved. Notably, Adeno-Associated Virus (AAVs)-based viral gene vectors and lipid-based nanocarriers have each advanced the in vivo delivery of gene therapies to various extents. This review aims to concisely summarize the pathophysiological foundations of CNS diseases and to shed light on the latest advancements in gene delivery vector technologies. It discusses the primary categories of these vectors, their respective advantages and limitations, and their specialized uses in the context of gene therapy delivery.}, } @article {pmid39662651, year = {2024}, author = {Keethedeth, N and Anantha Shenoi, R}, title = {Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment.}, journal = {Mitochondrion}, volume = {81}, number = {}, pages = {102000}, doi = {10.1016/j.mito.2024.102000}, pmid = {39662651}, issn = {1872-8278}, abstract = {Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.}, } @article {pmid39662532, year = {2025}, author = {Bayansan, O and Bhan, P and Chang, CY and Barmaver, SN and Shen, CP and Wagner, OI}, title = {UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106766}, doi = {10.1016/j.nbd.2024.106766}, pmid = {39662532}, issn = {1095-953X}, mesh = {Animals ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Caenorhabditis elegans/metabolism ; *rab3 GTP-Binding Proteins/metabolism/genetics ; *Synaptic Vesicles/metabolism ; Kinesins/metabolism/genetics ; Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Animals, Genetically Modified ; Pleckstrin Homology Domains ; Nerve Tissue Proteins ; Intercellular Signaling Peptides and Proteins ; }, abstract = {Kinesin-3 KIF1A (UNC-104 in C. elegans) is the major axonal transporter of synaptic vesicles and mutations in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), encompassing Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis and hereditary spastic paraplegia. UNC-104 binds to lipid bilayers of synaptic vesicles via its C-terminal PH (pleckstrin homology) domain. Since this interaction is relatively weak and non-specific, we hypothesize that other, more specific, interaction schemes exist. From the literature, it is evident that UNC-104 regulator SYD-2 interacts with UNC-10 and that UNC-10 itself interacts with RAB-3 bound to synaptic vesicles. RT-PCR and Western blot experiments expose genetic relationships between unc-10 and syd-2, but not between unc-10 and rab-3. Also, neither unc-10 nor rab-3 affects UNC-104 expression. However, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays reveal functional interactions between UNC-104, SYD-2, UNC-10 and RAB-3. Though both SNB-1 and RAB-3 are actively transported by UNC-104, motility of RAB-3 is facilitated in the presence of SYD-2 and UNC-10. Deletion of UNC-104's PH domain did not affect UNC-104/RAB-3 colocalization, but significantly affected UNC-104/SNB-1 colocalization. Similarly, motility of RAB-3-labeled vesicles is only slightly altered in nematodes carrying a point mutation in the PH domain, whereas movement of SNB-1 is significantly reduced in this mutant. Western blots from purified fractions of synaptic vesicles reveal strong reduction of UNC-104 in rab-3/unc-10 double mutants. Our findings suggest that the UNC-10/SYD-2 complex acts as a functional linker to connect UNC-104 to RAB-3-containing vesicles. Thus, this linker complex contributes to the specificity of motor/cargo interactions.}, } @article {pmid39662462, year = {2024}, author = {Huang, C and Qiu, L and Zhou, W and Shao, C and Wang, X and Zhang, Q and Chen, W and Xiong, M and Huang, M and Tang, M and Zou, L and Xu, X}, title = {A human-induced pluripotent stem cell (iPSC) line (SMUSHi006-A) from an ALS patient carrying a mutation c.1126C > T in the FUS gene.}, journal = {Stem cell research}, volume = {82}, number = {}, pages = {103604}, doi = {10.1016/j.scr.2024.103604}, pmid = {39662462}, issn = {1876-7753}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Four major genes associated with ALS-SOD1, TARDBP, FUS, and C9orf72-have been identified, with the fused in sarcoma (FUS) gene demonstrating considerable genetic heterogeneity. Our research group has previously established an induced pluripotent stem (iPS) cell line harboring the c.1562G > A mutation in the FUS gene. The objective of this study is to create another iPS cell line featuring the pathogenic c.1126C > T mutation in the FUS gene. This research aims not only to establish a disease model for ALS linked to FUS mutations but also to pave the way for potential therapeutic interventions.}, } @article {pmid39660938, year = {2024}, author = {Kashiwagi-Hakozaki, M and Ikemura, M and Naruse, H and Takahashi, Y and Toda, T and Ushiku, T}, title = {An autopsy case report of amyotrophic lateral sclerosis with unusual basophilic inclusions exhibiting immunopositivity for optineurin.}, journal = {Pathology international}, volume = {}, number = {}, pages = {}, doi = {10.1111/pin.13501}, pmid = {39660938}, issn = {1440-1827}, } @article {pmid39659975, year = {2024}, author = {Kim, HJ and Ban, JJ and Kang, J and Im, HR and Ko, SH and Sung, JJ and Park, SH and Park, JE and Choi, SJ}, title = {Single-cell analysis reveals expanded CD8[+] GZMK [high] T cells in CSF and shared peripheral clones in sporadic amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae428}, pmid = {39659975}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brain and spinal cord. Despite the crucial role of aberrant immune responses in ALS pathogenesis, studies investigating immunological profiles in the cerebrospinal fluid (CSF) of patients with ALS have reported inconsistent findings. Herein, we explored the intrathecal adaptive immune response and features of circulating T cells between CSF and blood of patients with ALS using single-cell RNA and T-cell receptor (TCR) sequencing. This study comprised a total of 11 patients with apparently sporadic ALS and three controls with non-inflammatory diseases. We collected CSF from all participants, and for three patients with ALS, we additionally obtained paired samples of peripheral blood mononuclear cells (PBMCs). Utilizing droplet-based single-cell RNA and TCR sequencing, we analysed immunological profiles, gene expression characteristics and clonality. Furthermore, we examined T-cell characteristics in both PBMC and CSF samples, evaluating the shared T-cell clones across these compartments. In the CSF, patients with ALS exhibited a lower proportion of CD4[+] T cells (45.2 versus 61.2%, P = 0.005) and a higher proportion of CD8[+] GZMK [hi] effector memory T cells (TEMs) than controls (21.7 versus 16.8%, P = 0.060). Higher clonality was observed in CD8[+] TEMs in patients with ALS compared with controls. In addition, CSF macrophages of patients with ALS exhibited a significant increase in chemokines recruiting CD8[+] TEMs. Immunohistochemical analysis showed slightly higher proportions of T cells in the perivascular and parenchymal spaces in patients with ALS than in controls, and CD8[+] TEMs co-localized with neurons or astrocytes in the motor cortices of patients with ALS. Clonally expanded CD8[+] GZMK [hi] TEMs primarily comprised shared T-cell clones between CSF and PBMCs. Moreover, the shared CD8[+] TEMs of PBMCs exhibited gene expression profiles similar to CSF T cells. Patients with ALS showed an increase in proportion and clonality of CD8[+] GZMK [hi] TEMs and activated features of macrophages in CSF. The shared T-cell clone between CSF and blood was mainly composed of expanded CD8[+] GZMK [hi] TEMs. In conclusion, single-cell immune profiling provided novel insights into the pathogenesis of ALS, characterized by activated macrophages and clonally expanded CD8[+] T cells potentially communicating with the central nervous system and peripheral circulation.}, } @article {pmid39659885, year = {2024}, author = {Wan, H and Qian, W and Wei, B and Tian, K and Chen, Z and Zhang, J and Chen, F}, title = {A bibliometric analysis of gene editing and amyotrophic lateral sclerosis (from 2004 to 2024).}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1499025}, pmid = {39659885}, issn = {1662-4548}, abstract = {OBJECTIVE: To learn more about gene editing and ALS, and to provide a comprehensive view of gene editing for further treatment of amyotrophic lateral sclerosis.

METHODS: We searched 1981 records from Web of Science core collection and Pubmed, Scopus, of which 1,292 records were obtained after exclusion. We then scientifically and metrologically analyzed these records for spatial and temporal distribution, author distribution, subject categories, subject distribution, references, and keywords using R, software CiteSpace and VOSviewer.

RESULTS: Our analysis provides basic information about research in the field, suggests that the field has stabilized over the past decade, and identifies potential partners for interested researchers. Current research in this area is focused on inflammatory mechanisms, immune mechanisms, related diseases, and associated cytokines in ALS.

CONCLUSION: RNA Editing, Antisense Bligonucleotide, and Glycine Receptor are cutting-edge research topics in this field, which is undergoing rapid development. We hope that this work will provide new ideas for advancing the scientific research and clinical application of ALS.}, } @article {pmid39659205, year = {2024}, author = {Alzahrani, AK and A S, A and Imran, M}, title = {Unraveling the molecular mechanisms of ALS: a network biology and structural modeling approach of investigating the impact of C9orf72 mutations.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/07391102.2024.2437682}, pmid = {39659205}, issn = {1538-0254}, abstract = {C9orf72 is a major genetic factor in Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disorder affecting brain and spinal cord neurons, and comprehending its mutational impact is crucial for developing ALS therapies. Therefore, the current study's protein-protein interaction (PPI) network for C9orf72 was meticulously mapped to identify key interactors that might influence the disease mechanism. Among the identified proteins, SMCR8 emerged as a prominent candidate due to its high connectivity (total network contribution = 7.896) within the C9orf72-associated network, suggesting a potential role in modulating the effects of C9orf72 mutations. Analysis of C9orf72 mutations highlighted the I525T mutation, which significantly destabilizes the protein, as indicated by a ΔΔG value of -2.02 kcal/mol. Further investigation involved comparing the structural dynamics of the wild-type C9orf72 and its mutant variants through molecular docking and dynamics simulations. The wild-type demonstrated more stable structural conformation over time, as shown by its RMSD profile than its mutant counterpart. However, after 80 nanoseconds, the mutant variant achieved a similar RMSD stability level. Intriguingly, the mutant formed a more stable complex with SMCR8, evident from its lower binding free energy (-64.18 kcal/mol compared to the wild type's -34.82 kcal/mol). Moreover, per-residue decomposition analysis further revealed critical interactions at specific residues. The wild-type protein showed a significant stabilizing interaction at Arg785, whereas the mutant favored Arg262, indicating a potential shift in binding affinity and site due to the mutation. This shift suggests an altered binding landscape in the mutant C9orf72, which might contribute to the dysregulated protein interactions and cellular processes associated with ALS pathology. The study thus underscores the pathological hyper-stability of the mutant C9orf72, highlighting its potential role in the progression of ALS.}, } @article {pmid39656022, year = {2024}, author = {Prentiss, AM and Baggio, C and Pagett, J and Kulinich, AO and Ethell, IM and Muzzarelli, K and Assar, Z and Pellecchia, M}, title = {Constrained β-Hairpins Targeting the EphA4 Ligand Binding Domain.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {24}, pages = {22245-22253}, pmid = {39656022}, issn = {1520-4804}, support = {R01 CA168517/CA/NCI NIH HHS/United States ; P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 NS129555/NS/NINDS NIH HHS/United States ; P20 CA242620/CA/NCI NIH HHS/United States ; R01 NS107479/NS/NINDS NIH HHS/United States ; }, mesh = {*Receptor, EphA4/metabolism/antagonists & inhibitors/chemistry ; Ligands ; Humans ; Binding Sites ; Protein Binding ; Peptides, Cyclic/chemistry/pharmacology/metabolism/chemical synthesis ; Drug Design ; Protein Domains/drug effects ; Models, Molecular ; }, abstract = {The activity of the receptor tyrosine kinase EphA4 has been implicated in several pathologies including oncology (gastric and pancreatic cancers) and neurodegenerative diseases (amyotrophic lateral sclerosis and Alzheimer's disease). However, advances in validating EphA4 as a possible drug target have been limited by the lack of suitable pharmacological inhibitors. Recently, we reported on the design of potent EphA4 agonistic agents targeting its ligand binding domain (LBD). Based on previous studies with a phage display cyclic peptide inhibitor, we designed a β-hairpin mimetic with high affinity for EphA4-LBD. These agents hold great promise for further validation and development of EphA4-based therapeutics. Moreover, our studies introduce a possible strategy for the design of constrained β-hairpin peptides.}, } @article {pmid39655696, year = {2025}, author = {Di Iacovo, A and D'Agostino, C and Bhatt, M and Romanazzi, T and Giovannardi, S and Cinquetti, R and Roseti, C and Bossi, E}, title = {The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16265}, pmid = {39655696}, issn = {1471-4159}, support = {860954//H2020 Marie Skłodowska-Curie Actions/ ; }, mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism/biosynthesis ; *Excitatory Amino Acid Transporter 2/metabolism/genetics/biosynthesis ; *Xenopus laevis ; Humans ; Oocytes/metabolism ; Female ; Neuroglia/metabolism ; }, abstract = {Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.}, } @article {pmid39655539, year = {2025}, author = {Canosa, A and Martino, A and Manera, U and Giuliani, A and Vasta, R and Palumbo, F and Grassano, M and Morbelli, SD and Pardini, M and Chiaravalloti, A and Schillaci, O and Leenders, KL and Kogan, RV and Polverari, G and Zocco, G and Pede, FD and Mattei, F and Cabras, S and Matteoni, E and Moglia, C and Calvo, A and Chiò, A and Pagani, M}, title = {Sex-related differences in amyotrophic lateral sclerosis: A 2-[[18]F]FDG-PET study.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16588}, pmid = {39655539}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; RF-2016- 02362405//Ministero della Salute/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; //Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Fluorodeoxyglucose F18 ; Aged ; *Sex Characteristics ; *Brain/diagnostic imaging/metabolism ; Adult ; }, abstract = {PURPOSE: We investigated sex-related brain metabolic differences in Amyotrophic Lateral Sclerosis (ALS) and healthy controls (HC).

METHODS: We collected two equal-sized groups of male (m-ALS) and female ALS (f-ALS) patients (n = 130 each), who underwent 2-[[18]F]FDG-PET at diagnosis, matched for site of onset, cognitive status and King's stage. We included 168 age-matched healthy controls, half female (f-HC) and half male (m-HC). We compared brain metabolism of males and females separately for ALS and HC, including age as covariate. A differential network analysis was performed to evaluate brain connectivity.

RESULTS: M-ALS showed relative hypometabolism of bilateral medial frontal, parietal and occipital cortices, and left temporal cortex, compared to f-ALS. In node-wise comparison, f-ALS showed significantly higher connectivity in right middle cingulate cortex and left superior and medial frontal gyrus. In HC we did not find any sex-related differences.

CONCLUSION: Sex resulted a major determinant of brain metabolism and connectivity in ALS patients.}, } @article {pmid39655175, year = {2024}, author = {Palm, A and Ekström, M and Emilsson, Ö and Ersson, K and Ljunggren, M and Sundh, J and Grote, L}, title = {Control of hypercapnia and mortality in home mechanical ventilation: the population-based DISCOVERY study.}, journal = {ERJ open research}, volume = {10}, number = {6}, pages = {}, pmid = {39655175}, issn = {2312-0541}, abstract = {BACKGROUND: Studies on the survival of patients with home mechanical ventilation (HMV) are sparse. We aimed to analyse the impact of controlled hypercapnia on survival over 27 years among patients with HMV in Sweden.

STUDY DESIGN AND METHODS: Population-based cohort study of adult patients starting HMV in the Swedish Registry for Respiratory Failure (Swedevox) during 1996-2022 cross-linked with the National Cause of Death registry. Mortality risk factors were analysed using crude and multivariable Cox regression models, including adjustments for anthropometrics, comorbidities, the underlying diagnosis causing chronic hypercapnic respiratory failure (CRF) and the control of hypercapnia (P aCO2 ≤6.0 kPa) at follow-up.

RESULTS: We included 10 190 patients (50.1% women, age 62.9±14.5 years). Control of hypercapnia at follow-up after 1.3±0.9 years was associated with lower mortality, hazard ratio (HR) 0.74 (95% CI 0.68-0.80) and the association was strongest in those with pulmonary disease, restrictive thoracal disease (RTD), obesity hypoventilation syndrome (OHS) and amyotrophic lateral sclerosis (ALS). Predictors for increased mortality included age, Charlson Comorbidity Index, supplemental oxygen therapy and acute start of HMV therapy. Median survival varied between 0.8 years (95% CI 0.8-0.9 (n=1401)) for ALS and 7.6 years (95% CI 6.9-8.6 (n=1061)) for neuromuscular disease. Three-year survival decreased from 76% (95% CI 71-80) between 1996 and 1998 to 52% (95% CI 50-55) between 2017 and 2019. When adjusting for underlying diagnosis and age, the association between start year and decreased survival disappeared, HR 1.00 (95% CI 0.99-1.01).

CONCLUSION: Controlling P aCO2 is a key treatment goal for survival in HMV therapy. Survival differed markedly between diagnosis and age groups, and survival rates have declined as the patient group has aged.}, } @article {pmid39655131, year = {2024}, author = {Mori, Y and Kenzaka, T}, title = {Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73320}, pmid = {39655131}, issn = {2168-8184}, abstract = {Amyloid light chain (AL) amyloidosis is a disease in which ALs, which are proteins with fibrous structures, are deposited in systemic organs, causing functional impairment. Diagnosis is often difficult because of non-specific and varied symptoms. We report a case of systemic AL amyloidosis that was diagnosed as a result of repeated syncope. A 76-year-old woman was brought to the emergency room with multiple episodes of loss of consciousness over the past five years. She visited the major hospital, where pulmonary thromboembolism and symptomatic epilepsy were considered possible causes. Orthostatic hypotension was observed after being transferred to our hospital for rehabilitation. We performed diagnostic tests, including blood tests, imaging, and a head-up tilt test, which confirmed severe orthostatic hypotension. A gastrointestinal biopsy with Congo red staining confirmed the presence of amyloid deposits. AL amyloidosis (λ) was diagnosed using immunohistochemical staining. Given her age and prolonged bed rest, she was determined that she could not tolerate chemotherapy and was discharged upon her request. To the best of our knowledge, this is the first report of systemic AL amyloidosis presenting with orthostatic hypotension severe enough to cause syncope due to autonomic neuropathy. Autonomic neuropathy should be considered, and amyloidosis should be included in the differential diagnosis when a patient presents with recurrent syncope.}, } @article {pmid39654963, year = {2024}, author = {Sun, P and Niu, L and He, P and Yu, H and Chen, J and Cui, H and Li, X}, title = {Trp-574-Leu and the novel Pro-197-His/Leu mutations contribute to penoxsulam resistance in Echinochloa crus-galli (L.) P. Beauv.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1488976}, pmid = {39654963}, issn = {1664-462X}, abstract = {Recently, due to the widespread use of the acetolactate synthase (ALS)-inhibiting herbicide penoxsulam in paddy fields in China, Echinochloa crus-galli (L.) P. Beauv. has become a problematic grass weed that is frequently not controlled, posing a threat to weed management and rice yield. There are many reports on target-site mutations of ALS inhibiting herbicides; however, the detailed penoxsulam resistance mechanism in E. crus-galli remains to be determined. Greenhouse and laboratory studies were conducted to characterize target-site resistance mechanisms in JL-R, AH-R, and HLJ-R suspected resistant populations of E. crus-galli survived the field-recommended dose of penoxsulam. The whole-plant dose-response testing of E. crus-galli to penoxsulam confirmed the evolution of moderate-level resistance in two populations, JL-R (9.88-fold) and HLJ-R (8.66-fold), and a high-level resistance in AH-R (59.71-fold) population. ALS gene sequencing identified specific mutations in resistant populations, including Pro-197-His in ALS1 for JL-R, Trp-574-Leu in ALS1 for AH-R, and Pro-197-Leu in ALS2 for HLJ-R. In vitro ALS activity assays demonstrated a significantly higher activity in AH-R compared to the susceptible population (YN-S). Molecular docking studies revealed that Trp-574-Leu mutation primarily reduced the enzyme's ability to bind to the triazole-pyrimidine ring of penoxsulam due to decreased π-π stacking interactions, while Pro-197-His/Leu mutations impaired binding to the benzene ring by altering hydrogen bonds and hydrophobic interactions. Additionally, the Pro-197-His/Leu amino acid residue changes resulted in alterations in the shape of the active channel, impeding the efficient entry of penoxsulam into the binding site in the ALS protein. The three mutant ALS proteins expressed via the Bac-to-Bac baculovirus system exhibited notably lower activity inhibition rates than the non-mutant ALS proteins to penoxsulam, indicating all three ALS mutations reduce sensitivity to penoxsulam. This study elucidated the distinct impacts of the Pro-197-His/Leu and Trp-574-Leu mutations in E. crus-galli to penoxsulam resistance. Notably, the Trp-574-Leu mutation conferred stronger resistance to penoxsulam compared to the Pro-197-His/Leu mutations in E. crus-galli. The Pro-197-His/Leu mutations were first detected in E. crus-galli conferring penoxsulam resistance. These findings provide deeper insights into the molecular mechanisms underlying target-site resistance to penoxsulam in E. crus-galli.}, } @article {pmid39654532, year = {2024}, author = {Dave, KD and Oskarsson, B and Yersak, J and Krauss, R and Heiman-Patterson, T and Lomen-Hoerth, C and Selig, WKD and Halpern Paul, I and Schaeffer, M and Garcia-Trujillo, B and Waldo, D and Thakur, N and Babu, S}, title = {Contributions of neurologists to diagnostic timelines of ALS and thinkALS as an early referral instrument for clinicians.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2432034}, pmid = {39654532}, issn = {2167-9223}, abstract = {Objectives: To evaluate neurologists and other clinicians' contributions to U.S. ALS diagnostic timelines. Background: Over the past two decades, the average time to ALS diagnosis in the U.S. has remained unchanged at 12 months. ALS patients see 3-4 clinicians prior to referral to an ALS specialist for diagnosis confirmation and/or treatment initiation. There is an urgent need to identify where delays occur, so that targeted clinician awareness may be raised about early suspicion and referrals. Methods: Review of Medicare claims database for health care utilization patterns by ALS beneficiaries during diagnostic journey. Survey of typical clinic wait times for new consultations reported by 75-78 ALS Certified Treatment Centers of Excellence (2019-2021). Results: During 2011-2021, 78,520 Medicare beneficiaries were diagnosed with ALS (T0). The mean (median) timelines between first neurologist ambulatory visit and T0, is 16.5 (11.0) months; mean ± SD for ALS/neuromuscular providers being 9.6 ± 12.6 months versus 16.7 ± 17.5 months for non-neuromuscular neurologists. During the 12-months preceding T0, an ALS patient undergoes median(max) 1.5(4.0) brain-MRIs, 1.6(6.0) spine-MRIs, and 1.3(4.0) electromyography studies. Greater than 75% of ALS centers consistently report ≤ 4 week wait times for new ALS consults. This study introduces "thinkALS," an easy-to-use clinical diagnostic and referral guide for non-ALS neurologists to tackle this challenge. Conclusions: This study is the first to provide metrics on how non-neuromuscular/ALS specialists contribute to ALS diagnostic timelines in the U.S.}, } @article {pmid39654263, year = {2024}, author = {Beck, V and Brooks, JL and Stephens, R}, title = {EXPRESS: The Effect of Swearing on Error-Related Negativity as an Indicator for State Disinhibition.}, journal = {Quarterly journal of experimental psychology (2006)}, volume = {}, number = {}, pages = {17470218241308560}, doi = {10.1177/17470218241308560}, pmid = {39654263}, issn = {1747-0226}, abstract = {INTRODUCTION: Swearing has been linked to increased strength performance (Stephens et al., 2022) and state disinhibition (Hirsch et al, 2011) may be the mechanism linking swearing and strength. Error-related negativity (ERN) is a neural signal associated with response monitoring. Its reduction has been proposed as neural marker for state disinhibition, and therefore we predicted that swearing would lead to a decreased ERN compared to neutral word repetition, indicating state disinhibition.

METHODS: The study (N=52) used a within-subjects experimental design with two conditions. Participants repeated either a swear or neutral word aloud for 10 seconds before engaging in an arrowhead flanker task, a grip strength task and several questionnaires. ERN was measured continually using EEG.

RESULTS: The study replicated previously found effects of swearing on strength, humour, positive emotion and distraction. Additionally, swearing was found to have a significant effect on state behavioural activation (BAS drive). However, results indicated no significant difference between conditions on ERN amplitude.

DISCUSSION: This pre-registered study has confirmed that, relative to a neutral word, repeating a swear word leads to increased performance on a grip strength task while also confirming effects of swearing on positive emotion, humour and distraction. Its novel contribution is confirming that swearing raises state behavioural activation. This supports application of Hirsh et al's (2011) state disinhibition theory to swearing to some extent, although the absence of any effect of swearing on ERN limits this interpretation.}, } @article {pmid39651269, year = {2024}, author = {O'Neill, K and Shaw, R and Bolger, I and , and Tam, O and Phatnani, H and Hammell, MG}, title = {ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.19.603731}, pmid = {39651269}, issn = {2692-8205}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this general heterogeneity, several common factors have been identified. For example, nearly all patients show pathological accumulations of phosphorylated TDP-43 protein in affected regions of the motor cortex and spinal cord. Moreover, large patient cohort studies have revealed that most patient samples can be grouped into a small number of ALS subtypes, as defined by their transcriptomic profiles. These ALS molecular subtypes can be grouped by whether postmortem motor cortex samples display signatures of: mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or dense TDP-43 pathology and associated transposable element de-silencing (ALS-TE). In this study, we have built a deep layer ALS neural network classifier (DANcer) that has learned to accurately assign patient samples to these ALS subtypes, and which can be run on either bulk or single-cell datasets. Upon applying this classifier to an expanded ALS patient cohort from the NYGC ALS Consortium, we show that ALS Molecular Subtypes are robust across clinical centers, with no new subtypes appearing in a cohort that has quadrupled in size. Signatures from two of these molecular subtypes strongly correlate with disease duration: ALS-TE signatures in cortex and ALS-Glia signatures in spinal cord, revealing molecular correlates of clinical features. Finally, we use single nucleus RNA sequencing to reveal the cell type-specific contributions to ALS subtype, as determined by our single-cell classifier (scDANCer). Single-cell transcriptomes reveal that ALS molecular subtypes are recapitulated in neurons and glia, with both ALS-wide shared alterations in each cell type as well as ALS subtype-specific alterations. In summary, ALS molecular subtypes: (1) are robust across large cohorts of sporadic and familial ALS patient samples, (2) represent a combination of cellular, genetic, and pathological features, and (3) correlate with clinical features of ALS.}, } @article {pmid39651224, year = {2024}, author = {Kodavati, M and Maloji Rao, VH and Mitra, J and Hegde, ML}, title = {Selective Inhibition of Cytosolic PARylation via PARG99: A Targeted Approach for Mitigating FUS-associated Neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.25.625276}, pmid = {39651224}, issn = {2692-8205}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are characterized by complex etiologies, often involving disruptions in functions of RNA/DNA binding proteins (RDBPs) such as FUS and TDP-43. The cytosolic mislocalization and aggregation of these proteins are linked to accumulation of unresolved stress granules (SGs), which exacerbate the disease progression. Poly-ADP-ribose polymerase (PARP)-mediated PARylation plays a critical role in this pathological cascade, making it a potential target for intervention. However, conventional PARP inhibitors are limited by their detrimental effects on DNA repair pathways, which are already compromised in ALS. To address this limitation, we investigated a strategy focused on targeting the cytosolic compartment by expressing the cytosol-specific, natural PAR- glycohydrolase (PARG) isoform, PARG99. Using ALS patient derived FUS mutant induced pluripotent cells (iPSCs) and differentiated neurons, we observed elevated levels of FUS in insoluble fractions in mutant cells compared to mutation-corrected isogenic lines. The insoluble FUS as well as TDP-43 levels increased further in sodium arsenite-treated or oxidatively stressed cells, correlating with accumulation of unresolved SGs. Notably, both PARG99 and PARP inhibitors reduced SG formation and insoluble FUS levels, however, PARG99 treated cells exhibited significantly lower DNA damage markers and improved viability under oxidative and arsenite stress. This study highlights the potential of PARG99 as a cytosol-specific intervention to mitigate FUS-associated toxicity while preserving critical nuclear DNA repair mechanisms, offering a promising strategy for addressing the underlying pathology of ALS and potentially other SG-associated neurodegenerative diseases.}, } @article {pmid39651197, year = {2024}, author = {Grant, OA and Iacoangeli, A and Zwamborn, RAJ and van Rheenen, W and Byrne, R and Van Eijk, KR and Kenna, K and van Vugt, JJFA and Cooper-Knock, J and Kenna, B and Vural, A and Topp, S and Campos, Y and Weber, M and Smith, B and Dobson, R and van Es, MA and Vourc'h, P and Corcia, P and de Carvalho, M and Gotkine, M and Panades, MP and Mora, JS and Mill, J and Garton, F and McRae, A and Wray, NR and Shaw, PJ and Landers, JE and Glass, JD and Shaw, CE and Basak, N and Hardiman, O and Van Damme, P and McLaughlin, RL and van den Berg, LH and Veldink, JH and Al-Chalabi, A and Al Khleifat, A}, title = {Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.22.624866}, pmid = {39651197}, issn = {2692-8205}, abstract = {Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3'UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.}, } @article {pmid39651147, year = {2024}, author = {Fleming, AC and Rao, NR and Wright, M and Savas, JN and Kiskinis, E}, title = {The ALS-associated co-chaperone DNAJC7 mediates neuroprotection against proteotoxic stress by modulating HSF1 activity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.01.626216}, pmid = {39651147}, issn = {2692-8205}, abstract = {The degeneration of neurons in patients with amyotrophic lateral sclerosis (ALS) is commonly associated with accumulation of misfolded, insoluble proteins. Heat shock proteins (HSPs) are central regulators of protein homeostasis as they fold newly synthesized proteins and refold damaged proteins. Heterozygous loss-of- function mutations in the DNAJC7 gene that encodes an HSP co-chaperone were recently identified as a cause for rare forms of ALS, yet the mechanisms underlying pathogenesis remain unclear. Using mass spectrometry, we found that the DNAJC7 interactome in human motor neurons (MNs) is enriched for RNA binding proteins (RBPs) and stress response chaperones. MNs generated from iPSCs with the ALS-associated mutation R156X in DNAJC7 exhibit increased insolubility of its client RBP HNRNPU and associated RNA metabolism alterations. Additionally, DNAJC7 haploinsufficiency renders MNs increasingly susceptible to proteotoxic stress and cell death as a result of an ablated HSF1 stress response pathway. Critically, expression of HSF1 in mutant DNAJC7 MNs is sufficient to rescue their sensitivity to proteotoxic stress, while postmortem ALS patient cortical neurons exhibit a reduction in the expression of HSF1 pathway genes. Taken together, our work identifies DNAJC7 as a crucial mediator of HNRNPU function and stress response pathways in human MNs and highlights HSF1 as a therapeutic target in ALS.}, } @article {pmid39650285, year = {2024}, author = {Hu, Y and Deeba, E and Kläppe, U and Öijerstedt, L and Andersson, J and Ruffin, N and Piehl, F and Ingre, C and Fang, F and Seitz, C}, title = {Immune cells and the trajectories of depression, anxiety, and cognitive function among people with amyotrophic lateral sclerosis.}, journal = {Brain, behavior, & immunity - health}, volume = {42}, number = {}, pages = {100907}, pmid = {39650285}, issn = {2666-3546}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) represents a complex syndrome characterized by motor, psychiatric, and cognitive symptoms, where associations between cellular immune features and non-motor manifestations remain unknown.

METHODS: In this cohort study, we enrolled 250 incident people with ALS (pwALS) assessed with the Hospital Anxiety and Depression Scale, and 226 pwALS with the Montreal Cognitive Assessment, including 218 overlapping pwALS. All individuals were diagnosed between January 2015 and January 2023 in Stockholm, Sweden. We applied joint latent class models to delineate distinct trajectories of anxiety, depression, and cognition, incorporating survival outcomes. A majority of the pwALS had data on leukocyte counts and flow cytometric analyses using a comprehensive T cell panel. We then used immune cell subtypes measured at diagnosis to predict trajectories of these outcomes following ALS diagnosis.

RESULTS: We identified two distinct trajectories for anxiety, depression, and cognitive function following ALS diagnosis. PwALS with longer survival displayed more stable trajectories, while those with shorter survival showed decreasing anxiety symptom, increasing depressive symptom, and declining cognitive function. Higher count of leukocytes at the time of ALS diagnosis tended to associate with anxiety and depression trajectories related to shorter survival. Among T cell subpopulations, several CD8[+] T cell subsets were associated with a stable trajectory of depressive symptom, and, in turn, better survival.

CONCLUSION: ALS-associated psychiatric and cognitive trajectories vary significantly between pwALS with different prognosis. Certain T cell subsets measured at diagnosis might be indicative of depression trajectories post-diagnosis.}, } @article {pmid39649550, year = {2024}, author = {Han, S and Li, RH and Gao, P}, title = {Gut microbiota participates and remodels host metabolism: From treating patients to treating their gut flora.}, journal = {World journal of gastroenterology}, volume = {30}, number = {45}, pages = {4839-4843}, pmid = {39649550}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; Animals ; Uric Acid/blood/metabolism ; Hyperuricemia/microbiology/drug therapy/blood/metabolism ; Metabolomics/methods ; Feces/microbiology ; }, abstract = {In this editorial, we comment on Liu et al's article published in the recent issue of the World Journal of Gastroenterology. Biochemically and pathologically, Liu et al proved that the urate-lowering activity of leech total protein (LTP) was mainly attributed to the rectification of gut microbiota. Specifically, we noticed the change in Bacteroides and Akkermansia after LTP administration. Both bacteria have been reported to alleviate metabolic dysfunction-associated steatohepatitis and other chronic metabolic diseases. LTP was administrated through intragastric manners. Most possibly, LTP would be digested by the gut microbiota further. The anti-hyperuricemia effects should, to the most possible extent, be exerted by the peptides or their secondary metabolic products. Human gut microbiota communicates with other organs through metabolites generated by the microbes or co-metabolized with the host. Whether the anti-hyperuricemia effect could be partially ascribed to the microbiota metabolites also deserves to be discussed. Although metabolomics analysis was performed for serum samples, fecal metabolomics was highly advocated which could facilitate exact mechanism explanation. This study implied that gut microbiota contains many unexplored targets with different therapeutic potentials. It is foreseeable that utilizing these targets can avoid the impairment or side effects of directly using human targets to some extent.}, } @article {pmid39649175, year = {2024}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Dos Santos Souza, C and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39649175}, issn = {2693-5015}, support = {R01 HL101388/HL/NHLBI NIH HHS/United States ; P50 HL083800/HL/NHLBI NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection of WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, } @article {pmid39647703, year = {2024}, author = {Watters, JJ and Bell, MC and Que, SKT}, title = {Regarding response to Watters et al's "Educational intervention targeting primary care residents improves skin cancer recognition in patients with skin of color".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.11.051}, pmid = {39647703}, issn = {1097-6787}, } @article {pmid39645528, year = {2024}, author = {Ríos-López, AL and Garza-Velásquez, MF and González, GM and Becerril-García, MA and Flores-Maldonado, O}, title = {Prevalence, virulence factors and antifungal susceptibility of oral isolates of Candida albicans from patients with cystic fibrosis in Mexico.}, journal = {Revista iberoamericana de micologia}, volume = {41}, number = {2-3}, pages = {31-36}, doi = {10.1016/j.riam.2024.09.001}, pmid = {39645528}, issn = {2173-9188}, mesh = {Humans ; *Cystic Fibrosis/microbiology/complications ; *Virulence Factors/genetics ; *Candida albicans/drug effects/isolation & purification/genetics ; Mexico/epidemiology ; *Antifungal Agents/pharmacology ; *Microbial Sensitivity Tests ; Female ; Male ; Adult ; Young Adult ; Adolescent ; *Candidiasis, Oral/microbiology/epidemiology ; Prevalence ; Child ; Drug Resistance, Fungal ; Biofilms/growth & development ; Mouth/microbiology ; Child, Preschool ; }, abstract = {BACKGROUND: Candida species are frequently isolated from the oral cavity of patients with cystic fibrosis. However, the information on the role of Candida in cystic fibrosis is scarce.

AIMS: This study aimed to evaluate the prevalence, virulence profile and antifungal susceptibility of oral isolates of Candida albicans recovered from patients with cystic fibrosis.

METHODS: Oropharyngeal swab samples were collected from sixty-five cystic fibrosis patients and sixty-five healthy individuals. Candida isolates were identified by MALDI-TOF VITEK-MS. Proteinase, phospholipase and esterase activity, biofilm production and level expression of ALS, SAP and PLB genes in C. albicans were evaluated. Minimal inhibitory concentration values were determined by means of an antifungal susceptibility test.

RESULTS: Oral Candida colonization in cystic fibrosis patients was 66.15%, while in healthy individuals was 36.92%. C. albicans was the most frequently isolated species. C. albicans strains from cystic fibrosis patients were high producers of protease and biofilm, and had higher expression levels of adhesin and protease-associated genes in comparison with healthy subjects. Among the C. albicans strains isolated from cystic fibrosis patients, 18.91% were resistant to itraconazole, while 16.21% exhibited resistance to ketoconazole and fluconazole, and only one strain was resistant to voriconazole.

CONCLUSIONS: This work represents a surveillance study on virulence patterns and antifungal susceptibility of Candida from the oropharyngeal tract in cystic fibrosis.}, } @article {pmid39645221, year = {2025}, author = {Bajpai, A and Bharathi, V and Patel, BK}, title = {Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.}, journal = {European journal of pharmacology}, volume = {987}, number = {}, pages = {177187}, doi = {10.1016/j.ejphar.2024.177187}, pmid = {39645221}, issn = {1879-0712}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *Antioxidants/pharmacology/therapeutic use ; *Huntington Disease/metabolism/drug therapy/pathology/genetics ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.}, } @article {pmid39645085, year = {2024}, author = {Ediriweera, GR and Sivaram, AJ and Cowin, G and Brown, ML and McAlary, L and Lum, JS and Fletcher, NL and Robinson, L and Simpson, JD and Chen, L and Wasielewska, JM and Byrne, E and Finnie, JW and Manavis, J and White, AR and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {221-235}, doi = {10.1016/j.jconrel.2024.11.074}, pmid = {39645085}, issn = {1873-4995}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.}, } @article {pmid39645043, year = {2024}, author = {Needle, C and Brinks, A and Shapiro, J and Lo Sicco, K}, title = {Response to Chen et al's "Emergence of Janus kinase inhibitors led to increase in proportion of severe alopecia areata patients receiving treatment: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.10.118}, pmid = {39645043}, issn = {1097-6787}, } @article {pmid39644980, year = {2025}, author = {Guerra San Juan, I and Brunner, JW and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106759}, doi = {10.1016/j.nbd.2024.106759}, pmid = {39644980}, issn = {1095-953X}, mesh = {*Kinesins/metabolism/genetics ; *Axonal Transport/physiology ; Humans ; *Mitochondria/metabolism ; *Motor Neurons/metabolism ; *Axons/metabolism ; PTB-Associated Splicing Factor/metabolism ; Nerve Regeneration/physiology ; Cells, Cultured ; Neuronal Outgrowth/physiology ; }, abstract = {Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro. KIF5A deficiency caused reduced neurite complexity in young neurons (DIV14) and defects in axonal regeneration. KIF5A deficiency did not affect neurofilament transport but impaired mitochondrial motility and anterograde speed at DIV42. Notably, KIF5A deficiency strongly reduced anterograde transport of splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules in DIV42 axons. Hence, KIF5A plays a critical role in promoting axonal regrowth after injury and in driving the anterograde transport of mitochondria and especially SFPQ-associated RNA granules in mature neurons.}, } @article {pmid39644798, year = {2024}, author = {Toko, M and Ohshita, T and Nakamori, M and Ueno, H and Akiyama, Y and Maruyama, H}, title = {Myelin measurement in amyotrophic lateral sclerosis with synthetic MRI: A potential diagnostic and predictive method.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123337}, doi = {10.1016/j.jns.2024.123337}, pmid = {39644798}, issn = {1878-5883}, abstract = {BACKGROUND: Myelin damage has recently been highlighted as a major causative factor of amyotrophic lateral sclerosis (ALS). Although myelin damage has been pathologically identified in ALS, it has not been clinically evaluated. This study aimed to quantify myelin volume using synthetic MRI to evaluate myelin damage in patients with ALS, and determine its association with clinical parameters.

METHODS: We evaluated patients with ALS (n = 35) and individuals (n = 16) without intracranial disease using synthetic magnetic resonance imaging (MRI) and measured total myelin volume (TMV), myelin fraction (MYF), and myelin partial volume (VMY) in the cerebral peduncle and the posterior limb of the internal capsule (PLIC). We also investigated factors associated with acquired quantitative values.

RESULTS: The TMV was significantly lower in the patients with ALS than in the control group (P = 0.045). The TMV (r = 0.42, P = 0.013) and MYF (r = 0.34, P = 0.047) significantly correlated with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores in the patients, and MYF was independent of the traditional white matter lesion grading score. The VMY of the PLIC was significantly lower in the ALS than the control group (P = 0.018), and the ALS group significantly correlated with ALSFRS-R scores (r = 0.36, P = 0.033).

CONCLUSIONS: Myelin damage can be quantified by synthetic MRI as reduced myelin volume, with the possibility of predicting prognoses in patients with ALS. Furthermore, myelin measurements in the PLIC might be a novel diagnostic marker for ALS.}, } @article {pmid39643934, year = {2024}, author = {Farrokhzad, R and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Insight Into Factors Influencing the Aggregation Process in Wild-Type and P66R Mutant SOD1: Computational and Spectroscopic Approaches.}, journal = {Proteins}, volume = {}, number = {}, pages = {}, doi = {10.1002/prot.26765}, pmid = {39643934}, issn = {1097-0134}, abstract = {Disturbances in metal ion homeostasis associated with amyotrophic lateral sclerosis (ALS) have been described for several years, but the exact mechanism of involvement is not well understood. To elucidate the role of metalation in superoxide dismutase (SOD1) misfolding and aggregation, we comprehensively characterized the structural features (apo/holo forms) of WT-SOD1 and P66R mutant in loop IV. Using computational and experimental methodologies, we assessed the physicochemical properties of these variants and their correlation with protein aggregation at the molecular level. Modifications in apo-SOD1 compared to holo-SOD1 were more pronounced in flexibility, stability, hydrophobicity, and intramolecular interactions, as indicated by molecular dynamics simulations. The enzymatic activities of holo/apo-WT SOD1 were 1.30 and 1.88-fold of the holo/apo P66R mutant, respectively. Under amyloid-inducing conditions, decreased ANS fluorescence intensity in the apo-form relative to the holo-form suggested pre-fibrillar species and amyloid aggregate growth due to occluded hydrophobic pockets. FTIR spectroscopy revealed that apo-WT-SOD1 and apo-P66R exhibited a mixture of parallel and intermolecular β-sheet structures, indicative of aggregation propensity. Aggregate species were identified using TEM, Congo red staining, and ThT/ANS fluorescence spectroscopy. Thermodynamic analyses with GdnHCl demonstrated that metal deficit, mutation, and intramolecular disulfide bond reduction are essential for initiating SOD1 misfolding and aggregation. These disruptions destabilize the dimer-monomer equilibrium, promoting dimer dissociation into monomers and decreasing the thermodynamic stability of SOD1 variants, thus facilitating amyloid/amorphous aggregate formation. Our findings offer novel insights into protein aggregation mechanisms in disease pathology and highlight potential therapeutic strategies against toxic protein aggregation, including SOD1.}, } @article {pmid39643926, year = {2024}, author = {Wang, J and Du, Y and Zhang, L and Deng, Y and Wang, T and Wang, S and Ji, M}, title = {Pro-197-Ser mutation combinations in acetolactate synthase (ALS) homoeologous genes affect ALS inhibitor herbicide resistance levels in Monochoria korsakowii.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8586}, pmid = {39643926}, issn = {1526-4998}, support = {32372594//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Monochoria korsakowii is a common broadleaf weed found in rice (Oryza sativa) fields. Acetolactate synthase (ALS) inhibitor herbicides are commonly used to control broadleaf weeds in rice fields. However, prolonged herbicide use has exacerbated resistance issues. In this study, we evaluated the resistance to ALS inhibitors in populations where the same mutation occurred separately and simultaneously in the two ALS homoeologous genes (ALS1 and ALS2) and investigated the resistance mechanisms in M. korsakowii.

RESULTS: Monochoria korsakowii exhibited high resistance to bensulfuron-methyl, low resistance to penoxsulam, and sensitivity to imazethapyr. Three resistant populations were identified: M-1 and M-2, which independently evolved the Pro-197-Ser mutation in ALS1 and ALS2, respectively, and M-3, which harbored this mutation in both ALS1 and ALS2. The sensitivity of ALS isolated from these populations to herbicide inhibition corresponded to the whole-plant resistance levels. Subsequently, we cloned and transformed Pro-197-Ser-mutated ALS1 and ALS2 into Arabidopsis thaliana. The resistance of homozygous A. thaliana to bensulfuron-methyl and penoxsulam aligned with bioassay trends. Furthermore, we measured the ploidy, relative expression, and copy number of ALS1 and ALS2, and found no significant differences, suggesting that the evolution of resistance was primarily attributed to the Pro-197-Ser mutation. Finally, we developed a derived cleaved amplified polymorphic sequence marker for detecting Pro-197-Ser mutation in ALS.

CONCLUSION: The same mutation occurring separately in homoeologous genes resulted in similar resistance levels, whereas simultaneous mutations in homoeologous genes led to increased resistance levels. © 2024 Society of Chemical Industry.}, } @article {pmid39642451, year = {2024}, author = {He, X}, title = {Hyperspectral Raman imaging with multivariate curve resolution-alternating least square (MCR-ALS) analysis for xylazine-containing drug mixtures.}, journal = {Forensic science international}, volume = {367}, number = {}, pages = {112314}, doi = {10.1016/j.forsciint.2024.112314}, pmid = {39642451}, issn = {1872-6283}, abstract = {Xylazine, increasingly implicated in illicit opioid overdose deaths, poses a significant public health threat due to its synergistic effects with fentanyl and resistance to naloxone reversal. Despite its rising prevalence, xylazine is not classified as a controlled substance, leading to its exclusion from routine forensic screening. This study introduces a novel analytical method combining Raman hyperspectral imaging with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to detect xylazine in drug mixtures containing common excipients such as acetaminophen, dipyrone, and mannitol. Utilizing only non-negativity constraints, MCR-ALS successfully resolved the Raman spectrum of xylazine at levels as low as 5 % without reference spectra. The method demonstrated robust performance, with percent variance explained (R[2]) values of 99.60 %, 99.80 %, and 99.91 % for the drug mixtures containing 25 %, 10 %, and 5 % xylazine, respectively.}, } @article {pmid39641862, year = {2024}, author = {Zhang, J and Zhang, X and Xiao, B and Ouyang, J and Wang, P and Peng, X}, title = {Mendelian randomization study of causal link from Cerebrospinal fluid metabolomics to neurodegenerative diseases.}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {15}, pmid = {39641862}, issn = {1364-6753}, support = {No. YZ2020MS04//President Foundation of The Fifth Affiliated Hospital, Southern Medical University/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/cerebrospinal fluid ; *Metabolomics/methods ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; Multiple Sclerosis/genetics/cerebrospinal fluid ; Alzheimer Disease/genetics/cerebrospinal fluid ; Parkinson Disease/genetics/cerebrospinal fluid ; Polymorphism, Single Nucleotide ; }, abstract = {To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach. Additionally, different GWAS summary data for NDDs were used to validate the initial results and perform sensitivity analyses to enhance the robustness of the findings. Finally, reverse MR analyses were conducted to assess the possibility of reverse causation. Combining results from the initial and replication phases of MR analysis, we identified potential causal relationships between various CSF metabolites and different NDDs. Specifically, we found potential causal relationships between five CSF metabolites and AD, six CSF metabolites and MS, and thirteen CSF metabolites and ALS. Further sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis indicated causal effects of AD on glucuronate and ALS on acetylcarnitine (C2). Our study, through genetic means, demonstrates close causal associations between the specific types of CSF metabolites and the risk of NDDS (AD, PD, MS, and ALS), providing useful guidance for future clinical researches.}, } @article {pmid39641521, year = {2025}, author = {Manera, U and Callegaro, S and Canosa, A and Palumbo, F and Grassano, M and Bombaci, A and Dagliati, A and Bosoni, P and Daviddi, M and Casale, F and Cabras, S and Matteoni, E and De Marchi, F and Mazzini, L and Moglia, C and Vasta, R and Calvo, A and Chiò, A}, title = {Croplands proximity is associated with amyotrophic lateral sclerosis incidence and age at onset.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16464}, pmid = {39641521}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Università e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; GA101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Humans ; Incidence ; *Age of Onset ; Female ; Male ; Middle Aged ; Aged ; *Crops, Agricultural ; Adult ; Registries ; Italy/epidemiology ; Risk Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from an intricate interplay between genetics and environmental factors. Many studies have explored living in rural areas as a possible risk factor for ALS, without focusing simultaneously on incidence, age at onset and phenotypic features.

OBJECTIVE: To evaluate the effect of croplands residential proximity on ALS incidence and phenotype, focusing on age of onset, site of onset and progression rate.

METHODS: The address history of ALS patients belonging to the population-based Piemonte and Valle d'Aosta registry (PARALS), diagnosed between 2007 and 2014, was obtained for the 20 years prior to the onset date. The smoothed ALS incidence per year (im) was compared with the percentage of area covered by each crop for each municipality. A proximity score was calculated for each cropland by geolocation, measuring the percentage of area surrounding patients' residence for variable radii, and was used to compare croplands exposure and phenotype.

RESULTS: We observed an increased ALS incidence in the municipalities with a higher percentage of area covered by arable crops (R = 0.191, p < 0.001). Age at onset was significantly lower in those patients who lived near arable crops, with a median anticipation ranging from 1.8 to 3.4 years; using historical data, a significant anticipation was found also for patients living near vineyards.

DISCUSSION: Our study proved a direct association between arable crops and ALS risk and an inverse association between arable crops and vineyards proximity and age at onset, suggesting the possible causative role of specific environmental contaminants.}, } @article {pmid39640847, year = {2024}, author = {Raineri, D and De Marchi, F and Vilardo, B and Barbero Mazzucca, C and Scotti, L and Kustrimovic, N and Mazzini, L and Cappellano, G and Chiocchetti, A}, title = {Circulating GLAST[+] EVs are increased in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1507498}, pmid = {39640847}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, hallmarked by the gradual deterioration of motor neurons, culminating in muscle weakness and fatal paralysis. The exact etiology of ALS remains elusive, and there is a critical need for reliable biomarkers to aid in diagnosis and monitoring of disease progression. Extracellular vesicles (EVs) have emerged as promising candidates for biomarker discovery in neurodegenerative diseases such as ALS, giving access to pathologically relevant tissues otherwise typically challenging or invasive to sample. Indeed, EVs can derive by many cell types within the central nervous system, cross the blood-brain barrier and reach the blood, where they can be easily measured. One of the central mechanisms implicated in ALS pathology is glutamate excitotoxicity, which involves excessive glutamate accumulation due to impaired uptake by astrocytes and other glial cells, leading to neuronal damage. GLAST is a key glutamate transporter responsible for maintaining extracellular gluta-mate levels, and its dysregulation is thought to contribute significantly to ALS development and associated neuropathogenesis. Here, we applied a quick and validated method, to evaluate GLAST[+] EVs in ALS patients' plasma and age-matched healthy controls. We found an increase in GLAST[+] EVs that holds promise for uncovering novel diagnostic and therapeutic avenues in ALS research.}, } @article {pmid39640633, year = {2024}, author = {Nikafshan Rad, H and Su, Z and Trinh, A and Hakim Newton, MA and Shamsani, J and Nygc Als Consortium, and Karim, A and Sattar, A}, title = {Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration.}, journal = {Heliyon}, volume = {10}, number = {20}, pages = {e38583}, pmid = {39640633}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterized by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalized medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS. This work utilizes an innovative approach by employing a machine learning-facilitated, multi-omic model to develop a more comprehensive knowledge of ALS. Through unsupervised clustering on gene expression profiles, 9,847 genes associated with ALS pathways are isolated and integrated with 7,699 genes containing rare, presumed pathogenic genomic variants, leading to a comprehensive amalgamation of 17,546 genes. Subsequently, a Variational Autoencoder is applied to distil complex biomedical information from these genes, culminating in the creation of the proposed Multi-Omics for ALS (MOALS) model, which has been designed to expose intricate genotype-phenotype interconnections within the dataset. Our meticulous investigation elucidates several pivotal ALS signaling pathways and demonstrates that MOALS is a superior model, outclassing other machine learning models based on single omic approaches such as SNV and RNA expression, enhancing accuracy by 1.7 percent and 6.2 percent, respectively. The findings of this study suggest that analyzing the relationships within biological systems can provide heuristic insights into the biological mechanisms that help to make highly accurate ALS diagnosis tools and achieve more interpretable results.}, } @article {pmid39639468, year = {2024}, author = {Arango-Cortes, ML and Giraldo-Cadavid, LF and Latorre Quintana, M and Forero-Cubides, JD and Gonzalez-Bermejo, J}, title = {Diaphragm pacing compared with mechanical ventilation in patients with chronic respiratory failure caused by diaphragmatic dysfunction: a systematic review and meta-analysis.}, journal = {Expert review of respiratory medicine}, volume = {18}, number = {12}, pages = {1101-1111}, doi = {10.1080/17476348.2024.2421846}, pmid = {39639468}, issn = {1747-6356}, mesh = {Humans ; *Respiration, Artificial/adverse effects ; *Diaphragm/physiopathology ; *Respiratory Insufficiency/therapy/physiopathology/etiology ; *Quality of Life ; *Electric Stimulation Therapy ; *Respiratory Paralysis/therapy/physiopathology/etiology ; Treatment Outcome ; Spinal Cord Injuries/complications/physiopathology/therapy ; Length of Stay ; Chronic Disease ; }, abstract = {BACKGROUND: The effectiveness of diaphragmatic electrical stimulation (DES) compared to mechanical ventilation (MV) in improving clinical outcomes such as quality-of-life (QOL) and hospital stay remains inconsistent.

METHODS: We conducted a systematic review and meta-analysis by searching PubMed, Scopus, Google Scholar, LILACS, and IEEE Xplore. We included comparative studies (randomized controlled trials and observational studies) of DES administered via the phrenic nerve or intramuscular electrodes, compared with MV in adults with diaphragmatic paralysis or paresis. Two authors independently extracted data and assessed bias, with discrepancies resolved by a senior author. Results were pooled using the inverse variance method.

RESULTS: Out of 1,290 articles, nine were included in the systematic review, totaling 852 subjects. In spinal cord injury (SCI), one study reported lower mortality with DES, while three found no difference compared to MV. In these patients, DES was associated with shorter hospital stay, similar QOL, and heterogeneous results on respiratory infections. In amyotrophic lateral sclerosis (ALS), DES was associated with higher mortality and similar QOL compared to MV. Most SCI studies had a serious risk of bias.

CONCLUSION: DES shows potential in reducing hospital stay and respiratory infections in SCI but is associated with higher mortality in ALS.}, } @article {pmid39638345, year = {2025}, author = {Webster, CP and Hall, B and Crossley, OM and Dauletalina, D and King, M and Lin, YH and Castelli, LM and Yang, ZL and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Ferraiuolo, L and De Vos, KJ and Hautbergue, GM and Shaw, PJ and West, RJ and Azzouz, M}, title = {RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.}, journal = {Life science alliance}, volume = {8}, number = {2}, pages = {}, pmid = {39638345}, issn = {2575-1077}, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Dipeptides/metabolism ; *ATPases Associated with Diverse Cellular Activities/metabolism/genetics ; *DNA Helicases/genetics/metabolism ; *Mice, Transgenic ; DNA Repeat Expansion/genetics ; Carrier Proteins/metabolism/genetics ; Motor Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; }, abstract = {A G4C2 hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models. Therefore, decreasing RAN-DPRs may be of therapeutic benefit in the context of C9ALS/FTD. In this study, we found that C9ALS/FTD patients have reduced expression of the AAA+ family members RuvBL1 and RuvBL2, which have both been implicated in aggregate clearance. We report that overexpression of RuvBL1, but to a greater extent RuvBL2, reduced C9orf72-associated DPRs in a range of in vitro systems including cell lines, primary neurons from the C9-500 transgenic mouse model, and patient-derived iPSC motor neurons. In vivo, we further demonstrated that RuvBL2 overexpression and consequent DPR reduction in our Drosophila model was sufficient to rescue a number of DPR-related motor phenotypes. Thus, modulating RuvBL levels to reduce DPRs may be of therapeutic potential in C9ALS/FTD.}, } @article {pmid39638270, year = {2025}, author = {Ruzzante, B and Fruzzetti, F and Cattaneo, M and Lauria Pinter, G and Marcuzzo, S and Candiani, G and Bono, N}, title = {Harnessing osmotic shock for enhanced intracellular delivery of (nano)cargos.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125008}, doi = {10.1016/j.ijpharm.2024.125008}, pmid = {39638270}, issn = {1873-3476}, mesh = {*Osmotic Pressure ; Humans ; *Cell Survival/drug effects ; Nanoparticles/administration & dosage/chemistry ; Drug Delivery Systems/methods ; Fibroblasts/drug effects/metabolism ; Animals ; Cell Size ; Cell Line ; Cells, Cultured ; }, abstract = {Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery. In this study, we utilized osmotic shock to enhance (nano)cargos internalization. We examined the effects of hypotonic/hypertonic shock on both primary and cell lines, assessing parameters such as cell viability, cell volume, membrane tension changes, and particle uptake. Our results indicate that short-lived osmotic shock does not harm cells. Hypotonic shock induced temporary shape changes lasting up to 5 min, followed by a 15-minute recovery period. Importantly, hypotonic shock increased the uptake of 100-nm and 500-nm particles by ∼ 3- and ∼ 5-fold, respectively, compared to isotonic conditions. In contrast, the hypertonic shock did not impact cell behavior or particle uptake. Notably, the internalization mechanisms triggered by osmotic shock operate independently of active endocytic pathways, making hypotonic stimulation particularly beneficial for hard-to-treat cells. When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions. In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred.}, } @article {pmid39637982, year = {2024}, author = {Vallée, S and Deneux, V and Funaro, D and Marcoux, D and Powell, J and Hatami, A and Coulombe, J and Piram, M and McCuaig, CC}, title = {Long-term evolution of prepubertal-onset anogenital lichen sclerosus: A 35-year retrospective and cross-sectional study from a single tertiary care maternal and pediatric center.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.09.086}, pmid = {39637982}, issn = {1097-6787}, abstract = {BACKGROUND: Anogenital lichen sclerosus (ALS) in children may persist after puberty with potential clinical repercussions.

OBJECTIVE: The purpose of this study was to evaluate post pubertal evolution of girls with ALS diagnosed in the prepubertal period based on physical examination, the persistence of functional symptoms and the effect on quality of life.

METHODS: We retrospectively reviewed 65 cases of girls with prepubertal-onset ALS. Onset, signs/symptoms, photos, evolution and treatment were collected from the medical records. Subsequently, 30 of these 65 patients were assessed for persistence of signs/symptoms by physical examination and/or standardized questionnaire.

RESULTS: Signs of active disease after puberty based on physical examination were present in 92% (N=23) of examined patients. A high proportion of cases with persistent ALS after puberty were asymptomatic (47%, N=14).

LIMITATIONS: This is a single center retrospective study with a limited number of patients. Half of our original cohort could not be reached or declined a follow-up visit.

CONCLUSION: Prepubertal lichen sclerosus is a chronic condition that can be asymptomatic after puberty despite continued disease activity. We recommend long-term follow-up of patients with prepubertal ALS to prevent associated morbidity.}, } @article {pmid39636751, year = {2025}, author = {Desai, AB and Agarwal, A and Mohamed, AS and Mohamed, KH and Middlebrooks, EH and Bhatt, AA and Gupta, V and Kumar, N and Sechi, E and Flanagan, EP and López Chiriboga, S}, title = {Motor Neuron Diseases and Central Nervous System Tractopathies: Clinical-Radiologic Correlation and Diagnostic Approach.}, journal = {Radiographics : a review publication of the Radiological Society of North America, Inc}, volume = {45}, number = {1}, pages = {e240067}, doi = {10.1148/rg.240067}, pmid = {39636751}, issn = {1527-1323}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging ; Diagnosis, Differential ; Magnetic Resonance Imaging/methods ; Pyramidal Tracts/diagnostic imaging ; }, abstract = {White matter tracts within the central nervous system are organized into ascending and descending pathways that transmit sensory input and motor output, respectively. Tractopathy, or damage to these tracts, can impair sensory or motor functions. Motor neuron diseases are pathologic processes affecting the upper or lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of acquired motor neuron disease. Traditionally, ALS has affected upper and lower motor neurons of the extremities, torso, and head and neck. There are several ALS variants, some of which affect only the upper motor neurons (eg, primary lateral sclerosis), lower motor neurons (eg, progressive muscular atrophy), or motor neurons of the head and neck (eg, progressive bulbar palsy). Characteristic imaging features of ALS include abnormal T2 hyperintensity within the brain along the corticospinal tract, as well as cortical susceptibility signal intensity along the precentral gyrus, termed the "motor band" sign. Spinal muscular atrophy is a less common primary motor neuron disease and appears on images as atrophy of the anterior horn of the spinal cord, as well as proximal muscle atrophy. In addition to pure motor neuron diseases, there are numerous toxic and metabolic conditions, genetic disorders, infectious diseases, and immune-mediated disorders that can secondarily affect the corticospinal tracts (corticospinal tractopathies), producing symptoms of upper motor neuron injury. These tractopathies are visible at MRI as T2-hyperintense lesions along varying segments of the corticospinal tract. A comprehensive diagnostic approach that integrates clinical symptoms with radiologic and laboratory findings is crucial to distinguish among these varied conditions. [©]RSNA, 2024 Supplemental material is available for this article.}, } @article {pmid39636698, year = {2024}, author = {Nona, RJ and Henderson, RD and Mccombe, PA}, title = {Routine blood biochemical biomarkers in amyotrophic lateral sclerosis: Systematic review and cohort analysis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/21678421.2024.2435976}, pmid = {39636698}, issn = {2167-9223}, abstract = {Introduction: Blood biochemical biomarkers, including urate, creatinine, albumin, and creatine kinase, have been shown to be useful in ALS. To provide further information about the roles of these four biomarkers roles we performed a systematic review. In addition, we also performed a new study of the role of these biomarkers in predicting survival, using data from our local ALS cohort. Methods: (1) Using established databases and other sources, we searched for papers about the use of urate, creatinine, albumin, and creatine kinase as biomarkers in ALS. Included articles were reviewed for information about biomarker levels in ALS and controls, association with markers of functional decline, and survival. (2) For our local ALS cohort, we performed survival analysis, Cox-proportionate-hazard ratio and ROC curves to investigate the use of these biomarkers in predicting survival. Results: (1) For systematic review, 104 papers were included. There was some variability in the findings. For urate, there was evidence of decreased levels in ALS, with higher levels associated ith longer survival. For creatinine, there was evidence of decreased levels in ALS, and higher levels correlated with longer survival. For albumin, some reports of reduced levels in ALS, but no consistent association with survival. For creatine kinase, some reports of increased levels in ALS, with inconsistent association with survival. (2) For the local ALS cohort there was evidence that urate and creatinine were associated with survival, but no significant association with survival. There was less evidence for albumin and CK. Discussion: This study provides support for further studies of these readily available biochemical measurement as bioamerkers in ALS.}, } @article {pmid39635310, year = {2024}, author = {Yuan, J and Zhang, YJ and Wen, W and Liu, XC and Chen, FL and Yang, Y}, title = {Afferent loop syndrome of a patient with recurrent fever: A case report.}, journal = {World journal of radiology}, volume = {16}, number = {11}, pages = {678-682}, pmid = {39635310}, issn = {1949-8470}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare complication, Aoki et al reported that the incidence of distal gastrectomy in Billroth-II is 0.3%-1.0%. The clinical manifestations of ALS are atypical, which can manifest as severe abdominal pain, vomiting, obstructive jaundice, malnutrition, etc.

CASE SUMMARY: The patient was a 58-year-old man who complained of recurrent high fever for more than 1 week. Laboratory tests showed an increase in neutrophil ratio, procalcitonin, C-reactive protein, and abnormal liver function. Enhanced computed tomography scan of the abdomen showed small intestinal obstruction between the anastomosis of the gastrojejunum, bile duct, and pancreaticoduodenum. Gastroscopy revealed significant narrowing of the lumen 15 cm from the anastomosis into the afferent loop. After performing balloon dilation and placement of the nutrition tube, the patient did not experience further fever.

CONCLUSION: ALS is relatively rare after pancreaticoduodenectomy, and the treatment depends on the nature of the obstructive lesion. The traditional treatment method is surgery, and in recent years, endoscopy has provided a new treatment method for ALS.}, } @article {pmid39634573, year = {2024}, author = {Braimah, RO and Taiwo, AO and Olasoji, HO and Legbo, JN and Amundson, M and Ibikunle, AA and Suleiman, IK and Bala, M and Ile-Ogedengbe, BO}, title = {Braimah-Taiwo et al New Classification System and Treatment Algorithm of Mandibulo-Maxillary Synostosis Related to Noma. Field Experience From Noma Children Hospital Sokoto, Nigeria.}, journal = {Craniomaxillofacial trauma & reconstruction}, volume = {17}, number = {4}, pages = {279-290}, pmid = {39634573}, issn = {1943-3875}, abstract = {STUDY DESIGN: This was a retrospective study at Noma Children Hospital, Sokoto, Nigeria, from January 2018 to December 2021.

OBJECTIVE: The main objective of this appraisal was to present Braimah-Taiwo et al's new classification system for mandibulo-maxillary synostosis secondary to noma and also to provide a guide to their treatment.

METHODS: Noma with mandibulo-maxillary synostosis was the main inclusion criteria. Excluded were cases of acute noma and noma without mandibulo-maxillary synostosis. Data retrieved include demographics of patients and extent of bony ankylosis and mandibulo-maxillary synostosis.

RESULTS: A total of 64 patients (30 (46.9%) males and 34 (53.1%) females) were managed. Ages ranged from 6 to 40 years with mean ± SD (18.2 ± 7.6) years. Regarding the new classification system of mandibulo-maxillary synostosis, 6 (9.4%) patients presented with Type 1 (Mild joint obliteration)±Soft tissue scarring, 24 (37.5%) presented with Type II (Total joint obliteration)±Soft tissue scarring, 21 (32.8%) presented with Type III (Coronoid, zygoma and maxilla) ±Soft tissue scarring, 4 (6.3%) presented with Type IV (Condyle, glenoid fossa, coronoid, sigmoid notch and zygoma) ±Soft tissue scarring, 7 (10.9%) presented with Type V (Condyle, glenoid fossa, coronoid, sigmoid notch, zygoma and pterygo-maxilla) ±Soft tissue scarring, while 2 (3.1%) patients presented with Type VI (condyle, glenoid fossa, coronoid, sigmoid notch, zygoma, pterygo-maxilla and the orbit) ±Soft tissue scarring.

CONCLUSIONS: Pattern of tissue destruction in noma patients is complex involving both soft and hard tissues. This new classification will guide surgeons in the effective management of these patients.}, } @article {pmid39633896, year = {2024}, author = {Bhaskaran, S and Piekarz, KM and Brown, J and Yang, B and Ocañas, SR and Wren, JD and Georgescu, C and Bottoms, C and Murphy, A and Thomason, J and Saunders, D and Smith, N and Towner, R and Van Remmen, H}, title = {The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505369}, pmid = {39633896}, issn = {1662-4548}, abstract = {Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and late-stage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.}, } @article {pmid39633494, year = {2024}, author = {Ko, VI and Ong, K and Kwon, DY and Li, X and Pietrasiewicz, A and Harvey, JS and Lulla, M and Bhat, G and Cleveland, DW and Ravits, JM}, title = {CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {187}, pmid = {39633494}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Phosphorylation ; *DNA-Binding Proteins/metabolism/genetics ; *Casein Kinase Idelta/metabolism/genetics ; *Casein Kinase 1 epsilon/metabolism/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology/drug effects ; Mice, Inbred C57BL ; Male ; Mice, Knockout ; }, abstract = {Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.}, } @article {pmid39631325, year = {2024}, author = {Zhang, Y and Liu, Q and Xie, H and Zhang, W and Lin, X and Zhang, H and Yu, H and Ma, Y and Zhang, C and Geng, H and Shi, N and Cui, L and Li, B and Li, YF}, title = {Fecal microbiota transplantation as an effective way in treating methylmercury-poisoned rats.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177850}, doi = {10.1016/j.scitotenv.2024.177850}, pmid = {39631325}, issn = {1879-1026}, mesh = {Animals ; *Methylmercury Compounds/metabolism ; *Fecal Microbiota Transplantation ; Rats ; *Gastrointestinal Microbiome ; Male ; Feces/microbiology ; }, abstract = {Methylmercury (MeHg) can cause devastating neurotoxicity in animals and human beings. Gut microbiota dysbiosis has been found in MeHg-poisoned animals. Fecal microbiota transplantation (FMT) has been shown to improve clinical outcomes in a variety of diseases such as epilepsy, amyotrophic lateral sclerosis (ALS) and autism. The aim of this study was to investigate the effects of FMT on MeHg-poisoned rats. FMT treatment was applied to MeHg-poisoned rats for 14 days. The neurobehavior, weight changes, dopamine (DA), the total Hg and MeHg level were evaluated. Besides, the gut microbiota and metabolites change in feces were also checked. It was found that FMT helped weight gain, alleviated the neurological disorders, enhanced fecal mercury excretion and MeHg demethylation, reconstructed gut microbiome and promoted the production of gut-brain axis related-metabolites in MeHg-poisoned rats. This study elaborates on the therapeutic efficacy of FMT in treating of MeHg-poisoned rats, which sheds lights on the treatment of neurological diseases like Minamata Disease and even Parkinson's Disease.}, } @article {pmid39630626, year = {2024}, author = {Szeky, B and Jurakova, V and Fouskova, E and Feher, A and Zana, M and Karl, VR and Farkas, J and Bodi-Jakus, M and Zapletalova, M and Pandey, S and Kucera, R and Lochman, J and Dinnyes, A}, title = {Efficient derivation of functional astrocytes from human induced pluripotent stem cells (hiPSCs).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0313514}, pmid = {39630626}, issn = {1932-6203}, mesh = {*Astrocytes/cytology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Cell Differentiation ; *S100 Calcium Binding Protein beta Subunit/metabolism ; Cytokines/metabolism ; Aquaporin 4/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Cells, Cultured ; }, abstract = {Astrocytes are specialized glial cell types of the central nervous system (CNS) with remarkably high abundance, morphological and functional diversity. Astrocytes maintain neural metabolic support, synapse regulation, blood-brain barrier integrity and immunological homeostasis through intricate interactions with other cells, including neurons, microglia, pericytes and lymphocytes. Due to their extensive intercellular crosstalks, astrocytes are also implicated in the pathogenesis of CNS disorders, such as ALS (amyotrophic lateral sclerosis), Parkinson's disease and Alzheimer's disease. Despite the critical importance of astrocytes in neurodegeneration and neuroinflammation are recognized, the lack of suitable in vitro systems limits their availability for modeling human brain pathologies. Here, we report the time-efficient, reproducible generation of astrocytes from human induced pluripotent stem cells (hiPSCs). Our hiPSC-derived astrocytes expressed characteristic astrocyte markers, such as GFAP, S100b, ALDH1L1 and AQP4. Furthermore, hiPSC-derived astrocytes displayed spontaneous calcium transients and responded to inflammatory stimuli by the secretion of type A1 and type A2 astrocyte-related cytokines.}, } @article {pmid39630042, year = {2024}, author = {Zinman, L and Duni, E and Abrahao, A}, title = {Rethinking Drug Reimbursement Criteria in Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {606-607}, doi = {10.1017/cjn.2023.320}, pmid = {39630042}, issn = {0317-1671}, } @article {pmid39629626, year = {2024}, author = {Boutin, RCT and Shobeirian, F and Adam, S and Lehman, A and Salvarinova, R and Friedman, JM}, title = {Immune Dysregulation in a Child With SOD1-Related Neurological Disease.}, journal = {American journal of medical genetics. Part A}, volume = {}, number = {}, pages = {e63949}, doi = {10.1002/ajmg.a.63949}, pmid = {39629626}, issn = {1552-4833}, support = {//Mining for Miracles (BCCH Foundation)/ ; //Genome British Columbia/ ; }, abstract = {Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS.}, } @article {pmid39628898, year = {2024}, author = {Stansberry, WM and Fiur, NC and Robins, MM and Pierchala, BA}, title = {Analysis of translatomic changes in the Ubqln2[P497S] model of ALS reveals that motor neurons express muscle-associated genes in non-disease states.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1491415}, pmid = {39628898}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressively worsening motor symptoms that lead to eventual fatal paralysis. The number of gene mutations associated with ALS have increased dramatically in recent years, suggesting heterogeneity in the etiology of ALS and the need to develop new models of the disease that encompass these pathologies. In 2011, mutations in the UBQLN2 gene were identified in families with both ALS and frontotemporal dementia (FTD) and have since been linked to ubiquitinated TDP43 inclusion pathology. The involvement of UBQLN2 in ubiquitination and proteasome function suggests an important role in proteostasis, which is reported to be impaired in ALS.

METHODS: A UBQLN2 mouse model was generated for the P497S mutation and recapitulates some of the motor symptoms of ALS. We utilized ribosomal profiling followed by mRNA sequencing of associated transcripts to characterize gene expression changes of motor neurons in the Ubqln2[P497S] model and evaluated ALS phenotypes in these animals.

RESULTS: At 12 months of age, we observed reduced motor neuron survival and neuromuscular junction denervation in these mice that translated into motor deficits observed in locomotor behavioral trials. The sequencing of motor neuron transcripts revealed that Wnt pathways and muscle-related transcripts were downregulated in Ubqln2[P497S] mice, while metabolic pathways were upregulated.

DISCUSSION: Surprisingly, genes often reported to be muscle-specific, such as Desmin and Acta1, were expressed in motor neurons and were dramatically downregulated in symptomatic Ubqln2[P497S] mice. The expression of muscle transcripts by motor neurons suggests their potentially supportive role in skeletal muscle maintenance.}, } @article {pmid39628659, year = {2024}, author = {Ye, Q and Li, X and Gao, W and Gao, J and Zheng, L and Zhang, M and Yang, F and Li, H}, title = {Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1481983}, pmid = {39628659}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.}, } @article {pmid39627937, year = {2024}, author = {Gielas, AM}, title = {Wounds and Vulnerabilities. The Participation of Special Operations Forces in Experimental Brain-Computer Interface Research.}, journal = {Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees}, volume = {}, number = {}, pages = {1-22}, doi = {10.1017/S096318012400063X}, pmid = {39627937}, issn = {1469-2147}, abstract = {Brain-computer interfaces (BCIs) exemplify a dual-use neurotechnology with significant potential in both civilian and military contexts. While BCIs hold promise for treating neurological conditions such as spinal cord injuries and amyotrophic lateral sclerosis in the future, military decisionmakers in countries such as the United States and China also see their potential to enhance combat capabilities. Some predict that U.S. Special Operations Forces (SOF) will be early adopters of BCI enhancements. This article argues for a shift in focus: the U.S. Special Operations Command (SOCOM) should pursue translational research of medical BCIs for treating severely injured or ill SOF personnel. After two decades of continuous military engagement and on-going high-risk operations, SOF personnel face unique injury patterns, both physical and psychological, which BCI technology could help address. The article identifies six key medical applications of BCIs that could benefit wounded SOF members and discusses the ethical implications of involving SOF personnel in translational research related to these applications. Ultimately, the article challenges the traditional civilian-military divide in neurotechnology, arguing that by collaborating more closely with military stakeholders, scientists can not only help individuals with medical needs, including servicemembers, but also play a role in shaping the future military applications of BCI technology.}, } @article {pmid39627617, year = {2024}, author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ}, title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {479}, pmid = {39627617}, issn = {1420-9071}, support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/analysis/metabolism ; *Cell Communication ; *Extracellular Vesicles/metabolism ; MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.}, } @article {pmid39624969, year = {2024}, author = {Yuan, D and Jiang, S and Xu, R}, title = {Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2399962}, pmid = {39624969}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy/epidemiology/genetics ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. Despite a large number of studies, the current prognosis of ALS is still not ideal. This article briefly describes the clinical features including epidemiology, genetic structure and clinical manifestations, as well as the progress of new diagnostic criteria and treatment of ALS. Meanwhile, we also discussed further both developments and improvements to enhance understanding and accelerating the introduction of the effective treatments of ALS.}, } @article {pmid39624674, year = {2024}, author = {Nakamura, K and Fujita, K and Suzuki, M and Kunugi, A and Hirozane, Y and Kunikata, T and Takahashi, B and Narazaki, G and Kondo, H and Haji, S and Hirai, K and Izumi, Y}, title = {Neuroinflammation and glycosylation-related cerebrospinal fluid proteins for predicting functional decline in amyotrophic lateral sclerosis: a proteomic study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1418320}, pmid = {39624674}, issn = {1664-2295}, abstract = {BACKGROUND: The rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS.

METHODS: We collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses.

RESULTS: In total, 26 proteins changed significantly (p < 0.05 and q < 0.10), with levels varying within a large dynamic range (fold change of >1.5 or < 0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: glycoprotein non-metastatic melanoma protein B (GPNMB; area under the curve [AUC], 0.88), glial fibrillary acidic protein (AUC, 0.81), glypican-1 (GPC1; AUC, 0.79), alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (AUC, 0.74), and chitinase-3-like protein 2 (CHI3L2; AUC, 0.73). Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate.

CONCLUSION: This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.}, } @article {pmid39623504, year = {2024}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {17}, number = {1}, pages = {54}, pmid = {39623504}, issn = {1756-0381}, support = {RSP2024R244//King Saud University/ ; }, abstract = {This research presents a predictive model aimed at estimating the progression of Amyotrophic Lateral Sclerosis (ALS) based on clinical features collected from a dataset of 50 patients. Important features included evaluations of speech, mobility, and respiratory function. We utilized an XGBoost regression model to forecast scores on the ALS Functional Rating Scale (ALSFRS-R), achieving a training mean squared error (MSE) of 0.1651 and a testing MSE of 0.0073, with R[2] values of 0.9800 for training and 0.9993 for testing. The model demonstrates high accuracy, providing a useful tool for clinicians to track disease progression and enhance patient management and treatment strategies.}, } @article {pmid39623474, year = {2024}, author = {Hoyle, AC and Stevenson, R and Leonhardt, M and Gillett, T and Martinez-Hernandez, U and Gompertz, N and Clarke, C and Cazzola, D and Metcalfe, BW}, title = {Exploring the 'EarSwitch' concept: a novel ear based control method for assistive technology.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {210}, pmid = {39623474}, issn = {1743-0003}, mesh = {Humans ; Female ; Male ; Adult ; Middle Aged ; *Self-Help Devices ; Aged ; Tensor Tympani/physiology ; Young Adult ; Nervous System Diseases/rehabilitation ; Adolescent ; Motor Neuron Disease/rehabilitation ; Communication Aids for Disabled ; Muscle Contraction/physiology ; Multiple Sclerosis/rehabilitation ; }, abstract = {BACKGROUND: Loss of communication with loved ones and carers is one of the most isolating and debilitating effects of many neurological disorders. Assistive technology (AT) supports individuals with communication, but the acceptability of AT solutions is highly variable. In this paper a novel ear based control method of AT, the concept of 'EarSwitch', is presented. This new approach is based on detecting ear rumbling, which is the voluntary contraction of the tensor tympani muscle (TTM), resulting in observable movement of the eardrum and a dull rumbling sound. 'EarSwitch' has the potential to be a discreet method that can complement existing AT control methods. However, only a subset of the population can ear rumble and little is known about the ability of rumbling in populations with neurological disorders.

METHODS: To explore the viability of the 'EarSwitch' concept as an AT control method we conducted in-depth online surveys with (N=1853) respondents from the general population and (N=170) respondents with self-declared neurological disorders including Motor Neurone Disease (MND) and Multiple Sclerosis (MS).This is the largest ever study to explore ear rumbling and the first to explore whether rumbling is preserved among individuals with neurological disorders. In addition, we validated rumbling, and investigated usability of the 'EarSwitch' concept as a control input, using in-person otoscopic examination with a subset of participants.

RESULTS: A significant proportion of the population with neurological disorders could benefit from 'EarSwitch' controllable AT. The upper bound prevalence of the ability to rumble without accompanying movements was 55% in the general population, 38% in the neurological population, and 20% of participants with MND (N=95) reported this ability. During the validation procedure, participants achieved high accuracy in self-reporting the ability to rumble (80%) and proved concept of using the 'EarSwitch' method to control a basic interface.

DISCUSSION: 'EarSwitch' is a potential new AT control method control, either by itself or as a supplement to other existing methods. Results demonstrate self-reported ear rumbling is present among patients with different neurological disorders, including MND. Further research should explore how well the ability to rumble is preserved in different types and stages of neurological disorders.}, } @article {pmid39622292, year = {2024}, author = {Ojo, O and Boateng, J and Pacella, R and Hanrahan, A and Essex, R and Dibley, L}, title = {Factors Influencing the Care and Management of Diabetic Foot Ulcers: A Scoping Review.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eprac.2024.11.010}, pmid = {39622292}, issn = {1530-891X}, abstract = {OBJECTIVE: The objective of this scoping review is to explore the experiences of patients' and healthcare practitioners on the factors that influence the care and management of diabetes-related foot ulcers (DFUs).

METHODS: Levac et al's 6-stage framework and the Preferred Reporting Items for Systematic Review and Meta-analysis extension for scoping reviews, guided the review. The SPIDER tool was used to define key elements of the review question. Searches for relevant articles were conducted in electronic databases (PUBMED, CINAHL, AMED, Embase, Cochrane Database of Systematic Reviews, and PsycINFO), Google Scholar, and hand searches of reference lists.

RESULTS: Eight articles met the inclusion criteria and were included in the review. Three themes were identified: Communication and Education about DFUs; Challenges of managing DFUs; and Barriers to treatment and management. The themes are presented as a narrative synthesis.

CONCLUSION: Inadequate knowledge of diabetic foot care by patients and inconsistent communication by healthcare professionals were primary factors affecting the effective management of diabetes-related foot ulcers. Consistent, patient-focused education that is supported by knowledgeable health care professionals should form the foundation of effective diabetic foot ulcer care.}, } @article {pmid39621905, year = {2024}, author = {Van Nerom, M and Ahmed, J and Lazar, T and Meszaros, A and Galand, Q and De Malsche, W and Van Lindt, J and Pancsa, R and Maes, D and Tompa, P}, title = {C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {50}, pages = {e2402847121}, pmid = {39621905}, issn = {1091-6490}, support = {952334//EC | Horizon 2020 Framework Programme (H2020)/ ; 778247//EC | Horizon 2020 Framework Programme (H2020)/ ; K124670//National Research, Development and Innovation Office/ ; K131702//National Research, Development and Innovation Office/ ; SRP51//Vrije Universiteit Brussel (VUB)/ ; A0-2004-070//European Space Agency (ESA)/ ; FWOSB77//Fonds Wetenschappelijk Onderzoek (FWO)/ ; 11D2522N//Fonds Wetenschappelijk Onderzoek (FWO)/ ; HBC.2022.0194//Agentschap Innoveren en Ondernemen (VLAIO)/ ; FK-142285//National Research, Development and Innovation Office/ ; BO/00174/22//Magyar Tudományos Akadémia (MTA)/ ; 184018//Tempus Közalapítvány (TPF)/ ; }, mesh = {*RNA Recognition Motif Proteins/metabolism/genetics/chemistry ; *Poly-ADP-Ribose Binding Proteins/metabolism/genetics/chemistry ; Humans ; *C9orf72 Protein/genetics/metabolism ; *RNA Helicases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Dipeptides/metabolism/chemistry ; *DNA Helicases/metabolism/genetics ; *Arginine/metabolism/chemistry ; *Nucleophosmin/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; Stress Granules/metabolism ; DNA-Binding Proteins/metabolism/genetics/chemistry ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism/genetics ; Protein Binding ; Phase Separation ; }, abstract = {The toxic effects of C9orf72-derived arginine-rich dipeptide repeats (R-DPRs) on cellular stress granules in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia remain unclear at the molecular level. Stress granules are formed through the switch of Ras GTPase-activating protein-binding protein 1 (G3BP1) by RNA from a closed inactive state to an open activated state, driving the formation of the organelle by liquid-liquid phase separation (LLPS). We show that R-DPRs bind G3BP1 a thousand times stronger than RNA and initiate LLPS much more effectively. Their pathogenic effect is underscored by the slow transition of R-DPR-G3BP1 droplets to aggregated, ThS-positive states that can recruit ALS-linked proteins hnRNPA1, hnRNPA2, and TDP-43. Deletion constructs and molecular simulations show that R-DPR binding and LLPS are mediated via the negatively charged intrinsically disordered region 1 (IDR1) of the protein, allosterically regulated by its positively charged IDR3. Bioinformatic analyses point to the strong mechanistic parallels of these effects with the interaction of R-DPRs with nucleolar nucleophosmin 1 (NPM1) and underscore that R-DPRs interact with many other similar nucleolar and stress-granule proteins, extending the underlying mechanism of R-DPR toxicity in cells. Our results also highlight characteristic differences between the two R-DPRs, poly-GR and poly-PR, and suggest that the primary pathological target of poly-GR is not NPM1 in nucleoli, but G3BP1 in stress granules in affected cells.}, } @article {pmid39621705, year = {2024}, author = {Foldvari, KM and Stolee, P and Neiterman, E and Boscart, V and Tong, C}, title = {"…but I know something's not right here": Exploring the diagnosis and disclosure experiences of persons living with ALS.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301249}, pmid = {39621705}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Caregivers/psychology ; Disclosure ; Focus Groups ; Truth Disclosure ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), an incurable motor neuron disease, primarily affects those between the ages of 60-79, and has an approximate post-diagnosis life-expectancy of only two to five years. The condition has an unpredictable but ultimately terminal trajectory that poses challenges for patients, caregivers and healthcare providers. While the diagnosis and disclosure are critical periods for intervention and support, knowledge regarding the relational, communicational and psychodynamic forces that occur within the process of diagnostic disclosure is relatively limited.

OBJECTIVES: The purpose of this study was to explore the experiences of persons living with ALS in the diagnosis and disclosure of the condition, with the support of their caregivers.

METHODS: We conducted a focus group and in-depth individual interviews with people living with ALS (n = 9), and caregivers (n = 9). The interviews were transcribed, cleaned, and anonymized, and then entered into NVivo 11 for thematic analysis.

RESULTS: Participants discussed the diagnostic process, including inklings and subtle changes prior to diagnosis, attempts at self-diagnosis, and the lengthy assessment process. Time was also a consideration in the diagnostic disclosure process, in which participants shared how the disclosure was the product of longstanding conversations with their care providers. It was described as rarely a shock to finally have confirmation. Participants shared their information seeking strategies and needs for a diagnosis that, for them, typically came with insufficient information on the disease, prognosis, and next steps.

SIGNIFICANCE: This project serves as a step in bridging the relevant gaps in our knowledge and understanding towards improved person-centered care practices in the diagnosis and disclosure of ALS.}, } @article {pmid39621188, year = {2024}, author = {Gerometta, M and Henderson, RD and Friend, R and Cooper, LT and Zhao, J and Boyd, AW and Bartlett, PF}, title = {Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {39621188}, issn = {1179-1918}, abstract = {BACKGROUND: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.

OBJECTIVE: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.

METHODS: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.

RESULTS: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (± 22.8) h in healthy volunteers (n = 20) and 74.4 (± 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (± 26.6) to 101.1 (± 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.

CONCLUSIONS: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.

CLINICAL TRIAL REGISTRATION: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).}, } @article {pmid39621126, year = {2024}, author = {Mikhailova, MM and Klein, OI and Patsaev, TD and Panteleyev, AA}, title = {Co-culture of postnatal mouse spinal cord and skeletal muscle explants as an experimental model of neuromuscular interactions.}, journal = {Histochemistry and cell biology}, volume = {163}, number = {1}, pages = {15}, pmid = {39621126}, issn = {1432-119X}, support = {1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; 1п.2.3//National Research Center "Kurchatov Institute"/ ; }, mesh = {Animals ; Mice ; *Muscle, Skeletal/metabolism ; *Coculture Techniques ; *Spinal Cord/metabolism ; Mice, Inbred C57BL ; Animals, Newborn ; }, abstract = {The intercommunication between nerves and muscles plays an important role in the functioning of our body, and its failure leads to severe neuromuscular disorders such as spinal muscular atrophy and amyotrophic lateral sclerosis. Understanding the cellular and molecular mechanisms underlying nerve-muscle interactions and mediating their mutual influence is an integral part of strategies aimed at curing neuromuscular diseases. Here, we propose a novel ex vivo experimental model for the spinal cord (SC) and skeletal muscle interactions which for the first time utilizes only fully formed (but not yet quite functional) postnatal tissues. The model represents an organotypic co-culture comprising a longitudinal slice of the mouse postnatal SC and an extensor digitorum longus (EDL) muscle explant placed in the "damage zone" of transversally dissected longitudinal slice of the SC. Using this model, we have shown that SC tissue stimulates muscle contractions and reduces the area occupied by acetylcholine receptors on muscle surface. In turn, EDL muscles stimulate the growth of SC-derived neurites. Thus, our organotypic model allows one to assess the mutual influence of neurons and muscles in a nearly natural setting which maintains the architecture and cellular composition of intact tissues. Therefore, this model may provide an effective platform for studying molecular and cellular mechanisms linked to defective neuromuscular interactions in associated pathologies.}, } @article {pmid39620262, year = {2025}, author = {Chen, Y and Sun, S and Yun, Y and Sun, X and Xin, J and Shao, K and Lin, P and Yu, D and Yan, C and Liu, S}, title = {Connectivity-based striatal subregion microstructural changes in sporadic amyotrophic lateral sclerosis patients: Relation to motor disability, cognitive deficits, and serum biomarkers.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16577}, pmid = {39620262}, issn = {1468-1331}, support = {2020M672067//China Postdoctoral Science Foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; NSFC82471395//National Natural Science Foundation of China/ ; ZR2023LSW020//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/etiology/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Corpus Striatum/diagnostic imaging/pathology ; Adult ; Neurofilament Proteins/blood ; Diffusion Tensor Imaging ; Diffusion Magnetic Resonance Imaging ; }, abstract = {BACKGROUND AND PURPOSE: To date, no previous studies have used multishell diffusion MRI to identify striatal microstructural damage in vivo in amyotrophic lateral sclerosis (ALS) patients. Thus, in the present study, we aimed to comprehensively explore connectivity-based selective striatal subregion microstructural damage in sporadic ALS patients and its associations with motor disability, cognitive deficits, and serum biomarkers.

METHODS: In this retrospective study, 79 ALS patients and 53 healthy controls (HCs) who underwent clinical assessment, serum neurofilament light (NfL) measurement, genetic testing, and multishell diffusion MRI scanning were included. Using a probabilistic tractography approach, the striatum was segmented into six subregions based on their corticostriatal connectivity. Three neurite orientation dispersion and density imaging (NODDI) parameters, the neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISO), of the connectivity-based striatal subregions were measured.

RESULTS: Compared with HCs, ALS patients had a significantly lower NDI in the bilateral motor and right frontal subregions, a significantly lower ODI in the right motor and frontal subregions, and a significantly higher ISO in the bilateral motor and frontal subregions of the striatum after familywise error (p < 0.05). Moreover, striatal subregion microstructural damage was significantly correlated with motor disabilities, cognitive deficits, and serum NfL levels in ALS patients (p = 0.020-0.002).

CONCLUSIONS: Our study provides clear evidence demonstrating that connectivity-based selective striatal subregion microstructural damage is a definite feature of sporadic ALS patients and suggesting that striatal damage may play an important role in motor disability and cognitive deficits in ALS patients.}, } @article {pmid39617896, year = {2024}, author = {Feng, R and Zhu, Q and Wang, A and Wang, H and Wang, J and Chen, P and Zhang, R and Liang, D and Teng, J and Ma, M and Ding, X and Wang, X}, title = {Effect of fecal microbiota transplantation on patients with sporadic amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {566}, pmid = {39617896}, issn = {1741-7015}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Fecal Microbiota Transplantation/methods ; Double-Blind Method ; Female ; Male ; Middle Aged ; Aged ; Gastrointestinal Microbiome/physiology ; Treatment Outcome ; Quality of Life ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients.

METHODS: Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6 months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n = 14) or a mixture of 0.9% saline and food coloring (E150c) as sham transplantation (placebo, n = 13). The primary outcome measured the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to week 35. Secondary outcomes included changes in gastrointestinal and respiratory functions, muscle strength, autonomic function, cognition, quality of life, intestinal microbiome composition, and plasm neurofilament light chain protein (NFL). Efficacy and safety outcomes were assessed in the intention-to-treat population.

RESULTS: A total of 27 randomized patients (47% women; mean age, 67.2 years), 24 participants completed the entire study. Notably, ALSFRS-R score changes exhibited no significant differences between FMT (6.1 [SD, 3.11]) and placebo (6.41[SD, 2.73]) groups from baseline to week 35. Secondary efficacy outcomes, encompassing respiratory function, muscle strength, autonomic function, cognition, quality of life, and plasm NFL, showed no significant differences. Nevertheless, the FMT group exhibited improvements in constipation, depression, and anxiety symptoms. FMT induced a shift in gut microbiome community composition, marked by increased abundance of Bifidobacterium, which persisted until week 15 (95% CI, 0.04 to 0.28; p = 0.01). Gastrointestinal adverse events were the primary manifestations of FMT-related side effects.

CONCLUSIONS: In this clinical trial involving 27 sporadic ALS patients, FMT did not significantly slow the decline in ALSFRS-R score. Larger multicenter trials are needed to confirm the efficacy of FMT in sporadic ALS patients and to explore the underlying biological mechanisms.

TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR 2200064504.}, } @article {pmid39617118, year = {2024}, author = {Liang, YF and Niu, ZX and Wu, ZW and Zhang, QY and Zhao, XY and Chao, LL and Li, H and Gao, WY}, title = {Catalytic insights of acetolactate synthases from different bacteria.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110248}, doi = {10.1016/j.abb.2024.110248}, pmid = {39617118}, issn = {1096-0384}, abstract = {Acetolactate synthase (ALS) is an essential enzyme involved in the biosynthesis of platform chemicals acetoin and 2,3-butanediol in several microorganisms. In this study, we investigated the catalytic differences among three bacterial ALSs involved in the ligation of two molecules of pyruvate or 2-ketobutyrate. Based on the findings, we predicted three amino acid residues in each enzyme that caused a discrepancy in accordance with the multi-sequence alignment and molecular docking experiments: I398, A402, and T480 in Bacillus subtilis ALS; V400, Y404, and S482 in Listeria seleigeri serovar 1/2b ALS; and M394, H398, and G476 in Klebsiella pneumoniae ALS. Subsequently, we mutually mutated the residues in the three ALSs. The data obtained confirmed our inference that these three residues in each enzyme are truly correlated with substrate recognition, particularly in recognizing compounds that are larger than pyruvate, such as 2-ketobutyrate, benzaldehyde, and nitrosobenzene. This study further clarifies the biochemical traits of ALSs derived from various bacteria and expands the scope of ALS research.}, } @article {pmid39616922, year = {2024}, author = {Santurtún, A and Medín, P and Riancho, JA and Santiago-Setién, M and Ortiz, F and López de Munain, A and Almendra, R and Riancho, J}, title = {Temporo-spatial analysis of amyotrophic lateral sclerosis in Spain: Altitude and land use as new determinants of the disease.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177796}, doi = {10.1016/j.scitotenv.2024.177796}, pmid = {39616922}, issn = {1879-1026}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Humans ; Male ; Female ; *Altitude ; Spatio-Temporal Analysis ; Middle Aged ; Aged ; Incidence ; Adult ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Currently, ALS is conceived as the result of the interaction between genetics, environmental factors, and aging. This study analyzed the spatial and temporal patterns of ALS in Spain, delving into the potential relationships between altitude, land cover, and this disease.

METHODOLOGY: ALS death data were collected over a 19-year period, including information on sex, age and municipality of residence. The standardized mortality rate was calculated for each municipality of residencia, and Anselin's local Moran's I statistic was used to identify clusters of high and low incidence. Altitude data were sourced from the Copernicus Land Monitoring Services, while land cover data came from CORINE satellite images and national agricultural statistics.

RESULTS: The average annual incidence of ALS deaths among adults was 2.5 per 100,000 people. Higher mortality rates were noted in males (2.8) than in females (2.3), with both sexes exhibiting a rising mortality trend in a temporal analysis. Cluster analysis revealed that high mortality areas were mostly located in the North and Northeast of the country. Municipalities in these clusters had significantly lower median altitudes and larger areas of Permanently Irrigated Arable Land and Broad-Leaved Forest.

CONCLUSION: This study provides new evidence about the increase in ALS cases in European countries during the last decades, reporting for the first time altitude and certain agricultural land uses as potential geographic determinants of the disease.}, } @article {pmid39616446, year = {2024}, author = {Rutkove, SB and McIlduff, CE and Stommel, E and Levy, S and Smith, C and Gutierrez, H and Verga, S and Samaan, S and Yator, C and Nanda, A and Sonbas-Cobb, B and Capella, T and Pastel, L and Doussan, A and Phipps, K and Murphy, E and Halter, R}, title = {Thoracic electrical impedance tomography for assessing progression of pulmonary dysfunction in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2434174}, pmid = {39616446}, issn = {2167-9223}, support = {R21 NS118434/NS/NINDS NIH HHS/United States ; }, abstract = {Objective: We compared thoracic electrical impedance tomography (EIT) with slow vital capacity (SVC) to determine if EIT could monitor pulmonary function in ALS patients longitudinally. Methods: Of 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) initially enrolled in the Pulmonary Function via Impedance Tomography (PuFIT) study, 22 ALS and 20 HCs returned for a follow-up visit ∼3.9 months later. All participants had thoracic EIT measurements performed simultaneously with standard SVC in upright and supine positions at both visits. EIT data from each measurement were summarized as a single parameter, the impedance-SVC (zSVC), representing an averaged impedance change across both lungs. We assessed alterations over time for both cohorts of participants. Results: Sufficient quality EIT and SVC data were available for 18 of the patients with ALS and 19 HCs. Over time, mean upright SVC significantly declined by 5% in the ALS group and did not change in the healthy group. Supine SVC showed no change in either group. Although mean trajectories of zSVC mirrored mean SVC trajectories in both participant cohorts, changes in zSVC in ALS patients did not reach significance, due to greater variability in the repeated measures. Conclusion: Despite strong cross-sectional correlations to SVC, EIT did not detect a decline in pulmonary function over approximately four months. Increased variability in EIT data explains the lack of sensitivity to change. Technological improvements and special care with electrode placement will be needed for EIT to reach its full potential in longitudinal assessment of pulmonary function in ALS.}, } @article {pmid39615150, year = {2024}, author = {Garbey, M and Lesport, Q and Öztosun, G and Ghodasara, V and Kaminski, HJ and Bayat, E}, title = {Improving care for amyotrophic lateral sclerosis with artificial intelligence and affective computing.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123328}, doi = {10.1016/j.jns.2024.123328}, pmid = {39615150}, issn = {1878-5883}, abstract = {BACKGROUND: Patients with ALS often face difficulties expressing emotions due to impairments in facial expression, speech, body language, and cognitive function. This study aimed to develop non-invasive AI tools to detect and quantify emotional responsiveness in ALS patients, providing objective insights. Improved understanding of emotional responses could enhance patient-provider communication, telemedicine effectiveness, and clinical trial outcome measures.

METHODS: In this preliminary exploratory study, fourteen patients with ALS had audio recordings performed during routine clinic visits while wearing a wireless pulse oximeter. Emotion-triggering questions related to symptom progression, breathing, mobility, feeding tube, and financial burden were randomly asked. The same questions were posed in separate psychiatric evaluations. Natural language processing (NLP) was used to analyze transcriptions, topic classifications, sentiment, and emotional states, combining pulse and speech data. AI-generated reports summarized the findings.

RESULTS: Pulse alterations consistent with emotional arousal were identified, with longer consultations and positive communication reducing pulse fluctuations. Financial concerns triggered the strongest emotional response, while discussions about breathing, mobility, and feeding tube increased anxiety. AI-generated reports prioritized patient concerns and streamlined documentation for providers.

CONCLUSIONS: This study introduces a novel approach to linking pulse and speech analysis to evaluate emotional responses in ALS patients. AI and affective computing provide valuable insights into emotional responses and disease progression, with potential applications for other neurological disorders. This approach could augment clinical trial outcomes by offering a more comprehensive view of patient well-being.}, } @article {pmid39614020, year = {2024}, author = {Shi, DL and Grifone, R and Zhang, X and Li, H}, title = {Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, function and regeneration.}, journal = {Journal of muscle research and cell motility}, volume = {}, number = {}, pages = {}, pmid = {39614020}, issn = {1573-2657}, support = {23545//the French Muscular Dystrophy Association/ ; 23545//the French Muscular Dystrophy Association/ ; }, abstract = {RNA-binding proteins are critically involved in the post-transcriptional control of gene expression during embryonic development and in adult life, contributing to regulating cell differentiation and maintaining tissue homeostasis. Compared to the relatively well documented functions of transcription factors, the regulatory roles of RNA-binding proteins in muscle development and function remain largely elusive. However, deficiency of many RNA-binding proteins has been associated with muscular defects, neuromuscular disorders and heart diseases, such as myotonic dystrophy, amyotrophic lateral sclerosis, and cardiomyopathy. Rbm24 is highly conserved among vertebrates and is one of the best characterized RNA-binding proteins with crucial implication in the myogenic and cardiomyogenic programs. It presents the distinctive particularity of displaying highly restricted expression in both skeletal and cardiac muscles, with changes in subcellular localization during the process of differentiation. Functional analyses using different vertebrate models have clearly demonstrated its requirement for skeletal muscle differentiation and regeneration as well as for myocardium organization and cardiac function, by regulating the expression of both common and distinct target genes in these tissues. The challenge remains to decipher the dynamic feature of post-transcriptional circuits regulated by Rbm24 during skeletal myogenesis, cardiomyogenesis, and muscle repair. This review discusses current understanding of its function in striated muscles and its possible implication in human disease, with the aim of identifying research gaps for future investigation.}, } @article {pmid39612826, year = {2024}, author = {Xu, H and Cheng, J and Leng, Q and Cao, R and Su, W and Sun, L and Xue, F and Han, Y and Wu, R}, title = {Characterization of acetolactate synthase genes and resistance mechanisms of multiple herbicide resistant Lolium multiflorum.}, journal = {Plant physiology and biochemistry : PPB}, volume = {219}, number = {}, pages = {109324}, doi = {10.1016/j.plaphy.2024.109324}, pmid = {39612826}, issn = {1873-2690}, abstract = {Combining imidazolinone-tolerant wheat with imazamox presents an effective solution to combat weed resistance. However, Lolium multiflorum, a troublesome resistant weed infesting wheat fields, may have developed resistance to imazamox, and the potential resistance mechanisms are intriguing. In this study, we explored the susceptibility of L. multiflorum to imazamox and investigated the resistance mechanisms, including the contribution of the target enzyme acetolactate synthase (ALS) to resistance and the presence of non-target-site resistance (NTSR). Eight L. multiflorum populations suspected of being resistant to imazamox were collected, and six populations exhibited resistance, ranging from 2.45-fold to 16.32-fold. The LmALS1 gene from susceptible population D3 plants and multiple copies of the LmALS gene (LmALS1, LmALS2, LmALS2α, LmALS3, LmALS3α, LmALS3β) from resistant populations D5 and D8 plants were separately amplified. Two mutations (Pro/Gln197 to Thr, Trp574 to Leu) were found in LmALS1 in the resistant populations. Compared to D3, LmALS1 was overexpressed in D5 but not in D8. The presence of LmALS1 mutants (LmALS1-Thr197 and LmALS1- Leu574), along with LmALS2, LmALS3, and their subunits, contribute to the resistance phenotype by increasing bonding energies, weakening hydrogen bonds, or decreasing protein binding pocket volumes and surface area. Additionally, D5 and D8 populations exhibited multiple resistance (>40-fold) to three other ALS inhibitors: pyroxsulam, flucarbazone-sodium, and mesosulfuron-methyl. Pre-treatment with malathion and 4-chloro-7-nitrobenzoxadiazole (cytochrome P450 monooxygenase and glutathione S-transferase inhibitors respectively) reversed the resistance of the D8 population and partially reversed the resistance of the D5 population to imazamox. This study characterizes ALS genes and extends our knowledge into the ALS resistance mechanisms involved in L. multiflorum. It also deepens our understanding of the complex diversification resistance mechanisms, thereby facilitating advances in weed resistance management strategies in wheat fields.}, } @article {pmid39612643, year = {2024}, author = {Egorov, VV and Grudinina, NA and Polyakov, DS and Zabrodskaya, YA and Gavrilova, NV and Shavlovsky, MM}, title = {Spontaneous formation of different forms of alpha-synuclein fibrils from a recombinant protein.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151068}, doi = {10.1016/j.bbrc.2024.151068}, pmid = {39612643}, issn = {1090-2104}, mesh = {*alpha-Synuclein/metabolism/chemistry ; *Recombinant Proteins/chemistry/metabolism/genetics ; Humans ; *Amyloid/chemistry/metabolism ; Protein Processing, Post-Translational ; Protein Conformation ; }, abstract = {Alpha-synuclein is a protein, the conformational changes of which lead to the development of such socially significant diseases as Parkinson's disease and amyotrophic lateral sclerosis. The methods for differential diagnostics of these diseases based on the use of alpha-synuclein in a non-native conformation obtained from patients as a seed for inducing fibrillogenesis and studying the morphology of the resulting amyloid-like fibrils were described in a number of studies. The authors associate such properties of the seed with the presence of post-translational modifications in the protein obtained from patients. At the same time, the production of fibrils differing in morphology from recombinant alpha-synuclein under various conditions of fibrillogenesis is also described. In this work, we show that the formation of morphologically distinct fibril types from recombinant alpha-synuclein lacking post-translational modifications is possible under the same conditions, and that spontaneously arising different fibril types, when used as a seed for fibrillogenesis, lead to the formation of recombinant protein fibrils morphological similar to the parental seed. The results of the work can be used both in studying the fundamental mechanisms of conformation transfer and in developing test systems for synucleinopathies.}, } @article {pmid39611550, year = {2024}, author = {Veyrat-Durebex, C and Osman, S and Al Ojaimi, Y and Gosset, P and Dupuy, C and Lefevre, A and Emond, P and Vourc'h, P and Corcia, P and Mereghetti, L and Kempf, F and Raoul, C and Blasco, H}, title = {Gut metabolomic and microbiota analyses in ALS mice reveal specific metabolites despite the absence of significant gut dysbiosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2433578}, pmid = {39611550}, issn = {2167-9223}, abstract = {OBJECTIVE: Over the past years, interest in the role of gut microbiota in neurodegenerative diseases has emerged. Despite numerous publications over the past decade, both in human and pre-clinical studies, there is no clear consensus on the microbiota's role or involvement in ALS. Few studies on mouse models of ALS highlighted a correlation between specific bacteria species and the prognostic or severity of the disease. Still these results lack reproducibility and remain controverted. In this article we present a study of fecal microbiota in the SOD1[G93A] mouse model associated with a metabolomic analysis of cecum content, compared to controls.

METHODS: Intestinal metabolomic profile and fecal microbiota were assessed in two cohorts of SOD[G93A] mice compared to wildtype controls at the terminal stage of the ALS disease.

RESULTS: Results showed a significant difference in metabolomic profile in SOD1[G93A] mice compared to controls but without a marked change in composition and diversity of fecal microbiota. Nevertheless, we observed an increase of Lachnospiraceae family, which are butyrate-producer bacteria, in SOD1[G93A] mice. Moreover, some metabolites with significantly different intestinal concentrations are partially produced and linked with intestinal bacteria, such as riboflavin, hippurate, and N-acetylputrescine, leaving us convinced of the interest in looking further into the role of the microbiota in ALS.

CONCLUSIONS: Despite an alteration of the intestinal metabolome in SOD1[G93A] mice, microbiota data did not show significant changes, underlying the need for further research.}, } @article {pmid39611310, year = {2025}, author = {Diaz, F and Thornton, JS and Wastling, SS and Asaab, A and Morrow, JM and Zafeiropoulos, N and Bresee, C and Allred, P and Avalos, P and Lewis, RA and Baloh, RH and Svendsen, CN}, title = {Longitudinal Quantitative MRI Provides Responsive Outcome Measures for Early and Late Muscle Changes in ALS.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {171-182}, doi = {10.1002/mus.28306}, pmid = {39611310}, issn = {1097-4598}, support = {CLIN2-09284//This study was supported with funding from The California Institute of Regenerative Medicine./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging ; Male ; Female ; Middle Aged ; Longitudinal Studies ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Aged ; *Disease Progression ; Adult ; Muscle Strength/physiology ; Outcome Assessment, Health Care ; }, abstract = {INTRODUCTION/AIMS: Studies have demonstrated the potential of muscle MRIs to measure disease progression in ALS. However, the responsiveness and utility of quantitative muscle MRIs in an ALS clinical trial remain unknown. This study aimed to determine the responsiveness of quantitative muscle MRIs to measure disease progression in ALS.

METHODS: Longitudinal quantitative muscle MRIs were obtained in an ALS study that delivered human neural progenitor cells to the spinal cord (NCT02943850). Participants underwent MRIs at baseline, 1, 3, 6, 9, and 12 months. MRI measures included fat fraction (ff), water T2 (T 2m), cross-sectional area (CSA), and remaining muscle area (RMA). Non-MRI measures included strength via Accurate Test of Limb Isometric Strength (ATLIS) and the ALSFRS-R. Standardized response means (SRM) were calculated at 1, 3, 6, and 12 months.

RESULTS: Significant increases in muscle FF and decreases in CSA and RMA were seen as early as 1 month from baseline. At 6 months, the most responsive measures were muscle FF (SRMthigh = 1.85, SRMcalf = 1.39), T 2m (SRMthigh = 1.2, SRMcalf = 1.71), CSA (SRMthigh = -1.58, SRMcalf = -1.14), RMA (SRMthigh = -1.77, SRMcalf = -1.28), and strength tested via ATLIS (SRMknee extension = -1.79, SRMknee flexion = -1.3). The ALSFRS-R was the least responsive at 6 months (SRM = -0.85). Muscle FF and T 2m correlated with ALSFRS-R leg subscores and MRI measures demonstrated varying degrees of correlation with strength.

DISCUSSION: High responsiveness and low variability make quantitative muscle MRI a novel and complementary outcome measure for ALS clinical trials.}, } @article {pmid39611137, year = {2024}, author = {Valančius, D and Burnytė, B and Masaitienė, R and Morkūnienė, A and Klimašauskienė, A}, title = {Rapidly Progressing and Early-Onset Forms of Amyotrophic Lateral Sclerosis Caused by a Novel SOD1 Variant in a Lithuanian Family.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200217}, pmid = {39611137}, issn = {2376-7839}, abstract = {OBJECTIVES: To describe a novel familial variant of superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS) in a Lithuanian family, highlighting its variable progression and implications for treatment inclusion criteria.

METHODS: This study presents the clinical and genetic findings of a family with the novel SOD1 variant, including one member diagnosed with early-onset ALS (onset <40 years) and one with a particularly rapidly progressing course of ALS.

RESULTS: The SOD1 variant NM_000454.5:c.446T>C, NP_000445.1:p.(Val149Ala) was identified in affected family members and 4 asymptomatic members aged 32-56 years. We present detailed disease course of the affected family members obtained during follow-up. Clinically, this variant is associated with variable disease progression, with the time from symptom onset to death ranging from 5 to 77 months.

DISCUSSION: The novel SOD1 variant p.Val149Ala in this Lithuanian family causes ALS of variable onset and course, including a case of early-onset ALS and one case of rapidly progressing ALS, necessitating recognition by the scientific community and development of tailored therapeutic approaches.}, } @article {pmid39610104, year = {2025}, author = {Bar Avi, O and Perlson, E}, title = {Navigating the pathways: TAR-DNA-binding-protein-43 aggregation, axonal transport, and local synthesis in amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {10}, pages = {2921-2922}, doi = {10.4103/NRR.NRR-D-24-00726}, pmid = {39610104}, issn = {1673-5374}, } @article {pmid39608855, year = {2024}, author = {Budworth, L and Wilson, B and Sutton-Klein, J and Basu, S and O'Keeffe, C and Mason, SM and Ang, A and Anne-Wilson, S and Reynard, K and Croft, S and Shah, AD and Bank, S and Conner, M and Lawton, R}, title = {Is emergency doctors' tolerance of clinical uncertainty on a novel measure associated with doctor well-being, healthcare resource use and patient outcomes?.}, journal = {Emergency medicine journal : EMJ}, volume = {}, number = {}, pages = {}, doi = {10.1136/emermed-2023-213256}, pmid = {39608855}, issn = {1472-0213}, abstract = {INTRODUCTION: Emergency doctors routinely face uncertainty-they work with limited patient information, under tight time constraints and receive minimal post-discharge feedback. While higher uncertainty tolerance (UT) among staff is linked with reduced resource use and improved well-being in various specialties, its impact in emergency settings is underexplored. We aimed to develop a UT measure and assess associations with doctor-related factors (eg, experience), patient outcomes (eg, reattendance) and resource use (eg, episode costs).

METHODS: From May 2021 to February 2022, emergency doctors (specialty trainee 3 and above) from five Yorkshire (UK) departments completed an online questionnaire. This included a novel UT measure-an adapted Physicians' Reaction to Uncertainty scale collaboratively modified within our team according to Hillen et al's (2017) UT model. The questionnaire also included well-being-related measures (eg, Brief Resilience Scale) and assessed factors like doctors' seniority. Patient encounters involving prespecified 'uncertainty-inducing' problems (eg, headache) were analysed. Multilevel regression explored associations between doctor-level factors, resource use and patient outcomes.

RESULTS: 39 doctors were matched with 384 patients. The UT measure demonstrated high reliability (Cronbach's α=0.92) and higher UT was significantly associated with better psychological well-being including greater resilience (Pearson's r=0.56; 95% CI=0.30 to 0.74) and lower burnout (eg, Cohen's d=-2.98; -4.62 to -1.33; mean UT difference for 'no' vs 'moderate/high' burnout). UT was not significantly associated with resource use (eg, episode costs: β=-0.07; -0.32 to 0.18) or patient outcomes including 30-day readmission (eg, OR=0.82; 0.28 to 2.35).

CONCLUSIONS: We developed a reliable UT measure for emergency medicine. While higher UT was linked to doctor well-being, its impact on resource use and patient outcomes remains unclear. Further measure validation and additional research including intervention trials are necessary to confirm these findings and explore the implications of UT in emergency practice.}, } @article {pmid39608699, year = {2025}, author = {Kale, MB and Wankhede, NL and Bishoyi, AK and Ballal, S and Kalia, R and Arya, R and Kumar, S and Khalid, M and Gulati, M and Umare, M and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Kopalli, SR and Fareed, M and Koppula, S}, title = {Emerging biophysical techniques for probing synaptic transmission in neurodegenerative disorders.}, journal = {Neuroscience}, volume = {565}, number = {}, pages = {63-79}, doi = {10.1016/j.neuroscience.2024.11.055}, pmid = {39608699}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; *Synaptic Transmission/physiology ; Animals ; Synapses/metabolism/pathology/physiology ; }, abstract = {Plethora of research has shed light on the critical role of synaptic dysfunction in various neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Synapses, the fundamental units for neural communication in the brain, are highly vulnerable to pathological conditions and are central to the progression of neurological diseases. The presynaptic terminal, a key component of synapses responsible for neurotransmitter release and synaptic communication, undergoes structural and functional alterations in these disorders. Understanding synaptic transmission abnormalities is crucial for unravelling the pathophysiological mechanisms underlying neurodegeneration. In the quest to probe synaptic transmission in NDDs, emerging biophysical techniques play a pivotal role. These advanced methods offer insights into the structural and functional changes occurring at nerve terminals in conditions like AD, PD, HD & ALS. By investigating synaptic plasticity and alterations in neurotransmitter release dynamics, researchers can uncover valuable information about disease progression and potential therapeutic targets. The review articles highlighted provide a comprehensive overview of how synaptic vulnerability and pathology are shared mechanisms across a spectrum of neurological disorders. In major neurodegenerative diseases, synaptic dysfunction is a common thread linking these conditions. The intricate molecular machinery involved in neurotransmitter release, synaptic vesicle dynamics, and presynaptic protein regulation are key areas of focus for understanding synaptic alterations in neurodegenerative diseases.}, } @article {pmid39608571, year = {2024}, author = {Diggins, L and Ross, D and Bhanot, S and Corallo, R and Daley, R and Patel, K and Lewis, O and Donahue, S and Thaddeus, J and Hiers, L and Syed, C and Eagerton, D and Mohanty, BK}, title = {CD spectra reveal the state of G-quadruplexes and i-motifs in repeated and other DNA sequences.}, journal = {Biophysical reports}, volume = {5}, number = {1}, pages = {100187}, pmid = {39608571}, issn = {2667-0747}, abstract = {The B-DNA of the genome contains numerous sequences that can form various noncanonical structures including G-quadruplex (G4), formed by two or more stacks of four guanine residues in a plane, and intercalating motif (i-motif [iM]) formed by alternately arranged C-C[+] pairs. One of the easy yet sensitive methods to study G4s and iMs is circular dichroism (CD) spectroscopy, which generates characteristic G4 and iM peaks. We have analyzed and compared the effects of various environmental factors including pH, buffer composition, temperature, flanking sequences, complimentary DNA strands, and single-stranded DNA binding protein (SSB) on the CD patterns of G4s and iMs generated by two groups of DNA molecules, one containing tandem repeats of GGGGCC and CCCCGG from the C9ORF72 gene associated with amyotrophic lateral sclerosis and frontotemporal dementia, and the second containing polyG/polyC clusters from oncogene promoter-proximal regions without such tandem repeats. Changes in pH caused drastic changes in CCCCGG-iM and GGGGCC-G4 and the changes were dependent on repeat numbers and G-C basepairing. In contrast, with the DNA sequences from the promoter-proximal regions of oncogenes, iMs disassembled upon pH changes with the peak slowly shifting to lower wavelength but the G4s did not show significant change. Complementary DNA strands and flanking DNA sequences also regulate G4 and iM formation. The SSB disassembled both G4s and iMs formed by almost all sequences suggesting an in vivo role for SSBs in the disassembly of G4s and iMs during DNA replication and other DNA transactions.}, } @article {pmid39606446, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39606446}, issn = {2693-5015}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, } @article {pmid39606178, year = {2024}, author = {Tröger, J and Dörr, F and Schwed, L and Linz, N and König, A and Thies, T and Barbe, MT and Orozco-Arroyave, JR and Rusz, J}, title = {Corrigendum: An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1488178}, doi = {10.3389/fdgth.2024.1488178}, pmid = {39606178}, issn = {2673-253X}, abstract = {[This corrects the article DOI: 10.3389/fdgth.2024.1440986.].}, } @article {pmid39605661, year = {2024}, author = {Zimyanin, V and Dash, BP and Großmann, D and Simolka, T and Glaß, H and Verma, R and Khatri, V and Deppmann, C and Zunder, E and Redemann, S and Hermann, A}, title = {Axonal transcriptome reveals upregulation of PLK1 as a protective mechanism in response to increased DNA damage in FUS [P525L] spinal motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.20.624439}, pmid = {39605661}, issn = {2692-8205}, abstract = {Mutations in the gene FUSED IN SARCOMA (FUS) are among the most frequently occurring genetic forms of amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS -ALS involves impaired DNA damage response and axonal degeneration. However, it is still poorly understood how these gene mutations lead to selective spinal motor neuron (MN) degeneration and how nuclear and axonal phenotypes are linked. To specifically address this, we applied a compartment specific RNA-sequencing approach using microfluidic chambers to generate axonal as well as somatodendritic compartment-specific profiles from isogenic induced pluripotent stem cells (iPSCs)-derived MNs. We demonstrate high purity of axonal and soma fractions and show that the axonal transcriptome is unique and distinct from that of somas including significantly fewer number of transcripts. Functional enrichment analysis revealed that differentially expressed genes (DEGs) in axons were mainly enriched in key pathways like RNA metabolism and DNA damage, complementing our knowledge of early phenotypes in ALS pathogenesis and known functions of FUS. In addition, we demonstrate a strong enrichment for cell cycle associated genes including significant upregulation of polo-like kinase 1 (PLK1) in FUS [P525L] mutant MNs. PLK1 was increased upon DNA damage induction and PLK1 inhibition further increased the number of DNA damage foci in etoposide-treated cells, an effect that was diminished in case of FUS mutant MNs. In contrast, inhibition of PLK1 increased late apoptotic or necrosis-induced neuronal cell death in mutant neurons. Taken together, our findings provide insights into compartment-specific transcriptomics in human FUS -ALS MNs and we propose that specific upregulation of PLK1 might represent an early event in the pathogenesis of ALS, possibly modulating DNA damage response and other associated pathways.}, } @article {pmid39605556, year = {2024}, author = {Singer-Clark, T and Hou, X and Card, NS and Wairagkar, M and Iacobacci, C and Peracha, H and Hochberg, LR and Stavisky, SD and Brandman, DM}, title = {Speech motor cortex enables BCI cursor control and click.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605556}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; }, abstract = {Decoding neural activity from ventral (speech) motor cortex is known to enable high-performance speech brain-computer interface (BCI) control. It was previously unknown whether this brain area could also enable computer control via neural cursor and click, as is typically associated with dorsal (arm and hand) motor cortex. We recruited a clinical trial participant with ALS and implanted intracortical microelectrode arrays in ventral precentral gyrus (vPCG), which the participant used to operate a speech BCI in a prior study. We developed a cursor BCI driven by the participant's vPCG neural activity, and evaluated performance on a series of target selection tasks. The reported vPCG cursor BCI enabled rapidly-calibrating (40 seconds), accurate (2.90 bits per second) cursor control and click. The participant also used the BCI to control his own personal computer independently. These results suggest that placing electrodes in vPCG to optimize for speech decoding may also be a viable strategy for building a multi-modal BCI which enables both speech-based communication and computer control via cursor and click.}, } @article {pmid39605399, year = {2024}, author = {Tuddenham, JF and Fujita, M and Khairallah, A and Harbison, C and Flowers, XE and Coronas-Samano, G and Maniatis, S and Daly, A and Schneider, JA and Teich, AF and Vonsattel, JPG and Sims, PA and Elyaman, W and Bradshaw, EM and Phatnani, H and Shneider, N and Bennett, DA and De Jager, PL and Przedborski, S and Menon, V and Olah, M}, title = {Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.12.623183}, pmid = {39605399}, issn = {2692-8205}, abstract = {Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.}, } @article {pmid39605053, year = {2024}, author = {Horiuchi, M and Watanabe, S and Komine, O and Takahashi, E and Kaneko, K and Itohara, S and Shimada, M and Ogi, T and Yamanaka, K}, title = {ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {184}, pmid = {39605053}, issn = {2051-5960}, support = {JP23K06826//Japan Society for the Promotion of Science/ ; JP19KK0214//Japan Society for the Promotion of Science/ ; JP22H00467//Japan Society for the Promotion of Science/ ; JP22ek0109426//Japan Agency for Medical Research and Development/ ; JP24wm0425014//Japan Agency for Medical Research and Development/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; }, mesh = {Animals ; *Oligodendroglia/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Mice, Transgenic ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Spinal Cord/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43[M337V] in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43[M337V] and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43[M337V] with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43[M337V]. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43[M337V] overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.}, } @article {pmid39604641, year = {2024}, author = {Mi, Y and Zhang, P and Hou, X and Ding, Y and Wang, Y and Du, H and Deng, M}, title = {A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {39604641}, issn = {2240-2993}, support = {No. 82273915//National Natural Science Foundation of China/ ; No. 82273915//National Natural Science Foundation of China/ ; No. 82273915//National Natural Science Foundation of China/ ; No. 82273915//National Natural Science Foundation of China/ ; No. 82273915//National Natural Science Foundation of China/ ; No. 82273915//National Natural Science Foundation of China/ ; No. 82273915//National Natural Science Foundation of China/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.}, } @article {pmid39603574, year = {2024}, author = {Wen, J and Li, Y and Qin, Y and Yan, L and Zhang, K and Li, A and Wang, Z and Yu, F and Lai, J and Yang, W and Liu, YU and Qin, D and Su, H}, title = {Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107518}, doi = {10.1016/j.phrs.2024.107518}, pmid = {39603574}, issn = {1096-1186}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Phenanthridines/pharmacology/therapeutic use ; *Amaryllidaceae Alkaloids/pharmacology/therapeutic use ; *Caenorhabditis elegans/drug effects/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; *Disease Models, Animal ; TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; }, abstract = {Aggregation of TAR-DNA binding protein-43 (TDP-43) is a pathological feature present in nearly 97 % cases of amyotrophic lateral sclerosis (ALS), making it an attractive target for pathogenic studies and drug screening. Here, we have performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly decreases the level of TDP-43[A315T] in a cellular model. We further demonstrate that lycorine reduces the level of TDP-43[A315T] both through inhibiting its synthesis and by promoting its degradation by the ubiquitin-proteasome system (UPS). Importantly, treatment with lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in TDP-43[A315T]-expressing Caenorhabditis elegans and mouse models. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS.}, } @article {pmid39603486, year = {2025}, author = {Krus, KL and Benitez, AM and Strickland, A and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice.}, journal = {Experimental neurology}, volume = {384}, number = {}, pages = {115068}, doi = {10.1016/j.expneurol.2024.115068}, pmid = {39603486}, issn = {1090-2430}, mesh = {Animals ; Mice ; *Stathmin/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Male ; }, abstract = {Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43[Q331K] knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.}, } @article {pmid39602529, year = {2024}, author = {Jin, S and Tian, Y and Hacker, J and Chen, X and Bertolio, M and Reynolds, C and Jarvis, R and Hu, J and Promes, V and Halim, D and Gao, FB and Yang, Y}, title = {Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model.}, journal = {Science advances}, volume = {10}, number = {48}, pages = {eadq3350}, pmid = {39602529}, issn = {2375-2548}, support = {R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R01 AG078728/AG/NIA NIH HHS/United States ; R01 NS118747/NS/NINDS NIH HHS/United States ; R01 NS125490/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Astrocytes/metabolism ; *Exosomes/metabolism ; Mice ; Humans ; *Cytokines/metabolism ; *Disease Models, Animal ; *Superoxide Dismutase-1/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; }, abstract = {Astrocyte secreted signals substantially affect disease pathology in neurodegenerative diseases. It remains little understood about how proinflammatory cytokines, such as interleukin-1α/tumor necrosis factor-α/C1q (ITC), often elevated in neurodegenerative diseases, alter astrocyte-secreted signals and their effects in disease pathogenesis. By selectively isolating astrocyte exosomes (A-Exo.) and employing cell type-specific exosome reporter mice, our current study showed that ITC cytokines significantly reduced A-Exo. secretion and decreased spreading of focally labeled A-Exo. in diseased SOD1G93A mice. Our results also found that A-Exo. were minimally associated with misfolded SOD1 and elicited no toxicity to mouse spinal and human iPSC-derived motor neurons. In contrast, A-Exo. were neuroprotective against excitotoxicity, which was completely diminished by ITC cytokines and partially abolished by SOD1G93A expression. Subsequent proteomic characterization of A-Exo. and genetic analysis identified that surface expression of glial-specific HepaCAM preferentially mediates A-Exo's axon protection effect. Together, our study defines a cytokine-induced loss-of-function mechanism of A-Exo. in protecting neurons from excitotoxicity in amyotrophic lateral sclerosis.}, } @article {pmid39602508, year = {2024}, author = {Lynch, EM and Pittman, S and Daw, J and Ikenaga, C and Chen, S and Dhavale, DD and Jackrel, ME and Ayala, YM and Kotzbauer, P and Ly, CV and Pestronk, A and Lloyd, TE and Weihl, CC}, title = {Seeding-competent TDP-43 persists in human patient and mouse muscle.}, journal = {Science translational medicine}, volume = {16}, number = {775}, pages = {eadp5730}, doi = {10.1126/scitranslmed.adp5730}, pmid = {39602508}, issn = {1946-6242}, mesh = {Animals ; Humans ; *DNA-Binding Proteins/metabolism ; Mice ; *Muscle, Skeletal/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Myositis, Inclusion Body/metabolism/pathology ; Disease Models, Animal ; }, abstract = {TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.}, } @article {pmid39601192, year = {2025}, author = {Sørensen, DM and Tankisi, H}, title = {Reliability of MScanFit Motor Unit Number Estimation in the Trapezius Muscle.}, journal = {Muscle & nerve}, volume = {71}, number = {2}, pages = {166-170}, doi = {10.1002/mus.28303}, pmid = {39601192}, issn = {1097-4598}, support = {//Aage & Johanne Louis-Hansens Foundation/ ; //Grosserer L. F. Foghts Foundation/ ; //Dagmar Marshalls Fond/ ; //The Jascha Foundation,/ ; //Lundbeck Foundation/ ; }, mesh = {Humans ; Male ; *Superficial Back Muscles/physiology ; Female ; Reproducibility of Results ; Adult ; *Electromyography/methods ; *Action Potentials/physiology ; Motor Neurons/physiology ; Young Adult ; Middle Aged ; Recruitment, Neurophysiological/physiology ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; }, abstract = {INTRODUCTION/AIMS: MScanFit motor unit number estimation (MUNE) is the most recent MUNE method which has shown promising results in extremity muscles, but it has not been applied to bulbar muscles. Bulbar muscles are particularly important in the diagnosis of amyotrophic lateral sclerosis (ALS). This study aimed to investigate the feasibility and reliability of MScanFit MUNE in the accessory nerve and trapezius muscles.

METHODS: A total of twenty healthy participants were examined twice within 1-2 weeks. We extracted the MScanFit MUNE and size parameter, and compound muscle action potential (CMAP) amplitude values. The reliability of these parameters was assessed using the intra-rater coefficient of variation (CoV), intraclass correlation coefficient (ICC), and Bland-Altman plots. We also correlated MUNE values with CMAP amplitudes using correlation coefficients.

RESULTS: Mean MUNE values (Day 1 = 132.1 and Day 2 = 137.4), CMAP amplitudes (Day 1 = 9.71 mV and Day 2 = 10.10 mV) and size parameters did not differ between the two sessions (p > 0.05). CoV showed excellent reliability for MUNE values, size parameters, and CMAP amplitudes (CoV < 7%) whereas ICCs showed moderate reliability for MUNE values (ICC = 0.619), poor to moderate reliability for size parameters (between 0.393 and 0.689), and good reliability for CMAP amplitude (ICC = 0.864) There was no correlation between MUNE values and CMAP amplitudes.

DISCUSSION: MScanFit MUNE is applicable and mostly reliable in the trapezius muscle. Further studies in patients are needed to investigate the sensitivity of MScanFit in this muscle in detecting motor unit loss, particularly in ALS.}, } @article {pmid39598374, year = {2024}, author = {Li, Y and Fu, J and Wang, H}, title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {11}, pages = {}, pmid = {39598374}, issn = {1424-8247}, support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; }, abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.}, } @article {pmid39598025, year = {2024}, author = {Vacchiano, V and Morabito, F and Bonan, L and Teodorani, L and Faini, C and Rizzo, G and Liguori, R}, title = {Reverse Split Hand as a Neurophysiological Hallmark of Spinal Muscular Atrophy.}, journal = {Journal of clinical medicine}, volume = {13}, number = {22}, pages = {}, pmid = {39598025}, issn = {2077-0383}, abstract = {Objective: Motor unit number estimation (MUNE) methods are crucial for estimating lower motor neuron loss in motor neuron diseases. The MScanFit MUNE (MScanFit) is a novel method that estimates MUNE values from compound motor action potential (CMAP) scans, demonstrating high sensitivity and reproducibility in detecting motor unit loss in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we aimed to characterize the pattern of motor unit loss in the hand intrinsic muscles of SMA patients compared to ALS patients and healthy controls (HC) using MScanFit MUNE. Methods: Patients diagnosed with ALS, adult SMA patients, and HC were prospectively enrolled. MScanFit examinations were performed on the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. To focus on the different patterns of motor neuron degeneration in the intrinsic hand muscles, the ratio of CMAP amplitude of APB to ADM (CMAP ratio) and the ratio of MUNE values of APB to those of the ADM muscle (MUNE ratio) were calculated. Results: The study included 46 ALS patients, 16 SMA patients, and 23 HC. MScanFit MUNE revealed distinct patterns of motor unit degeneration in SMA patients, notably more severe in the ADM than in the APB muscle, indicating a "reverse" split-hand phenomenon. Both CMAP and MUNE ratios demonstrated high diagnostic accuracy in distinguishing ALS from SMA, with the MUNE ratio performing better. Conclusions: MScanFit MUNE is a valuable tool for exploring distinct patterns of motor neuron degeneration in patients with different types of motor neuron diseases.}, } @article {pmid39596864, year = {2024}, author = {McKenna, MC and Kleinerova, J and Power, A and Garcia-Gallardo, A and Tan, EL and Bede, P}, title = {Quantitative and Computational Spinal Imaging in Neurodegenerative Conditions and Acquired Spinal Disorders: Academic Advances and Clinical Prospects.}, journal = {Biology}, volume = {13}, number = {11}, pages = {}, pmid = {39596864}, issn = {2079-7737}, support = {2023//Spastic Paraplegia Foundation/ ; }, abstract = {Introduction: Quantitative spinal cord imaging has facilitated the objective appraisal of spinal cord pathology in a range of neurological conditions both in the academic and clinical setting. Diverse methodological approaches have been implemented, encompassing a range of morphometric, diffusivity, susceptibility, magnetization transfer, and spectroscopy techniques. Advances have been fueled both by new MRI platforms and acquisition protocols as well as novel analysis pipelines. The quantitative evaluation of specific spinal tracts and grey matter indices has the potential to be used in diagnostic and monitoring applications. The comprehensive characterization of spinal disease burden in pre-symptomatic cohorts, in carriers of specific genetic mutations, and in conditions primarily associated with cerebral disease, has contributed important academic insights. Methods: A narrative review was conducted to examine the clinical and academic role of quantitative spinal cord imaging in a range of neurodegenerative and acquired spinal cord disorders, including hereditary spastic paraparesis, hereditary ataxias, motor neuron diseases, Huntington's disease, and post-infectious or vascular disorders. Results: The clinical utility of specific methods, sample size considerations, academic role of spinal imaging, key radiological findings, and relevant clinical correlates are presented in each disease group. Conclusions: Quantitative spinal cord imaging studies have demonstrated the feasibility to reliably appraise structural, microstructural, diffusivity, and metabolic spinal cord alterations. Despite the notable academic advances, novel acquisition protocols and analysis pipelines are yet to be implemented in the clinical setting.}, } @article {pmid39596631, year = {2024}, author = {Sneha, NP and Dharshini, SAP and Taguchi, YH and Gromiha, MM}, title = {Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596631}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Transcriptome ; *Spinal Cord/metabolism/pathology ; Frontal Lobe/metabolism/pathology ; Gene Regulatory Networks ; Motor Neurons/metabolism/pathology ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, and excitotoxicity. The frontal cortex is crucial for action initiation, planning, and voluntary movements whereas the spinal cord facilitates communication with the brain, walking, and reflexes. By investigating transcriptome data from the frontal cortex and spinal cord, we aim to elucidate common pathological mechanisms and pathways involved in ALS for understanding the disease progression and identifying potential therapeutic targets.

METHODS: In this study, we quantified gene and transcript expression patterns, predicted variants, and assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing functional interaction networks, and performing a gene enrichment analysis.

RESULTS: We found novel genes for the upregulation of immune response, and the downregulation of metabolic-related and defective degradation processes in both the spinal cord and frontal cortex. Additionally, we observed the dysregulation of histone regulation and blood pressure-related genes specifically in the frontal cortex.

CONCLUSIONS: These results highlight the distinct and shared molecular disruptions in ALS, emphasizing the critical roles of immune response and metabolic dysfunction in neuronal degeneration. Targeting these pathways may provide new therapeutic avenues to combat neurodegeneration and preserve neuronal health.}, } @article {pmid39596615, year = {2024}, author = {Papapanagiotou, AP and Anthimidou, EA and Eleftherohorinos, IG and Giantsis, IA}, title = {Comparison of Molecularly Identified Resistant and Susceptible Johnsongrass (Sorghum halepense L.) Populations at ALS Gene, in the Absence and Presence of Field Crops.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596615}, issn = {2073-4425}, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics ; *Sorghum/genetics/growth & development ; *Herbicides/pharmacology ; Plant Weeds/genetics/growth & development/drug effects ; Plant Proteins/genetics ; Zea mays/genetics/growth & development ; Crops, Agricultural/genetics/growth & development ; Genotype ; Biomass ; Helianthus/genetics/growth & development ; }, abstract = {BACKGROUND/OBJECTIVES: Johnsongrass (Sorghum halepense) is an erect tetraploid, perennial, C4 grass weed species categorized among the world's most noxious weeds due to its high competitive ability against crops and the increased number of field-evolved herbicide-resistant populations. The aim of the present study was to assess the growth rate and performance of resistant (R) johnsongrass genotypes hosting Trp574Leu target-site cross-resistance at ALS gene, inhibiting various herbicides, compared to susceptible (S) conspecific weeds, in the absence and presence of corn or sunflower antagonism.

METHODS: The aboveground biomass, tiller, and rhizome production ability of one S and one R johnsongrass population with a Trp574-Leu substitution conferring cross-resistance to ALS-inhibiting herbicides were compared under non-competitive conditions. Furthermore, the competitive ability of these two johnsongrass populations against corn or sunflower was determined in a target-neighborhood design.

RESULTS: The S and R johnsongrass populations displayed similar growth rates concerning aboveground biomass and tiller number, whereas the R population displayed a slightly greater growth rate for rhizome production compared to the S population. Both populations grown with corn produced more aboveground biomass than the ones grown with sunflowers. The aboveground biomass of corn was reduced to a greater extent than sunflower by the presence of both johnsongrass populations, while both crops were affected more by the S than by the R population.

CONCLUSIONS: Although the inheritance and the genetic background of plant materls were not addressed, the findings of this study indicate clearly that the growth rate and competitive ability of the ALS-resistant johnsongrass population are not associated with the resistance mechanism involved.}, } @article {pmid39596609, year = {2024}, author = {Luglio, A and Maggi, E and Riviello, FN and Conforti, A and Sorrentino, U and Zuccarello, D}, title = {Hereditary Neuromuscular Disorders in Reproductive Medicine.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596609}, issn = {2073-4425}, support = {PNRR-MR1-2022-12376108//European Union/ ; }, mesh = {Humans ; *Neuromuscular Diseases/genetics/diagnosis ; Female ; Pregnancy ; Reproductive Medicine/methods ; Genetic Testing/methods ; Prenatal Diagnosis ; Preimplantation Diagnosis ; Muscular Atrophy, Spinal/genetics ; Charcot-Marie-Tooth Disease/genetics/diagnosis ; }, abstract = {Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients' quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot-Marie-Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb-Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn.}, } @article {pmid39596581, year = {2024}, author = {Paubel, A and Marouillat, S and Dangoumau, A and Maurel, C and Haouari, S and Blasco, H and Corcia, P and Laumonnier, F and Andres, CR and Vourc'h, P}, title = {Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596581}, issn = {2073-4425}, mesh = {Animals ; *Ubiquitin-Conjugating Enzymes/genetics/metabolism ; Mice ; *Neurons/metabolism ; *Neurodevelopmental Disorders/genetics/pathology ; *Neurodegenerative Diseases/genetics ; *Hippocampus/metabolism ; *Cell Differentiation/genetics ; Neurogenesis/genetics ; Cells, Cultured ; N-Methylaspartate/pharmacology/metabolism ; }, abstract = {Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.}, } @article {pmid39596445, year = {2024}, author = {Jiang, LL and Zhang, XL and Hu, HY}, title = {Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596445}, issn = {1422-0067}, support = {31670782, 31700669//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Protein Aggregation, Pathological/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Aggregates ; }, abstract = {Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.}, } @article {pmid39595895, year = {2024}, author = {Pongrácová, E and Buratti, E and Romano, M}, title = {Prion-like Spreading of Disease in TDP-43 Proteinopathies.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595895}, issn = {2076-3425}, abstract = {TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. Given its association with numerous diseases, particularly ALS and FTLD, the mechanisms underlying TDP-43 aggregation and its impact on neuronal function have been extensively investigated. However, little is still known about the spreading of this pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics. Importantly, emerging strategies such as small molecule inhibitors, immunotherapies, and gene therapies targeting TDP-43 propagation offer promising avenues for developing effective treatments. By elucidating the mechanisms of TDP-43 spreading, we therefore aim to pave the way for novel therapies for TDP-43-related neurodegenerative diseases.}, } @article {pmid39595845, year = {2024}, author = {Rocha, PS and Bento, N and Svärd, H and Lopes, DM and Hespanhol, S and Folgado, D and Carreiro, AV and de Carvalho, M and Miranda, B}, title = {Voice Assessment in Patients with Amyotrophic Lateral Sclerosis: An Exploratory Study on Associations with Bulbar and Respiratory Function.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595845}, issn = {2076-3425}, support = {PTDC/MEC-NEU/6855/202//Fundação para a Ciência e Tecnologia/ ; }, abstract = {BACKGROUND: Speech production is a possible way to monitor bulbar and respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Moreover, the emergence of smartphone-based data collection offers a promising approach to reduce frequent hospital visits and enhance patient outcomes. Here, we studied the relationship between bulbar and respiratory functions with voice characteristics of ALS patients, alongside a speech therapist's evaluation, at the convenience of using a simple smartphone.

METHODS: For voice assessment, we considered a speech therapist's standardized tool-consensus auditory-perceptual evaluation of voice (CAPE-V); and an acoustic analysis toolbox. The bulbar sub-score of the revised ALS functional rating scale (ALSFRS-R) was used, and pulmonary function measurements included forced vital capacity (FVC%), maximum expiratory pressure (MEP%), and maximum inspiratory pressure (MIP%). Correlation coefficients and both linear and logistic regression models were applied.

RESULTS: A total of 27 ALS patients (12 males; 61 years mean age; 28 months median disease duration) were included. Patients with significant bulbar dysfunction revealed greater CAPE-V scores in overall severity, roughness, strain, pitch, and loudness. They also presented slower speaking rates, longer pauses, and higher jitter values in acoustic analysis (all p < 0.05). The CAPE-V's overall severity and sub-scores for pitch and loudness demonstrated significant correlations with MIP% and MEP% (all p < 0.05). In contrast, acoustic metrics (speaking rate, absolute energy, shimmer, and harmonic-to-noise ratio) significantly correlated with FVC% (all p < 0.05).

CONCLUSIONS: The results provide supporting evidence for the use of smartphone-based recordings in ALS patients for CAPE-V and acoustic analysis as reliable correlates of bulbar and respiratory function.}, } @article {pmid39595818, year = {2024}, author = {Ferullo, L and Risi, B and Caria, F and Olivieri, E and Poli, L and Gazzina, S and Leggio, U and Bertella, E and Giovanelli, G and Labella, B and Padovani, A and Filosto, M}, title = {Gold Coast Criteria in ALS Diagnosis: A Real-World Experience.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595818}, issn = {2076-3425}, abstract = {Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address these points, in 2019, a new set of diagnostic criteria was proposed, namely the Gold Coast criteria (GCC), characterized by a dichotomous diagnostic categorization, i.e., ALS or not ALS. Methods: In order to investigate the sensitivity, specificity, and clinical usefulness of GCC in a practical clinical setting, we retrospectively evaluated 131 patients diagnosed with ALS and 104 control subjects. ALSFRS-R score, electrophysiological tests, neuroradiological investigations, and CSF analysis were obtained. rEEC, Awaji, and GCC were applied at the first and last evaluations. Results: The sensitivity of GCC (93.1%; 96.1%) was greater than rEEC (71.8%; 87%) and Awaji criteria (77.8%; 89.3%) both at the first visit and last follow-up. The GCC's specificity (28.8%) is lower than that of the other two criteria (rEEC 45.2%; Awaji 43.3%). Conclusions: Our study suggests that in a real-world setting, the GCC are more sensitive and have substantially lower risk of false negative diagnoses than rEEC and Awaji criteria. Although rEEC had the highest specificity, they may delay the diagnosis. Systematically using the GCC could help to achieve an earlier diagnosis and quickly refer patients to the correct management. The low specificity of GCC is likely to not significantly impact patient recruitment in clinical trials; therefore, its use might allow a faster and earlier enrollment.}, } @article {pmid39595816, year = {2024}, author = {Shandiz, E and Fernandes, GL and Henkin, JS and McCombe, PA and Trajano, GS and Henderson, RD}, title = {Assessing the Effect of Riluzole on Motor Unit Discharge Properties.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595816}, issn = {2076-3425}, abstract = {Background. This study aims to determine if Riluzole usage can change the function and excitability of motor neurons. Methods. The clinical data and indices of motor neuron excitability were assessed using high-density surface EMG parameters from 80 ALS participants. The persistent inward current was assessed using the discharge rate from paired motor units obtained from the tibialis anterior muscle. This enabled the discharge rate at recruitment, peak discharge rates and the hysteresis of the recruitment-derecruitment frequencies (also known as delta F) to be calculated. Limbs were classified according to their strength. Results. No differences in these motor neuron discharge properties were found according to whether Riluzole was used. Conclusions. The possible interpretations of this finding are discussed.}, } @article {pmid39595812, year = {2024}, author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y}, title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595812}, issn = {2076-3425}, support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; }, abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.}, } @article {pmid39595543, year = {2024}, author = {Stoccoro, A and Coppedè, F}, title = {Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {14}, number = {11}, pages = {}, pmid = {39595543}, issn = {2218-273X}, mesh = {*DNA Methylation/drug effects ; Humans ; *Pesticides/toxicity/adverse effects ; *Neurodegenerative Diseases/genetics/metabolism/chemically induced ; *Epigenesis, Genetic/drug effects ; *Air Pollutants/toxicity/adverse effects ; Environmental Exposure/adverse effects ; Animals ; Metals, Heavy/toxicity/adverse effects ; Metals/toxicity/metabolism/adverse effects ; }, abstract = {Individuals affected by neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are dramatically increasing worldwide. Thus, several efforts are being made to develop strategies for stopping or slowing the spread of these illnesses. Although causative genetic variants linked to the onset of these diseases are known, they can explain only a small portion of cases. The etiopathology underlying the neurodegenerative process in most of the patients is likely due to the interplay between predisposing genetic variants and environmental factors. Epigenetic mechanisms, including DNA methylation, are central candidates in translating the effects of environmental factors in genome modulation, and they play a critical role in the etiology of AD, PD, and ALS. Among the main environmental exposures that have been linked to an increased risk for these diseases, accumulating evidence points to the role of heavy metals, pesticides, and air pollutants. These compounds could trigger neurodegeneration through different mechanisms, mainly neuroinflammation and the induction of oxidative stress. However, increasing evidence suggests that they are also capable of inducing epigenetic alterations in neurons. In this article, we review the available literature linking exposure to metals, pesticides, and air pollutants to DNA methylation changes relevant to neurodegeneration.}, } @article {pmid39595127, year = {2024}, author = {Cardona, F}, title = {Special Issue "Mechanisms and Novel Therapeutic Approaches for Neurodegenerative Diseases".}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595127}, issn = {2227-9059}, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are among the major health problems of the elderly, and represent a major global health challenge due to their increasing prevalence and complex pathophysiological mechanisms [...].}, } @article {pmid39594452, year = {2024}, author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP}, title = {Inhibition of Accumulation of Neutral Lipids and Their Hydroperoxide Species in Hepatocytes by Bioactive Allium sativum Extract.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594452}, issn = {2076-3921}, abstract = {Our ongoing research suggests that extracts from plant-based foods inhibit the accumulation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These findings suggest their potential use in the alleviation of metabolic dysfunction-associated fatty liver disease (MAFLD) and its most severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH). Allium extracts (ALs: AL1-AL9) were used to assess their ability to reduce lipid droplet accumulation (LDA) and oxidized lipid droplet accumulation (oxLDA) by inhibiting neutral lipid accumulation and oxidation in LD. Among the tested Allium extracts, AL1, AL3, and AL6 demonstrated substantial inhibitory effects on the LDA. Furthermore, AL1 extract showed real-time inhibition of LDA in HepG2 cells in DMEM supplemented with oleic acid (OA) within 12 h of treatment. Our lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] species in hepatocytes under OA and linoleic acid loading conditions. These results suggest that Allium-based foods inhibit LD accumulation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolomic analysis of AL1-the bioactive LDAI extract-using both LC-MS/MS and 1D-NMR [[1]H, [13]C, and Dept (135 and 90)] approaches revealed that AL1 contains mainly carbohydrates and glucoside metabolites, including iridoid glucosides, as well as minor amino acids, organosulfur compounds, and organic acids such as the antioxidant ascorbic acid (KA2 = S13), and their derivatives, suggesting that AL1 could be a potential resource for the development of functional foods and in drug discovery targeting MAFLD/MASH and other related diseases.}, } @article {pmid39593881, year = {2024}, author = {Favier, G and Rocha, DS}, title = {Overview of Tensor-Based Cooperative MIMO Communication Systems-Part 2: Semi-Blind Receivers.}, journal = {Entropy (Basel, Switzerland)}, volume = {26}, number = {11}, pages = {}, pmid = {39593881}, issn = {1099-4300}, abstract = {Cooperative MIMO communication systems play an important role in the development of future sixth-generation (6G) wireless systems incorporating new technologies such as massive MIMO relay systems, dual-polarized antenna arrays, millimeter-wave communications, and, more recently, communications assisted using intelligent reflecting surfaces (IRSs), and unmanned aerial vehicles (UAVs). In a companion paper, we provided an overview of cooperative communication systems from a tensor modeling perspective. The objective of the present paper is to provide a comprehensive tutorial on semi-blind receivers for MIMO one-way two-hop relay systems, allowing the joint estimation of transmitted symbols and individual communication channels with only a few pilot symbols. After a reminder of some tensor prerequisites, we present an overview of tensor models, with a detailed, unified, and original description of two classes of tensor decomposition frequently used in the design of relay systems, namely nested CPD/PARAFAC and nested Tucker decomposition (TD). Some new variants of nested models are introduced. Uniqueness and identifiability conditions, depending on the algorithm used to estimate the parameters of these models, are established. Two families of algorithms are presented: iterative algorithms based on alternating least squares (ALS) and closed-form solutions using Khatri-Rao and Kronecker factorization methods, which consist of SVD-based rank-one matrix or tensor approximations. In a second part of the paper, the overview of cooperative communication systems is completed before presenting several two-hop relay systems using different codings and configurations in terms of relaying protocol (AF/DF) and channel modeling. The aim of this presentation is firstly to show how these choices lead to different nested tensor models for the signals received at destination. Then, by capitalizing on these models and their correspondence with the generic models studied in the first part, we derive semi-blind receivers to jointly estimate the transmitted symbols and the individual communication channels for each relay system considered. In a third part, extensive Monte Carlo simulation results are presented to compare the performance of relay systems and associated semi-blind receivers in terms of the symbol error rate (SER) and channel estimate normalized mean-square error (NMSE). Their computation time is also compared. Finally, some perspectives are drawn for future research work.}, } @article {pmid39593143, year = {2024}, author = {Clarke, BE and Ziff, OJ and Tyzack, G and Petrić Howe, M and Wang, Y and Klein, P and Smith, CA and Hall, CA and Helmy, A and Howell, M and Kelly, G and Patani, R}, title = {Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {90}, pmid = {39593143}, issn = {1750-1326}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Valosin Containing Protein/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; *Lysosomes/metabolism ; Mice ; Mutation/genetics ; Phenotype ; Motor Neurons/metabolism/pathology ; Astrocytes/metabolism ; }, abstract = {BACKGROUND: Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood.

METHODS: Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes.

RESULTS: Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes.

CONCLUSIONS: VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.}, } @article {pmid39592088, year = {2024}, author = {Mahakalakar, N and Mohariya, G and Taksande, B and Kotagale, N and Umekar, M and Vinchurney, M}, title = {"Nattokinase as a potential therapeutic agent for preventing blood-brain barrier dysfunction in neurodegenerative disorders".}, journal = {Brain research}, volume = {1849}, number = {}, pages = {149352}, doi = {10.1016/j.brainres.2024.149352}, pmid = {39592088}, issn = {1872-6240}, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by progressive destruction of neurons and cognitive impairment, and thorough studies have provided evidence that these pathologies have a close relationship to the failure of the blood-brain barrier (BBB). Nattokinase (NK), a protease found in fermented soybeans, has been extensively studied because it displays powerful neuroprotective abilities, which is why current research was reviewed in the present article. It was concluded that there is enough evidence in preclinical studies using experimental animals that NK supplementation can alleviate the condition related to BBB dysfunction, reduce brain inflammation, and improve cognitive ability. Furthermore, the study of NK on the cardiovascular system leads to certain assumptions, which include the impact on vasculature function and the ability to manage blood flow, which is the key feature of BBB integrity. Such assumed mechanisms are fibrinolytic action, anti-inflammatory and antioxidant action, and endothelium function modulation. There are many positive research findings, and it seems that NK may serve as an effective opponent for BBB breakdown; however, a new research level should be taken to disclose the application and therapeutic use of NK in brain neurodegenerative disease.}, } @article {pmid39592063, year = {2024}, author = {Lorenc, F and Dupuis, L and Cassel, R}, title = {Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {203}, number = {}, pages = {106748}, doi = {10.1016/j.nbd.2024.106748}, pmid = {39592063}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; *Frontotemporal Dementia/pathology/physiopathology ; Humans ; Animals ; *Neurons/pathology ; *Neural Inhibition/physiology ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia are two fatal neurodegenerative disorders. They are part of a pathophysiological continuum, displaying clinical, neuropathological, and genetic overlaps. There is compelling evidence that neuronal circuit dysfunction is an early feature of both diseases. Impaired neuronal excitability, imbalanced excitatory and inhibitory influences, and altered functional connectivity have been reported. These phenomena are likely due to combined alterations in the various cellular components involved in the functioning of neuronal networks. This review focuses on one of these cellular components: inhibitory neurons. We assess the evidence for inhibitory neuron impairments in amyotrophic lateral sclerosis and frontotemporal dementia, as well as the mechanisms leading to the loss of inhibition. We also discuss the contributions of these alterations to symptoms, and the potential therapeutic strategies for targeting inhibitory neuron deficits.}, } @article {pmid39591907, year = {2024}, author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK}, title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151062}, doi = {10.1016/j.bbrc.2024.151062}, pmid = {39591907}, issn = {1090-2104}, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; }, abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.}, } @article {pmid39589985, year = {2024}, author = {Tkachenko, K and González-Saíz, JM and Calvo, AC and Lunetta, C and Osta, R and Pizarro, C}, title = {Comparative Blood Profiling Based on ATR-FTIR Spectroscopy and Chemometrics for Differential Diagnosis of Patients with Amyotrophic Lateral Sclerosis-Pilot Study.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589985}, issn = {2079-6374}, support = {N· 801586//European Union's H2020/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/blood ; Humans ; Pilot Projects ; Diagnosis, Differential ; Spectroscopy, Fourier Transform Infrared ; Middle Aged ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neurodegenerative disease characterized by poor prognosis. Currently, screening and diagnostic methods for ALS remain challenging, often leading to diagnosis at an advanced stage of the disease. This delay hinders the timely initiation of therapy, negatively impacting patient well-being. Additionally, misdiagnosis with other neurodegenerative disorders that present similar profiles often occurs. Therefore, there is an urgent need for a cost-effective, rapid, and user-friendly tool capable of predicting ALS onset. In this pilot study, we demonstrate that infrared spectroscopy, coupled with chemometric analysis, can effectively identify and predict disease profiles from blood samples drawn from ALS patients. The selected predictive spectral markers, which are used in various discriminant models, achieved an AUROC sensitivity of almost 80% for distinguishing ALS patients from controls. Furthermore, the differentiation of ALS at both the initial and advanced stages from other neurodegenerative disorders showed even higher AUROC values, with sensitivities of 87% (AUROC: 0.70-0.97). These findings highlight the elevated potential of ATR-FTIR spectroscopy for routine clinical screening and early diagnosis of ALS.}, } @article {pmid39589981, year = {2024}, author = {Mohaček-Grošev, V and Škrabić, M and Gebavi, H and Blažek Bregović, V and Marić, I and Amendola, V and Grdadolnik, J}, title = {Binding of Glutamic Acid to Silver and Gold Nanoparticles Investigated by Surface-Enhanced Raman Spectroscopy.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589981}, issn = {2079-6374}, support = {croatian-slovenian bilateral project//Ministry of Scirence and Education of the Republic of Croatia/ ; }, mesh = {*Spectrum Analysis, Raman ; *Glutamic Acid/chemistry ; *Silver/chemistry ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; Hydrogen-Ion Concentration ; }, abstract = {Glutamate is the most important excitatory neurotransmitter, which is relevant for the study of several diseases such as amyotrophic lateral sclerosis and Alzheimer. It is the form L-glutamic acid (Glu) takes at physiologically relevant pHs. The surface-enhanced Raman spectra of Glu obtained at pH values ranging from 3.3 to 12 are collected in the presence of silver and gold colloids and on solid substrates. The observed bands are compared with the positions of calculated normal modes for free neutral glutamic acid, glutamic acid monohydrate, glutamic acid bound to gold and silver atoms, and sodium glutamate. Although gold atoms prefer to bind to the NH2 group as compared to carbonyl groups, silver atoms prefer binding to hydroxyl groups more than binding to the amino group. SERS spectra of glutamic acid solutions with a pH value of 12, in which both carboxylic groups are deprotonated, indicate a complexation of the glutamic acid dianion with the sodium cation, which was introduced into the solution to adjust the pH value. Further research towards an optimal substrate is needed.}, } @article {pmid39589881, year = {2024}, author = {Jean Gregoire, M and Sirtori, R and Donatelli, L and Morgan Potts, E and Collins, A and Zamor, D and Katenka, N and Fallini, C}, title = {Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2406998121}, pmid = {39589881}, issn = {1091-6490}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; Early Career Development Award//RI-INBRE/ ; R01NS116143//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM103430//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Dendrites/metabolism ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Neurons/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Cerebral Cortex/metabolism/pathology ; }, abstract = {Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.}, } @article {pmid39589500, year = {2025}, author = {Apolloni, S and D'Ambrosi, N}, title = {Biochemical dissection of STAT3 signaling in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3229-3230}, doi = {10.4103/NRR.NRR-D-24-00862}, pmid = {39589500}, issn = {1673-5374}, } @article {pmid39589178, year = {2024}, author = {Peng, Y and Zhou, L and Jin, Y and Wu, D and Chen, N and Zhang, C and Liu, H and Li, C and Ning, R and Yang, X and Mao, Q and Liu, J and Zhang, P}, title = {Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-00630}, pmid = {39589178}, issn = {1673-5374}, abstract = {The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca2+ signaling. Conversely, Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases-such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.}, } @article {pmid39589160, year = {2025}, author = {Wang, Y and Li, D and Xu, K and Wang, G and Zhang, F}, title = {Copper homeostasis and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3124-3143}, doi = {10.4103/NRR.NRR-D-24-00642}, pmid = {39589160}, issn = {1673-5374}, abstract = {Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.}, } @article {pmid39588282, year = {2024}, author = {Dash, BP and Freischmidt, A and Helferich, AM and Ludolph, AC and Andersen, PM and Weishaupt, JH and Hermann, A}, title = {Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1457704}, pmid = {39588282}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.}, } @article {pmid39587229, year = {2024}, author = {Wang, C and Wang, S and Xue, Y and Zhong, Y and Li, H and Hou, X and Kang, DD and Liu, Z and Tian, M and Wang, L and Cao, D and Yu, Y and Liu, J and Cheng, X and Markovic, T and Hashemi, A and Kopell, BH and Charney, AW and Nestler, EJ and Dong, Y}, title = {Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {39587229}, issn = {1546-1696}, abstract = {Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood-brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10-oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an amyotrophic lateral sclerosis mouse model.}, } @article {pmid39585162, year = {2024}, author = {Savvidis, C and Kouroglou, E and Kallistrou, E and Ragia, D and Dionysopoulou, S and Gavriiloglou, G and Tsiama, V and Proikaki, S and Belis, K and Ilias, I}, title = {IGFBP-2 in Critical Illness: A Prognostic Marker in the Growth Hormone/Insulin-like Growth Factor Axis.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {4}, pages = {621-630}, pmid = {39585162}, issn = {1873-149X}, abstract = {Critical illness (CI) triggers complex disruptions in the growth hormone (GH)/insulin-like growth factor (IGF) axis, significantly affecting the dynamics of insulin-like growth-factor-binding proteins (IGFBPs). Among these, IGFBP-2 shows a sustained elevation during CI, which inversely correlates with serum levels of IGF-1, IGFBP-3, and the acid-labile subunit (ALS). Although IGFBP-2 does not directly interact with ALS, it may influence the availability of IGFs by competing with other IGFBPs for binding to IGF-1 and IGF-2. Research suggests that this persistent elevation of IGFBP-2 is largely driven by cytokine activity during CI, reflecting an adaptive response rather than a direct result of GH/IGF axis dysregulation. The clinical importance of IGFBP-2 is emphasized by its correlation with disease severity in conditions like sepsis and coronavirus disease 2019 (COVID-19), where its levels are markedly elevated compared to healthy controls and are similar to those observed in sepsis from various causes. Beyond its role in endocrine regulation, IGFBP-2 appears to play a part in metabolic and inflammatory pathways. Elevated IGFBP-2 levels have been linked to increased mortality and longer hospital stays, indicating its potential utility as a prognostic marker. Furthermore, measuring plasma IGFBP-2 may have other diagnostic applications, aiding in the assessment of CI when traditional biomarkers are inconclusive.}, } @article {pmid39585060, year = {2024}, author = {Magni, E and Hochsprung, A and Cáceres-Matos, R and Pabón-Carrasco, M and Heredia-Camacho, B and Solís-Marcos, I and Luque-Moreno, C}, title = {Effects of Respiratory Training on Pulmonary Function, Cough, and Functional Independence in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1332-1342}, pmid = {39585060}, issn = {2035-8385}, abstract = {BACKGROUND: Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications.

OBJECTIVES: The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS.

METHODS: A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger.

RESULTS: FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up.

CONCLUSION: A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function.}, } @article {pmid39584466, year = {2024}, author = {Daneshpour, A and Rezvanimehr, A and Niktalab, P and Sharif, H and Yazdanpanah, N and Saleki, K and Rezaei, N}, title = {Exploring the role of vault complex in the nervous system: a literature review.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {39584466}, issn = {2191-0200}, abstract = {Vault RNAs (vtRNAs) are a novel group of non-coding RNAs that are involved in various signaling mechanisms. vtRNAs are joined by three proteins major vault protein (MVP), vault poly (ADP-ribose) polymerase (VPARP), and telomerase-associated protein 1 (TEP1) to form the vault complex. In humans, only four vtRNA including vtRNA 1-1, vtRNA 1-2, vtRNA 1-3, vtRNA 2-1) have been discovered. In nerve cells, vtRNA is involved in synapse formation through MAPK signaling. vtRNA travels to the distal area of neurites as a key unit in the vault complex. Moreover, tRNA is detached from the vault complex in the neurite via a mitotic kinase Aurora-A-reliant MVP phosphorylation. Several molecules contribute to the formation of vtRNAs. For instance, SRSF2 and NSUN2 and their attachment to vtRNA1-1 determines the production of small-vtRNAs. Through the same factors, vtRNAs could play a role in neurodevelopmental deficits. Addition the role of vtRNA expression and vault proteins has been recently studied in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as well as brain cancers. While the mechanisms of vtRNA involvement in neurological disorders is not well-demonstrated, we believe this could be related to the impact of vtRNA regulation in autophagy, immunoregulation, RNA stability, cellular stress, apoptosis, and regulation of other epigenetic pathways. The present review captures the state-of-the-art regarding the role of vtRNAs in neurodevelopment, normal nervous system function, and neurological disorders.}, } @article {pmid39583905, year = {2024}, author = {Townley, MA}, title = {Spinneret spinning field ontogeny and life history observations in the spider Palpimanus uncatus (Araneae: Palpimanidae).}, journal = {The Journal of arachnology}, volume = {52}, number = {1}, pages = {41-70}, pmid = {39583905}, issn = {0161-8202}, support = {P20 GM113131/GM/NIGMS NIH HHS/United States ; }, abstract = {As in other Palpimanidae, two pairs of posterior spinnerets present in typical Araneomorphae are vestigial in Palpimanus uncatus Kulczyński, 1909, with only the anterior lateral spinneret (ALS) pair prominent. Nevertheless, in late juvenile and adult females, spigots appear in the ancestral posterior spinneret region (PS). Consistent with these spigots serving cylindrical silk glands, females construct substantial egg sacs. While juveniles and adults exhibit a compressed PS, in postembryos it is fully extended. Piriform silk gland (PI) spigots form a linear array on ALSs from the 1[st] stadium, increasing in number during ontogeny by addition of PIs of the tartipore-accommodated (T-A) subtype (i.e., functional during proecdyses). The number of T-A PIs added from one stadium to the next and locations occupied by their spigots often exhibit a stereotypic pattern, especially consistent in early instars. The number of non-T-A PIs remains constant through ontogeny from the 1[st] stadium: one per ALS rather than the two per ALS inferred in a few araneoids. The secondary major ampullate silk gland (2° MaA) spigot, primitively uni-shafted among araneomorphs, has become modified into a multi-shafted spigot with extended base, the number of shafts increasing during ontogeny. However, the multiple ducts that connect to the shafts continue to be accommodated during proecdysis by a single enormous tartipore. Sexual dimorphism is present, with late stadium females having greater numbers of T-A PI spigots and 2° MaA spigot shafts. Observations are presented pertaining to feeding behavior, sexual cannibalism (absent), habitat, winter diapause, numbers of molts, and longevity.}, } @article {pmid39582565, year = {2024}, author = {Byeon, H}, title = {Glymphatic system function in diverse glucose metabolism states.}, journal = {World journal of diabetes}, volume = {15}, number = {11}, pages = {2245-2250}, pmid = {39582565}, issn = {1948-9358}, abstract = {The rising prevalence of diabetes and prediabetes globally necessitates a deeper understanding of associated complications, including glymphatic system dysfunction. The glymphatic system, crucial for brain waste clearance, is implicated in cognitive decline and neurodegenerative diseases like Alzheimer's disease. This letter explores recent research on glymphatic function across different glucose metabolism states. Tian et al's study reveals significant glymphatic dysfunction in type 2 diabetes mellitus patients, evidenced by lower diffusion tensor imaging analysis along perivascular space indices compared to those with normal glucose metabolism and prediabetes. The research also reveals a link between glymphatic dysfunction and cognitive impairment. Additional research underscores the role of glymphatic impairment in neurodegenerative diseases. These findings highlight the importance of integrating glymphatic health into diabetes management and suggest potential biomarkers for early diagnosis and targeted therapeutic interventions.}, } @article {pmid39581840, year = {2024}, author = {Hannaford, A and Pavey, N and Menon, P and van den Bos, MAJ and Kiernan, MC and Simon, N and Vucic, S}, title = {Muscle ultrasound aids diagnosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clinph.2024.11.008}, pmid = {39581840}, issn = {1872-8952}, abstract = {OBJECTIVE: There is a need for improved diagnostic tools in Amyotrophic Lateral Sclerosis (ALS). Our objective was to assess muscle ultrasound as a diagnostic tool in patients with ALS and determine a simplified screening protocol to aid implementation in clinical practice.

METHODS: Ultrasound of bulbar and limb muscles was prospectively performed on all patients referred to a single centre with suspected ALS. Clinical measures of disease severity and upper motor neuron impairment were also recorded. Receiver operating characteristic (ROC) curves were calculated to assess the diagnostic utility of muscle ultrasound.

RESULTS: 94 patients initially suspected of ALS were recruited to this observational cohort study. Forty-four were subsequently diagnosed as ALS and 50 as disease mimics. ALS patients demonstrated a higher frequency and more generalised distribution of fasciculations compared to mimics. A simplified 5 muscle screening protocol exhibited an AUC of 0.94 (95 %CI 0.89-0.99) in discriminating ALS from mimics. The presence of ≥ 3 fasciculating muscles detected using this screening protocol was 89 % sensitive and 88 % specific for the diagnosis of ALS.

CONCLUSIONS: Muscle ultrasound, screening as few as 5 muscles, has diagnostic utility in ALS.

SIGNIFICANCE: Muscle ultrasound enhances clinical diagnosis in ALS.}, } @article {pmid39581338, year = {2025}, author = {Kokona, B and Cunningham, NR and Quinn, JM and Jacobsen, DR and Garcia, FJ and Galindo, SM and Petrucelli, L and Stafford, WF and Laue, TM and Fairman, R}, title = {Studying C9orf72 dipeptide repeat polypeptide aggregation using an analytical ultracentrifuge equipped with fluorescence detection.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115720}, pmid = {39581338}, issn = {1096-0309}, support = {P40 OD018537/OD/NIH HHS/United States ; R15 NS081681/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics ; *Caenorhabditis elegans/genetics ; *Dipeptides/chemistry ; Ultracentrifugation ; Drosophila melanogaster/genetics ; Humans ; Protein Aggregates ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Peptides/chemistry/genetics/analysis ; Fluorescence ; }, abstract = {Sedimentation velocity, using an analytical ultracentrifuge equipped with fluorescence detection, and electrophoresis methods are used to study aggregation of proteins in transgenic animal model systems. Our previous work validated the power of this approach in an analysis of mutant huntingtin aggregation. We demonstrate that this method can be applied to another neurodegenerative disease studying the aggregation of three dipeptide repeats (DPRs) produced by aberrant translation of mutant c9orf72 containing large G4C2 hexanucleotide repeats. These repeat expansions are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We analyzed the aggregation patterns of (Gly-Pro)47, (Gly-Ala)50, and (Gly-Arg)50 fused to fluorescent proteins in samples prepared from D. melanogaster, and (Gly-Ala)50 in C. elegans, using AU-FDS and SDD-AGE. Results suggest that (GP)47 is largely monomeric. In contrast, (GA)50 forms both intermediate and large-scale aggregates. (GR)50 is partially monomeric with some aggregation noted in SDD-AGE analysis. The aggregation of this DPR is likely to represent co-aggregated states with DNA and/or RNA. The power of these methods is the ability to gather data on aggregation patterns and characteristics in animal model systems, which may then be used to interpret the mitigation of aggregation through genetic or molecular therapeutic interventions.}, } @article {pmid39580968, year = {2024}, author = {Lewandowski, SA and Kular, L and Jagodic, M}, title = {Epigenetic age acceleration as a biomarker of amyotrophic lateral sclerosis severity?.}, journal = {EBioMedicine}, volume = {110}, number = {}, pages = {105470}, pmid = {39580968}, issn = {2352-3964}, } @article {pmid39580792, year = {2024}, author = {Kaplan, E and Weissbach, A and Kadmon, G and Nahum, E and Stein, J}, title = {Plasma exchange using peripheral arterial and venous access in the pediatric intensive care unit.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18075}, pmid = {39580792}, issn = {1537-2995}, abstract = {OBJECTIVE: Therapeutic plasma exchange (TPE) is a vital therapeutic modality in pediatric intensive care units (PICU) for various indications. Traditionally, pediatric TPE is performed via a large bore, double lumen catheter, whose insertion necessitates deep sedation, and poses risk of hemorrhagic and thrombotic complications. Building on our previous success utilizing percutaneous radial artery catheters (ALs) for apheresis procedures, we present our experience with ALs for TPE procedures in the PICU.

METHODS: A retrospective cohort study, conducted in the PICU of a tertiary, university affiliated pediatric hospital, including all children aged 19 years and younger, who underwent TPE using an AL for vascular access, between 2018 and 2023. TPE procedures were evaluated for utility (the procedure was performed as planned) and safety.

RESULTS: A total of 72 procedures were performed on 20 children, using ALs for inlet access and peripheral intra-venous catheters for blood return. Procedure success rate was 94%, with AL malfunction causing transient delays in 6%. All were successfully completed following AL replacement. ALs were mostly 20 and 22 gauge, predominantly located in the radial artery. AL gauge did not significantly affect flow rate or procedure duration.

CONCLUSIONS: Our findings support AL use for vascular access, as a viable alternative to the traditional large bore, double lumen catheters most often used for TPE in children. Benefits of AL use may include a decrease in sedation requirements and a lower risk of vascular complications. Further investigation is warranted, for consideration as routine practice in PICUs.}, } @article {pmid39579998, year = {2024}, author = {Baroukhian, J and Seiffert-Sinha, K and Sinha, AA}, title = {Response to Kasperkiewicz et al's "Pemphigus following herpes simplex infection: A global comprehensive cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.07.1536}, pmid = {39579998}, issn = {1097-6787}, } @article {pmid39579996, year = {2024}, author = {Watanabe, Y and Yamaguchi, Y}, title = {Regarding response to Yamaguchi et al's "Anti-SS-A antibody is a potential predictor of severe Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.11.030}, pmid = {39579996}, issn = {1097-6787}, } @article {pmid39579963, year = {2024}, author = {Carracedo, S and Launay, A and Dechelle-Marquet, PA and Faivre, E and Blum, D and Delarasse, C and Boué-Grabot, E}, title = {Purinergic-associated immune responses in neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {243}, number = {}, pages = {102693}, doi = {10.1016/j.pneurobio.2024.102693}, pmid = {39579963}, issn = {1873-5118}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; Animals ; *Receptors, Purinergic/metabolism ; }, abstract = {The chronic activation of immune cells can participate in the development of pathological conditions such as neurodegenerative diseases including Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, compelling evidence indicates that purinergic signaling plays a key role in neuro-immune cell functions. The extracellular release of adenosine 5'-triphosphate (ATP), and its breakdown products (ADP and adenosine) provide the versatile basis for complex purinergic signaling through the activation of several families of receptors. G-protein coupled adenosine A2A receptors, ionotropic P2X and G-protein coupled P2Y receptors for ATP and other nucleotides are abundant and widely distributed in neurons, microglia, and astrocytes of the central nervous system as well as in peripheral immune cells. These receptors are strongly linked to inflammation, with a functional interplay that may influence the intricate purinergic signaling involved in inflammatory responses. In the present review, we examine the roles of the purinergic receptors in neuro-immune cell functions with particular emphasis on A2AR, P2X4 and P2X7 and their possible relevance to specific neurodegenerative disorders. Understanding the molecular mechanisms governing purinergic receptor interaction will be crucial for advancing the development of effective immunotherapies targeting neurodegenerative diseases.}, } @article {pmid39579350, year = {2024}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Protocol for handling and using SOD1 mice for amyotrophic lateral sclerosis pre-clinical studies.}, journal = {STAR protocols}, volume = {5}, number = {4}, pages = {103459}, pmid = {39579350}, issn = {2666-1667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that has no proper cure. Pre-clinical studies on ALS mice are an essential milestone toward clinical trials. Here, we present a protocol for handling and using SOD1[G37R] mice for ALS pre-clinical studies. We describe steps for breeding, genotyping, monitoring, and behavioral testing of mice. We then detail procedures for perfusion, organ harvesting, and immunostaining for postmortem analysis. This protocol can be easily modified for other mouse lines. For complete details on the use and execution of this protocol, please refer to Alfahel et al.[1].}, } @article {pmid39578404, year = {2024}, author = {Phrathep, DD and Abdo, Z and Tadros, M and Lewandowski, E and Evans, J}, title = {The role of osteopathic manipulative treatment for dystonia: a literature review.}, journal = {Journal of osteopathic medicine}, volume = {}, number = {}, pages = {}, pmid = {39578404}, issn = {2702-3648}, abstract = {CONTEXT: Dystonia is a movement disorder that causes involuntary muscle contractions leading to abnormal movements and postures, such as twisting. Dystonia is the third most common movement disorder in the United States, with as many as 250,000 people affected. Because of its complexity, dystonia presents a significant challenge in terms of management and treatment. Despite limited research, osteopathic manipulative treatment (OMT) has been considered as an adjunctive treatment due to its inexpensive and noninvasive nature, as opposed to other modalities such as botulinum toxin injections, deep brain stimulation (DBS), and transcranial magnetic stimulation, which are often expensive and inaccessible. OMT treatments performed in case studies and series such as balanced ligamentous tension/articular ligamentous strain (BLT/ALS), muscle energy (ME), high-velocity low-amplitude (HVLA), and myofascial release (MFR) have shown reduction of pain and muscle hypertonicity, including in patients with dystonia.

OBJECTIVES: The studies reviewed in this paper provide a snapshot of the literature regarding the current evidence of OMT's role for dystonia.

METHODS: A medical reference librarian conducted a thorough literature search across multiple databases including PubMed and Google Scholar to find articles relevant to the use of OMT for dystonia. The search employed a combination of Medical Subject Headings (MeSH) terms and keywords related to osteopathic medicine and dystonia to ensure precise retrieval of relevant articles within the last 20 years. Despite limited research on the topic, all four relevant reports found in the literature were selected for review.

RESULTS: Of the four relevant reports, case series and studies highlighted the potential benefits of OMT in managing dystonia, particularly cervical dystonia and foot dystonia. OMT has shown promising results addressing pain, stiffness, and impaired motor function. In cases of foot dystonia in Parkinson's disease, OMT has helped improve gait and reduce pain by targeting somatic dysfunctions (SDs) associated with dystonia, such as abnormalities in foot progression angle (FPA) and musculoskeletal imbalances. Also, OMT has been found to alleviate symptoms of cervical dystonia, including tremors, muscle spasms, and neck stiffness. These interventions performed in case studies and series led to improvements in gait biomechanics in foot dystonia and overall symptom severity in patients with cervical dystonia.

CONCLUSIONS: Currently, botulinum toxin, oral medications, physical therapy, and rehabilitation are commonly utilized in managing dystonia. The studies reviewed in this paper suggest that these treatments may lead to improvements in pain and muscle hypertonicity in patients with dystonia. It is important to investigate whether factors such as the type of dystonia (eg, focal vs. segmental) and its underlying cause (eg, idiopathic, trauma, infection, autoimmune, medication side effects) influence treatment outcomes. Further research is recommended to explore the role of OMT in managing dystonia.}, } @article {pmid39578133, year = {2024}, author = {Travaglia, A and Lal, S and Pullagura, SR}, title = {Advancing ALS research: public-private partnerships to accelerate drug and biomarker development.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2024.10.008}, pmid = {39578133}, issn = {1878-108X}, abstract = {Developing effective treatments for amyotrophic lateral sclerosis (ALS) has been hindered by both the complexity of the disease and decentralized research efforts. By fostering collaboration, standardization, and inclusivity, the Accelerating Medicines Partnership® (AMP®) ALS initiative aims to lay the foundation for future discoveries in ALS biomarkers and treatments.}, } @article {pmid39577830, year = {2024}, author = {Morikawa, K and Izumiya, Y and Takashio, S and Kawano, Y and Oguni, T and Kuyama, N and Oike, F and Yamamoto, M and Tabata, N and Ishii, M and Hanatani, S and Hoshiyama, T and Kanazawa, H and Matsuzawa, Y and Usuku, H and Yamamoto, E and Ueda, M and Tsujita, K}, title = {Early experience with daratumumab-containing regimens in patients with light-chain cardiac amyloidosis.}, journal = {Journal of cardiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jjcc.2024.11.003}, pmid = {39577830}, issn = {1876-4738}, abstract = {BACKGROUND: Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. Treatment with daratumumab, an anti-human CD38 monoclonal antibody, led to higher frequencies of complete hematologic response and better clinical outcomes compared with conventional treatment. This study sought to evaluate the survival benefit of daratumumab-containing regimens in patients with AL cardiac amyloidosis.

METHODS AND RESULTS: We examined 65 consecutive patients with AL cardiac amyloidosis (mean age: 67.2 ± 10.4 years, male: 69 %) who underwent chemotherapy. We divided patients into a daratumumab group, which used daratumumab-containing regimens before second-line treatment (n = 32), and a conventional treatment group (n = 33). Compared with the conventional treatment group, the daratumumab group tended to be older, but there were no significant differences between groups in biomarkers and echocardiographic parameters. A total of 26 patients (40 %) died (median follow-up duration: 395 days). Kaplan-Meier survival analysis showed that the daratumumab group had significantly lower mortality compared with the conventional treatment group (p = 0.04; log-rank test). Cox hazard analysis revealed that use of daratumumab-containing regimens was associated with lower mortality after adjustment for the revised Mayo staging of AL amyloidosis (hazard ratio: 0.32; 95 % confidence interval: 0.12 to 0.85; p = 0.02).

CONCLUSION: Daratumumab-containing regimens may be associated with improved survival in patients with AL cardiac amyloidosis.}, } @article {pmid39577774, year = {2025}, author = {Olesen, MA and Villavicencio-Tejo, F and Cuevas-Espinoza, V and Quintanilla, RA}, title = {Unknown roles of tau pathology in neurological disorders. Challenges and new perspectives.}, journal = {Ageing research reviews}, volume = {103}, number = {}, pages = {102594}, doi = {10.1016/j.arr.2024.102594}, pmid = {39577774}, issn = {1872-9649}, mesh = {Humans ; *tau Proteins/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Tauopathies/metabolism/pathology ; Aging/metabolism/pathology ; }, abstract = {Aging presents progressive changes that increase the susceptibility of the central nervous system (CNS) to suffer neurological disorders (NDs). Several studies have reported that an aged brain suffering from NDs shows the presence of pathological forms of tau protein, a microtubule accessory protein (MAP) critical for neuronal function. In this context, accumulative evidence has shown a pivotal contribution of pathological forms of tau to Alzheimer's disease (AD) and tauopathies. However, current investigations have implicated tau toxicity in other NDs that affect the central nervous system (CNS), including Parkinson's disease (PD), Huntington's disease (HD), Traumatic brain injury (TBI), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). These diseases are long-term acquired, affecting essential functions such as motor movement, cognition, hearing, and vision. Previous evidence indicated that toxic forms of tau do not have a critical contribution to the genesis or progression of these diseases. However, recent studies have shown that these tau forms contribute to neuronal dysfunction, inflammation, oxidative damage, and mitochondrial impairment events that contribute to the pathogenesis of these NDs. Recent studies have suggested that these neuropathologies could be associated with a prion-like behavior of tau, which induces a pathological dissemination of these toxic protein forms to different brain areas. Moreover, it has been suggested that this toxic propagation of tau from neurons into neighboring cells impairs the function of glial cells, oligodendrocytes, and endothelial cells by affecting metabolic function and mitochondrial health and inducing oxidative damage by tau pathology. Therefore, in this review, we will discuss current evidence demonstrating the critical role of toxic tau forms on NDs not related to AD and how its propagation and induced-bioenergetics failure may contribute to the pathogenic mechanism present in these NDs.}, } @article {pmid39577687, year = {2025}, author = {Li, Z and Zhang, Y and Li, D and Du, X and Chen, L and Guo, Y}, title = {Microglial upregulation of CD109 expression in spinal cord of amyotrophic lateral sclerosis mouse model and its role in modulating inflammation and TGFβ/SMAD pathway.}, journal = {Neuroscience}, volume = {564}, number = {}, pages = {202-213}, doi = {10.1016/j.neuroscience.2024.11.053}, pmid = {39577687}, issn = {1873-7544}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Microglia/metabolism ; *Spinal Cord/metabolism/pathology ; *Up-Regulation ; Mice ; *Smad Proteins/metabolism ; *Signal Transduction/physiology ; *Disease Models, Animal ; *Antigens, CD/metabolism ; *Transforming Growth Factor beta/metabolism ; Mice, Transgenic ; Inflammation/metabolism ; Lipopolysaccharides/pharmacology ; Transforming Growth Factor beta1/metabolism ; }, abstract = {CD109 is a multifunctional coreceptor, whose function has been widely studied in tumor progression and metastasis. One of the reported primary roles of CD109 involves down-regulating TGFβ signaling. However, the role of CD109 in central nervous system, especially neurodegenerative disease, is barely known. Here, we examined the expression changes and cellular location of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice, and explored the role and mechanism of CD109 on LPS-treated BV2 microglia and primary microglia derived from SOD1-G93A mice. Our results showed an increased expression of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice. Further cellular localization analysis demonstrated that proliferating microglia contributed mainly to the upregulation of CD109 and TGFβ1. Moreover, CD109 intervention in vitro partially reduced inflammatory response and TGFβ/SMAD pathway activation in both LPS-treated BV2 microglia and primary SOD1-G93A microglia. Thus, CD109 was involved in pathogenesis of ALS mice, and interventions targeting on CD109 modulation could be a potential therapeutic strategy for ALS.}, } @article {pmid39577621, year = {2024}, author = {Reiche, L and Plaack, B and Lehmkuhl, M and Weyers, V and Gruchot, J and Picard, D and Perron, H and Remke, M and Knobbe-Thomsen, C and Reifenberger, G and Küry, P and Kremer, D}, title = {HERV-W envelope protein is present in microglial cells of the human glioma tumor microenvironment and differentially modulates neoplastic cell behavior.}, journal = {Microbes and infection}, volume = {}, number = {}, pages = {105460}, doi = {10.1016/j.micinf.2024.105460}, pmid = {39577621}, issn = {1769-714X}, abstract = {Gliomas are the most common parenchymal tumors of the central nervous system (CNS). With regard to their still unclear etiology, several recent studies have provided evidence of a new category of pathogenic elements called human endogenous retroviruses (HERVs) which seem to contribute to the evolution and progression of many neurological diseases such as amyotrophic lateral sclerosis (ALS), schizophrenia, chronic inflammatory polyneuropathy (CIDP) and, particularly, multiple sclerosis (MS). In these diseases, HERVs exert effects on cellular processes such as inflammation, proliferation, and migration. In previous studies, we demonstrated that in MS, the human endogenous retrovirus type-W envelope protein (HERV-W ENV) interferes with lesion repair through the activation of microglia (MG), the innate myeloid immune cells of the CNS. Here, we now show that HERV-W ENV is also present in the microglial cells (MG) of the tumor microenvironment (TME) in gliomas. It modulates the behavior of glioblastoma (GBM) cell lines in GBM/MG cocultures by altering their gene expression, secreted cytokines, morphology, proliferation, and migration properties and could thereby contribute to key tumor properties.}, } @article {pmid39577228, year = {2025}, author = {Sojdeh, S and Safarkhani, M and Daneshgar, H and Aldhaher, A and Heidari, G and Nazarzadeh Zare, E and Iravani, S and Zarrabi, A and Rabiee, N}, title = {Promising breakthroughs in amyotrophic lateral sclerosis treatment through nanotechnology's unexplored frontier.}, journal = {European journal of medicinal chemistry}, volume = {282}, number = {}, pages = {117080}, doi = {10.1016/j.ejmech.2024.117080}, pmid = {39577228}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Nanotechnology ; Genetic Therapy ; Animals ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {This review explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author's prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.}, } @article {pmid39577115, year = {2024}, author = {Abdian, S and Fakhri, S and Moradi, SZ and Khirehgesh, MR and Echeverría, J}, title = {Saffron and its major constituents against neurodegenerative diseases: A mechanistic review.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {135}, number = {}, pages = {156097}, doi = {10.1016/j.phymed.2024.156097}, pmid = {39577115}, issn = {1618-095X}, mesh = {Animals ; Humans ; *Carotenoids/pharmacology/therapeutic use ; *Crocus/chemistry ; Cyclohexenes/pharmacology ; Glucosides/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/chemistry/pharmacology ; Phytochemicals/pharmacology ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Terpenes/pharmacology ; Vitamin A/analogs & derivatives ; }, abstract = {BACKGROUND: Neurodegeneration has been recognized as the main pathophysiological alteration in the majority of brain-related diseases. Despite contemporary attempts to provide acceptable medicinal therapies, the conclusion has not been much beneficial. Besides, the complex pathophysiological mechanisms behind neurodegenerative diseases (NDDs) urge the needs for finding novel multi-target agents. Accordingly, saffron with major active constituents and as multi-targeting agents have shown beneficial effects in modulating NDDs with higher efficacy and lower side effects.

PURPOSE: The present study provides a systematic and comprehensive review of the existing in vitro, in vivo, and clinical data on the effectiveness, and signaling pathways of saffron and its key phytochemical components in the management of NDDs. The need to develop novel saffron delivery systems is also considered.

METHODS: Studies were identified through a systematic and comprehensive search in Science Direct, PubMed, and Scopus databases through April 30, 2024. The whole saffron major constituents (e.g., saffron, crocin, crocetin, picrocrocin, and safranal) and NDDs (e.g., neuro*, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington*, Parkinson*, Alzheimer*, and brain) were selected as keywords to find related studies. In the systematic analysis, 64 articles were directly included in the current study. Additional reports were added within the comprehensive studies in the review.

RESULTS: Saffron and its active metabolites crocin, crocetin, safranal, and picrocrocin have shown acceptable efficacy in managing NDDs like Alzheimer's disease, Parkinson's disease, Attention deficit hyperactivity disorder, depression, and other NDDs via modulating apoptotic (e.g., caspases, Bax/Bcl-2, cytochrome c, and death receptors), inflammatory (e.g., NF-κB, IL-1β, IL-6, TNF-α, and COX-2), and oxidative strass (e.g., Nrf2, GSH, GPx, CAT, SOD, MDA, ROS, and nitrite) signaling pathways. The presented in vitro, in vivo, and clinical evidences showed us a better future of controlling NDDs with higher efficacy, while decreasing associated side effects with no significant toxicity. Additionally, employing novel delivery systems could increase the efficacy of saffron phytoconstituents to resolve the issues pharmacokinetic limitations.

CONCLUSION: Saffron and its major constituents employ anti-inflammatory, anti-apoptotic and antioxidant mechanisms in modulating several dysregulated-signaling pathways in NDDs. However, further research is necessary to elucidate the precise underlying mechanisms in exploring the feasibility of using saffron active compounds against NDDs. More studies should focus on dose-response relationships, long-term effects, highlighting key mechanisms, and designing more well-controlled clinical trials. Additionally, developing stable and cost-benefit novel delivery systems in future works helps to remove the pharmacokinetic limitations of saffron major constituents.}, } @article {pmid39575748, year = {2024}, author = {Xu, Z and He, S and Begum, MM and Han, X}, title = {Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {16-18}, pages = {1073-1099}, doi = {10.1089/ars.2024.0676}, pmid = {39575748}, issn = {1557-7716}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Myelin Sheath/metabolism ; *Lipid Metabolism ; Animals ; Lipids ; }, abstract = {Significance: Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. Recent Advances: With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. Critical Issues: This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. Future Directions: By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. Antioxid. Redox Signal. 00, 000-000.}, } @article {pmid39575564, year = {2024}, author = {Olofsson, J and Bergström, S and Mravinacová, S and Kläppe, U and Öijerstedt, L and Zetterberg, H and Blennow, K and Ingre, C and Nilsson, P and Månberg, A}, title = {Cerebrospinal fluid levels of NfM in relation to NfL and pNfH as prognostic markers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2024.2428930}, pmid = {39575564}, issn = {2167-9223}, abstract = {Objective: To evaluate the prognostic potential of neurofilament medium chain (NfM) in CSF from patients with ALS and explore its relationship with the extensively studied neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH). Method: CSF levels of NfL, NfM, and pNfH were analyzed in 235 samples from patients with ALS, ALS mimics, and healthy controls in a well-characterized cohort from Karolinska ALS Clinical Research Center in Stockholm, Sweden. NfM levels were analyzed using an antibody-based suspension bead-array and NfL and pNfH levels were measured using ELISA. Clinical data, including ALS Revised Functional Rating Scale (ALSFRS-R), and survival outcomes were utilized for disease progression estimations. Result: Increased NfM levels were observed in patients with ALS compared with mimics and healthy controls. Similarly, higher NfM levels were found in fast compared with slow progressing patients for baseline and longitudinal progression when evaluating both total and subscores of ALSFRS-R. These findings were consistent with the results observed for NfL and pNfH. All three proteins, used individually as well as in combination, showed comparable performance when classifying fast vs slow progressing patients (AUCs 0.78-0.85). For all neurofilaments, higher survival probability was observed for patients with low CSF levels. Conclusion: Based on this cross-sectional study, the prognostic value provided by NfM aligns with the more established markers, NfL and pNfH. Additional investigations with independent cohorts and longitudinal studies are needed to further assess the potential added value of NfM.}, } @article {pmid39574866, year = {2024}, author = {Manohar, R and Yang, FX and Stephen, CD and Schmahmann, JD and Eklund, NM and Gupta, AS}, title = {At-home wearables and machine learning capture motor impairment and progression in adult ataxias.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574866}, support = {R01 NS117826/NS/NINDS NIH HHS/United States ; R01 NS134597/NS/NINDS NIH HHS/United States ; }, abstract = {A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behavior. Here we test whether movement-building block characteristics (i.e., submovements), obtained from the wrist and ankle during natural behavior at home, can sensitively capture disease progression in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis (ALS) and ataxia telangiectasia (A-T). Remotely collected cross-sectional (n = 76) and longitudinal data (n = 27) were analyzed from individuals with ataxia (SCAs 1, 2, 3, and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal ALS data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, strongly separated ataxia and control populations, and had high within-week reliability. The composite outcomes trained on longitudinal ALS data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can accurately capture the ataxia phenotype and sensitively measure disease progression. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.}, } @article {pmid39574800, year = {2024}, author = {Bouajila, N and Domenighetti, C and Aubin, HJ and Naassila, M}, title = {Alcohol consumption and its association with cancer, cardiovascular, liver and brain diseases: a systematic review of Mendelian randomization studies.}, journal = {Frontiers in epidemiology}, volume = {4}, number = {}, pages = {1385064}, pmid = {39574800}, issn = {2674-1199}, abstract = {BACKGROUND: The health effects of alcohol consumption, particularly regarding potential protective benefits of light to moderate intake compared to abstinence, remain a subject of ongoing debate. However, epidemiological studies face limitations due to imprecise exposure measurements and the potential for bias through residual confounding and reverse causation. To address these limitations, we conducted a systematic review of Mendelian Randomization (MR) studies examining the causal relationship between alcohol consumption and cancers, cardiovascular, liver, and neurological diseases.

METHODOLOGY: We searched PubMed, ScienceDirect and Embase and Europe PMC up to 05/2024 for MR studies investigating the association of genetically predicted alcohol consumption with cancers, cardiovascular, liver and neurological diseases. We assessed methodological quality based on key elements of the MR design a genetic association studies tool.

RESULTS: We included 70 MR studies that matched our inclusion criteria. Our review showed a significant association of alcohol consumption with multiple cancers such as oral and oropharyngeal, esophageal, colorectal cancers, hepatocellular carcinoma and cutaneous melanoma. While the available studies did not consistently confirm the adverse or protective effects of alcohol on other cancers, such as lung cancer, as suggested by observational studies. Additionally, MR studies confirmed a likely causal effect of alcohol on the risk of hypertension, atrial fibrillation, myocardial infraction and vessels disease. However, there was no evidence to support the protective effects of light to moderate alcohol consumption on cognitive function, Alzheimer's disease, and amyotrophic lateral sclerosis, as reported in observational studies while our review revealed an increased risk of epilepsy and multiple sclerosis. The available studies provided limited results on the link between alcohol consumption and liver disease.

CONCLUSIONS: Despite the valuable insights into the causal relationship between alcohol consumption and various health outcomes that MR studies provided, it is worth noting that the inconsistent ability of genetic instrumental variables to distinguish between abstainers, light and moderate drinkers makes it difficult to differentiate between U or J-shaped vs. linear relationships between exposure and outcome. Additional research is necessary to establish formal quality assessment tools for MR studies and to conduct more studies in diverse populations, including non-European ancestries.

www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021246154, Identifier: PROSPERO (CRD42021246154).}, } @article {pmid39574607, year = {2024}, author = {Fürtjes, AE and Foote, IF and Xia, C and Davies, G and Moodie, J and Taylor, A and Liewald, DC and Redmond, P and Corley, J and McIntosh, AM and Whalley, HC and Maniega, SM and Hernández, MV and Backhouse, E and Ferguson, K and Bastin, ME and Wardlaw, J and de la Fuente, J and Grotzinger, AD and Luciano, M and Hill, WD and Deary, IJ and Tucker-Drob, EM and Cox, SR}, title = {Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574607}, issn = {2692-8205}, support = {P2C HD042849/HD/NICHD NIH HHS/United States ; R01 AG073593/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 MH120219/MH/NIMH NIH HHS/United States ; P30 AG066614/AG/NIA NIH HHS/United States ; U54 MH091657/MH/NIMH NIH HHS/United States ; }, abstract = {A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference (ICV-TBV), ratio (TBV/ICV), and regression-residual method (TBV~ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales (r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline (r = 0.36), frailty (r = 0.24), age-moderated brain shrinkage (r = 0.45), and longitudinally-measured atrophic changes (r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV (rg = 0.75). We performed the largest genetic study of LBA to date (N = 43,110), which was highly heritable (h [2] SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h [2] = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16, a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.}, } @article {pmid39574440, year = {2024}, author = {Kaur, N and Verma, AK and Girdhar, M and Kumar, A and Siddiqui, MA and Al-Khedhairy, AA and Malik, T and Mohan, A}, title = {Genome-wide analysis of the Cannabis sativa cytochrome P450 monooxygenase superfamily and uncovering candidate genes for improved herbicide tolerance.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1490036}, pmid = {39574440}, issn = {1664-462X}, abstract = {Cannabis sativa is an economically important crop, yet weed management remains a significant challenge due to limited herbicide options. Cytochrome P450 enzymes play crucial roles in plant metabolism, including herbicide detoxification. This study aimed to identify and characterize the CYP gene family in Cannabis and investigate their potential role in herbicide metabolism. We identified 225 CYP proteins encoded by 221 genes in the Cannabis genome, classified into 9 clans and 47 families. The majority of CsCYPs were predicted to be located in endomembrane system and chromosomal mapping revealed that they were present in all the chromosomes. Motif and gene structure analysis supported the results from phylogenetic analysis. The gene duplication analysis results showed that tandem duplication plays a pivotal role in evolutionary expansion of CsCYP superfamily. Promoter analysis revealed various cis-acting elements involved in stress, light, hormone and development responses. Molecular docking simulations identified several CsCYPs with strong binding affinities to ALS-inhibiting herbicides, particularly bispyribac-sodium, propoxycarbazone-sodium, and pyriftalid. CsCYP_215, CsCYP_213, CsCYP_217 and CsCYP_14 emerged as promising candidates for herbicide metabolism. Analysis of binding site residues revealed the importance of hydrophobic and aromatic interactions in herbicide binding. This study provides the first comprehensive characterization of the CYP gene family in C. sativa and offers new insights into their potential roles in herbicide metabolism. The identification of promising herbicide-metabolizing CYP candidates opens new avenues for developing herbicide-tolerant Cannabis varieties, potentially addressing key challenges in weed management and crop productivity.}, } @article {pmid39572918, year = {2024}, author = {Changkakoti, L and Rajabalaya, R and David, SR and Balaraman, AK and Sivasubramanian, H and Mukherjee, AK and Bala, A}, title = {Exploration of the Role of Vitamins in Preventing Neurodegenerative Diseases: Comprehensive Review on Preclinical and Clinical Findings.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X327677240902105443}, pmid = {39572918}, issn = {1875-6190}, abstract = {Neurodegenerative diseases (NDDs) are a multifaceted and heterogeneous group of complex diseases. Unfortunately, a cure for these conditions has yet to be found, but there are ways to reduce the risk of developing them. Studies have shown that specific vitamins regulate the brain molecules and signaling pathways, which may help prevent degeneration. This review focuses on examining the role of vitamins in preventing five significant types of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). This review also highlights promising and controversial findings about the potential impact of vitamins on this group of diseases. Several developed countries standardize daily dietary vitamin intake to meet nutrient requirements, improve health, and prevent chronic diseases like NDDs. However, more research is necessary to gain a more comprehensive understanding of their therapeutic benefits, including studies exploring different drug-dose paradigms, diverse humanized animal models, and clinical trials conducted in various locations.}, } @article {pmid39572390, year = {2024}, author = {Morales, JMN and Alcaraz, MR and Loto, A and Parellada, EA and Tulli, F and Morán Vieyra, FE and Borsarelli, CD}, title = {Chemometric modeling of spectroscopic data for characterizing the visible-light-driven photocatalytic N-dealkylation of rhodamine B on a TiO2 film.}, journal = {Photochemistry and photobiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/php.14043}, pmid = {39572390}, issn = {1751-1097}, support = {PIP-2020-101043CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PUE-2018-035//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; PICT-2019-02052//Fondo para la Investigación Científica y Tecnológica/ ; 23A/254//Universidad Nacional de Santiago del Estero/ ; }, abstract = {The green-light driven photocatalytic N-deethylation reaction of Rhodamine B (RhB) on a TiO2 film was investigated by UV-vis absorption and fluorescence emission spectroscopies, in addition to HPLC and HR-MS, to ascertain the nature of the reaction products. The evolution of the photocatalytic reaction was chemometrically analyzed using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) of the spectroscopic data to obtain the kinetic and spectral decomposition of the RhB derivatives involved in the reaction. This was then compared with the results obtained by standard HPLC analysis. The MCR-ALS analysis yielded satisfactory spectral and kinetic profiles for RhB and the fully deethylated product, Rhodamine 110. However, the spectral profiles for the N-triethyl (3EtRh) and the mixture of the two isomeric N-diethyl (2EtRh) derivatives exhibited some spectral distortions due to significant spectral overlap between these compounds. In contrast to the HPLC analysis, the MCR-ALS could not resolve the N-ethylrhodamine (EtRh) derivative. The deethylation reactions occurred via independent zero-order steps at the surface of TiO2, indicating that the RhB degradation reaction is governed by the adsorption-desorption equilibrium of the dye and derivatives on the photocatalyst surface, thereby enhancing the diffusion of compounds on the surface.}, } @article {pmid39572211, year = {2024}, author = {Benatar, M and Heiman-Patterson, TD and Cooper-Knock, J and Brickman, D and Casaletto, KB and Goutman, SA and Vinceti, M and Dratch, L and Arias, JJ and Swidler, J and Turner, MR and Shefner, J and Westeneng, HJ and van den Berg, LH and Al-Chalabi, A and , and , }, title = {Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS/FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334339}, pmid = {39572211}, issn = {1468-330X}, abstract = {There is a growing understanding of the presymptomatic stages of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and nascent efforts aiming to prevent these devastating neurodegenerative diseases have emerged. This progress is attributable, in no small part, to the altruism of people living with pathogenic variants at elevated genetic risk for ALS/FTD via their willingness to participate in natural history studies and disease prevention trials. Increasingly, this community has also highlighted the urgent need to develop paradigms for providing appropriate clinical care for those at elevated risk for ALS and FTD. This manuscript summarises recommendations emanating from a multi-stakeholder Workshop (Malvern, Pennsylvania, 2023) that aimed to develop guidance for at-risk carriers and their treating physicians. Clinical care recommendations span genetic testing (including counselling and sociolegal implications); monitoring for the emergence of early motor, cognitive and behavioural signs of disease; and the use of Food and Drug Administration-approved small molecule drugs and gene-targeting therapies. Lifestyle recommendations focus on exercise, smoking, statin use, supplement use, caffeine intake and head trauma, as well as occupational and environmental exposures. While the evidence base to inform clinical and lifestyle recommendations is limited, this guidance document aims to appraise carriers and clinicians of the issues and best available evidence, and also to define the research agenda that could yield more evidence-informed guidelines.}, } @article {pmid39572209, year = {2024}, author = {Grassano, M}, title = {Navigating the presymptomatic frontier in genetic ALS and FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334924}, pmid = {39572209}, issn = {1468-330X}, } @article {pmid39571437, year = {2025}, author = {Parastar, H and Yazdanpanah, H and Weller, P}, title = {Non-targeted volatilomics for the authentication of saffron by gas chromatography-ion mobility spectrometry and multivariate curve resolution.}, journal = {Food chemistry}, volume = {465}, number = {Pt 2}, pages = {142074}, doi = {10.1016/j.foodchem.2024.142074}, pmid = {39571437}, issn = {1873-7072}, mesh = {*Crocus/chemistry ; *Ion Mobility Spectrometry/methods ; Food Contamination/analysis ; Gas Chromatography-Mass Spectrometry ; Volatile Organic Compounds/chemistry/analysis ; Discriminant Analysis ; Multivariate Analysis ; Principal Component Analysis ; Least-Squares Analysis ; Iran ; }, abstract = {In the present contribution, a novel non-targeted volatilomic study based on headspace GC-IMS (HS-GC-IMS) was developed for the authentication and geographical origin discrimination of saffron. In this regard, multivariate curve resolution-alternating least squares (MCR-ALS) was employed to recover the pure GC elution and IMS profiles of saffron metabolites. Iranian saffron samples from seven important areas were analyzed by HS-GC-IMS. The resulting second-order GC-IMS datasets were organized in a augmented matrix and processed using MCR-ALS with various constraints. The MCR-ALS resolved GC profiles were analyzed by different pattern recognition techniques; principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and data driven-soft independent modeling of class analogy (DD-SIMCA). The saffron samples were assigned to their seven geographical origins with an accuracy of 89.0 %. Additionally, four adulterants (style, safflower, madder and calendula) were reliably detected with over 94.0 % accuracy. In this context, GC-IMS substantially outperformed the commonly used FT-NIR spectroscopy approach.}, } @article {pmid39571211, year = {2025}, author = {Wang, Z and Wu, P and Zhao, Y and Li, X and Kong, D}, title = {Application of excitation-emission matrix fluorescence spectroscopy and chemometrics for quantitative analysis of emulsified oil concentration.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {328}, number = {}, pages = {125423}, doi = {10.1016/j.saa.2024.125423}, pmid = {39571211}, issn = {1873-3557}, abstract = {Emulsified oil concentration is an important index for quantitative analysis of sea surface oil spill pollution, and the development of a fast and effective quantitative analysis method for emulsified oil concentration plays a crucial role in the estimation of oil spill volume and post-spill assessment. A quantitative analysis method for emulsified oil concentration based on excitation-emission matrix (EEM) fluorescence spectroscopy and chemometrics was proposed. Firstly, the EEM fluorescence spectra of two emulsified oils were measured using a FLS1000 fluorescence spectrometer. Then, the measured EEM fluorescence spectra were decomposed by parallel factor analysis (PARAFAC), and several key excitation wavelengths were filtered from the loading matrix obtained from the decomposition. Subsequently, the three-band fluorescence index (TBFI) at these excitation wavelengths was calculated and combined with the optimal band selection algorithm, from which the optimal emission band combinations were selected. Finally, the selected optimal emission bands were combined with partial least squares regression (PLSR) to establish a prediction model for emulsified oil concentration. By comparing the prediction results with those based on PARAFAC-PLSR and multivariate curve resolved-alternating least squares (MCR-ALS)-PLSR models, the TBFI-PLSR model showed the best results in the quantitative analysis of emulsified oil concentration. The coefficient of determination, mean square relative error, and ratio of performance to interquartile distance for the gasoline and diesel fuel emulsion validation sets were 0.93, 3.67%, 4.72, and 0.93, 3.72%, 4.60, respectively.}, } @article {pmid39570667, year = {2024}, author = {Burks, CA and Brenner, MJ}, title = {Commentary on Von Sneidern et al's "Evaluation and Treatment of Acute Facial Palsy: Opportunities for Optimization at a Single Institution."-Bridging the Gap Between Guidelines and Practice.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/fpsam.2024.0263}, pmid = {39570667}, issn = {2689-3622}, } @article {pmid39570437, year = {2024}, author = {Maity, D and Kaundal, RK}, title = {Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39570437}, issn = {1590-3478}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor neuron degeneration, leading to muscle weakness and paralysis, with no effective treatments available. Early diagnosis could slow disease progression and optimize treatment. MicroRNAs (miRNAs) are being investigated as potential biomarkers due to their regulatory roles in cellular processes and stability in biofluids. However, variability across studies complicates their diagnostic utility in ALS. This study aims to identify significantly dysregulated miRNAs in ALS through meta-analysis to elucidate disease mechanisms and improve diagnostic strategies.

METHODS: We systematically searched PubMed, Google Scholar, and the Cochrane Library, following predefined inclusion and exclusion criteria. The primary effect measure was the standardized mean difference (SMD) with a 95% confidence interval, analyzed using a random-effects model. Additionally, we used network pharmacology to examine the targets of dysregulated miRNAs and their roles in ALS pathology.

RESULTS: Analysing 34 studies, we found significant upregulation of hsa-miR-206, hsa-miR-133b, hsa-miR-23a, and hsa-miR-338-3p, and significant downregulation of hsa-miR-218, hsa-miR-21-5p, and hsa-let-7b-5p in ALS patients. These miRNAs are involved in ALS pathophysiology, including stress granule formation, nuclear pore complex, SMCR8 and Sig1R dysfunction, histone methyltransferase complex alterations, and MAPK signaling perturbation, highlighting their critical role in ALS progression.

CONCLUSION: This study identifies several dysregulated miRNAs in ALS patients, offering insights into their role in the disease and potential as diagnostic biomarkers. These findings enhance our understanding of ALS mechanisms and may inform future diagnostic strategies. Validating these results and exploring miRNA-based interventions are crucial for improving ALS diagnosis and treatment outcomes.}, } @article {pmid39569894, year = {2024}, author = {Brannigan, JFM and Liyanage, K and Horsfall, HL and Bashford, L and Muirhead, W and Fry, A}, title = {Brain-computer interfaces patient preferences: a systematic review.}, journal = {Journal of neural engineering}, volume = {21}, number = {6}, pages = {}, doi = {10.1088/1741-2552/ad94a6}, pmid = {39569894}, issn = {1741-2552}, mesh = {*Brain-Computer Interfaces ; Humans ; *Patient Preference ; Adult ; Middle Aged ; Spinal Cord Injuries/rehabilitation/psychology/physiopathology ; Amyotrophic Lateral Sclerosis/psychology/rehabilitation/physiopathology ; }, abstract = {Objective. Brain-computer interfaces (BCIs) have the potential to restore motor capabilities and functional independence in individuals with motor impairments. Despite accelerating advances in the performance of implanted devices, few studies have identified patient preferences underlying device design, and each study typically captures a single aetiology of motor impairment. We aimed to characterise BCI patient preferences in a large cohort across multiple aetiologies.Approach. We performed a systematic review of all published studies reporting patient preferences for BCI devices, including both qualitative and quantitative data. We searched MEDLINE, Embase, and CINAHL from inception to 18 April 2023. Two reviewers independently screened articles and extracted data on demographic information, device use, invasiveness preference, device design, and functional preferences.Main results. From 1316 articles identified, 28 studies met inclusion criteria, capturing preferences from 1701 patients (mean age 42.1-64.3 years). The most represented conditions were amyotrophic lateral sclerosis (n= 15 studies, 53.6%) and spinal cord injury (n= 13 studies 46.4%). Individuals with motor impairments prioritised device accuracy over other design characteristics. In four studies where patients ranked performance characteristics, accuracy was ranked first each time. We found that the speed and accuracy of BCI systems in recent publications exceeds reported patient preferences, however this performance has been achieved with a level of training and setup burden that would not be tolerated by most patients. Preferences varied by disease aetiology and severity; amyotrophic lateral sclerosis patients typically prioritised communication functions, whereas spinal cord injury patients emphasised limb control and sphincteric functions.Significance.Our findings highlight that despite advances in BCI performance exceeding patient expectations, there remains a need to reduce training and setup burdens to enhance usability. Moreover, patient preferences differ across conditions and impairment severities, underscoring the importance of personalised BCI configurations and tailored training regimens to meet individual needs.}, } @article {pmid39569650, year = {2024}, author = {Luo, S and Wang, X and Ma, B and Liu, D and Li, L and Wang, L and Ding, N and Zou, L and Wang, J and Pan, J and Sang, D and Zhou, H and Qu, H and Lu, Y and Yang, L}, title = {Therapeutic potential of Simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation.}, journal = {Biomolecules & biomedicine}, volume = {}, number = {}, pages = {}, doi = {10.17305/bb.2024.11218}, pmid = {39569650}, issn = {2831-090X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type (WT) mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using H&E staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.}, } @article {pmid39569145, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and Mckeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, ŁJ and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.26.620312}, pmid = {39569145}, issn = {2692-8205}, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72 Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72 Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show C9orf72 Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb of C9orf72 as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72 Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72 Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72 Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72 Exp mice, implicating C9orf72 Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, } @article {pmid39568840, year = {2024}, author = {Souayah, N and Chong, ZZ and Patel, T and Nasar, A and Pahwa, A and W Sander, H}, title = {Regression equation analysis enhances detection of conduction slowing beyond axonal loss in diabetic neuropathy.}, journal = {Heliyon}, volume = {10}, number = {21}, pages = {e39712}, pmid = {39568840}, issn = {2405-8440}, abstract = {OBJECTIVES: To evaluate the utility of regression analysis in the assessment of conduction slowing in diabetic distal symmetrical polyneuropathy (DSP) and in identifying superimposed demyelination beyond fiber loss.

BACKGROUND: Causes of conduction slowing beyond pure axonal loss has been attributed to an additional demyelinating component. We therefore evaluated the utility of regression analysis in the assessment of conduction slowing in diabetic DSP and in identifying superimposed demyelination beyond fiber loss.

METHODS: We previously established regression analysis to develop confidence intervals that assess the range of conduction slowing from primary demyelination in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). In this study, by using the regression equations, we analyzed conduction slowing in patients with diabetic DSP.

RESULTS: Mean conduction velocity (CV) was significantly slower in diabetic DSP than in the non-diabetic DSP for all tested nerves. More patients were found to fulfill the regression equation criteria in the diabetic group compared to the non-diabetic group (47.0 % vs. 23.3 %). The estimated likelihood of having more than two motor nerves with CV slowing in the demyelination range by American Academy of Neurology or regression equations criteria was significantly higher in the diabetic DSP (0.73) compared to non-diabetic DSP (0.52).

CONCLUSIONS: Conduction slowing in diabetic DSP beyond what is expected exclusively from axonal loss could be identified by regression analysis.}, } @article {pmid39568376, year = {2024}, author = {Held-Bradford, EC and Sells, M and Longhurst, JK and Doherty, M}, title = {Variation in amyotrophic lateral sclerosis presentation and outcomes based on phenotype and physical therapy movement system diagnosis: a case series.}, journal = {Physiotherapy theory and practice}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/09593985.2024.2430745}, pmid = {39568376}, issn = {1532-5040}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease and presentation varies. There is limited description of this variability and how physical therapy (PT) specific movement system diagnoses (MSD) may impact care.

PURPOSE: The purpose of this case series is to describe the variability of ALS presentation longitudinally across early, middle, and late stages of ALS based on phenotype and MSD.

METHODS: Four individuals were selected from an ALS clinic chart review representing a unique combination of phenotypes and MSDs (Case 1: bulbar onset force production deficit (FPD), Case 2: bulbar onset fractionated movement deficit (FMD), Case 3: limb onset FPD, Case 4: limb onset FMD). Descriptions of care over 9 years included outcomes of disability (ALS Functional Rating scale-revised), activity (10 Meter Walk Test, Five Times Sit to Stand Test, Trunk Impairment Scale-version 2), and impairment (strength and spasticity).

RESULTS: Persons with ALS were seen every 3 to 6 months (10 to 19 visits total). Determination of MSD was hardest to complete in early stage bulbar onset ALS. Patterns of decline through stages varied by MSD and phenotype, most notably in length of time in middle stage. Limb onset FMD had the slowest progression. Falls and fall related injuries were most frequent in limb onset ALS but falls occurred in all cases.

CONCLUSION: The combination of MSD and phenotype enhanced variability description offers new insights into clinical decision-making in ALS care.}, } @article {pmid39568060, year = {2024}, author = {Abbas, AEF and Abdelshafi, NA and Gamal, M and Halim, MK and Said, BAM and Naguib, IA and Mansour, MMA and Morshedy, S and Salem, YA}, title = {Simultaneously quantifying a novel five-component anti- migraine formulation containing ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine using UV spectrophotometry and chemometric models.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {233}, pmid = {39568060}, issn = {2661-801X}, support = {TU-DSPP-2024-49//Taif University/ ; }, abstract = {This study presents a new method for simultaneously quantifying a complex anti-migraine formulation containing five components (ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine) using UV spectrophotometry and chemometric models. The formulation presents analytical challenges due to the wide variation in component concentrations (ERG: PRO: CAF: CAM: MEC ratio of 0.075:20:8:5:4) and highly overlapping UV spectra. To create a comprehensive validation dataset, the Kennard-Stone Clustering Algorithm was used to address the limitations of arbitrary data partitioning in chemometric methods. Three different chemometric models were evaluated: Classical Least Squares (CLS), Partial Least Squares (PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Among these, MCR-ALS demonstrated excellent performance, achieving recovery values of 98-102% for all components, accompanied by minimal root mean square errors of calibration (0.072-0.378) and prediction (0.077-0.404). Moreover, the model exhibited high accuracy, with relative errors ranging from 1.936 to 3.121%, bias-corrected mean square errors between 0.074 and 0.389, and a good sensitivity (0.2097-1.2898 μg mL[-1]) for all components. The Elliptical Joint Confidence Region analysis further confirmed the predictive performance of the models, with MCR-ALS consistently showing the smallest ellipses closest to the ideal point (slope = 1, intercept = 0) for most analytes, indicating superior accuracy and precision. The approach's sustainability was rigorously assessed using six advanced metrics, validating its environmental friendliness, economic viability, and practical application. This approach effectively resolves complex pharmaceutical formulations, contributing to sustainable development objectives in quality control processes.}, } @article {pmid39567497, year = {2024}, author = {Zhu, Z and Song, M and Ren, J and Liang, L and Mao, G and Chen, M}, title = {Copper homeostasis and cuproptosis in central nervous system diseases.}, journal = {Cell death & disease}, volume = {15}, number = {11}, pages = {850}, pmid = {39567497}, issn = {2041-4889}, mesh = {Humans ; *Copper/metabolism ; *Homeostasis ; *Central Nervous System Diseases/metabolism/pathology ; Animals ; }, abstract = {Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.}, } @article {pmid39567371, year = {2024}, author = {Nuzum, ND and Deady, C and Kittel-Schneider, S and Cryan, JF and O'Mahony, SM and Clarke, G}, title = {More than just a number: the gut microbiota and brain function across the extremes of life.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2418988}, pmid = {39567371}, issn = {1949-0984}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Brain/microbiology ; Animals ; Brain-Gut Axis/physiology ; Alzheimer Disease/microbiology/physiopathology ; Neurodegenerative Diseases/microbiology ; }, abstract = {Understanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.}, } @article {pmid39565466, year = {2024}, author = {Crowley, PD and Mira, P and Saleh, OMA}, title = {Minocycline susceptibility in Stenotrophomonas maltophilia: a closer look at institutional data amid CLSI breakpoint revisions.}, journal = {European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10096-024-04995-5}, pmid = {39565466}, issn = {1435-4373}, abstract = {In this letter we respond Bakthavatchalam et al's brief report on susceptibility of Stenotrophomonas maltophilia to Minocycline in the setting of new susceptibility breakpoints. We outline our institution's experience with this organism and new data of susceptibility with the breakpoint of < 1 mg/L from the past 5 months showing 93.8% of 144 isolates remained susceptible.}, } @article {pmid39564190, year = {2024}, author = {Cavaliere, F and Hermann, DM and Magliaro, C}, title = {Editorial: Human brain organoids to model neurodegenerative diseases at the BOSS23 Brain Organoid Summer School.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1501036}, doi = {10.3389/fncel.2024.1501036}, pmid = {39564190}, issn = {1662-5102}, } @article {pmid39564171, year = {2024}, author = {Byeon, H}, title = {Holistic approaches to mitigating psychological distress in gynecological cancer patients.}, journal = {World journal of psychiatry}, volume = {14}, number = {11}, pages = {1766-1771}, pmid = {39564171}, issn = {2220-3206}, abstract = {This article delves into the psychological impact of gynecological malignancies and suggests pathways to improve the quality of life (QoL) for affected patients. Building on Shang et al's comprehensive analysis, this piece integrates insights from various studies to highlight the profound influence of psychological and physical symptoms on patients undergoing treatment for gynecological cancers. The study underscores that anxiety and depression significantly exacerbate the disease's toll. Factors such as physical exercise and digital and interactive health interventions show promise in mitigating these adverse effects. The article emphasizes the necessity for a holistic care approach that addresses both physical and emotional needs. Recommendations include enhanced training for healthcare providers, public awareness campaigns, streamlined diagnostic pathways, and improved access to specialist care. These integrated strategies aim to ensure that women facing gynecological cancers can maintain an optimal QoL through comprehensive and multidisciplinary care models.}, } @article {pmid39563746, year = {2024}, author = {Moyana, TN}, title = {Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test.}, journal = {World journal of gastroenterology}, volume = {30}, number = {42}, pages = {4576-4582}, pmid = {39563746}, issn = {2219-2840}, mesh = {Humans ; *Alanine Transaminase/blood ; *Biomarkers/blood ; Mass Screening/methods/standards ; Fatty Liver/diagnosis/blood/epidemiology ; Obesity/complications/diagnosis/epidemiology ; Early Diagnosis ; Reference Values ; Male ; Liver/pathology ; Non-alcoholic Fatty Liver Disease/diagnosis/blood/epidemiology ; }, abstract = {The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al's work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.}, } @article {pmid39563026, year = {2025}, author = {Hawley, ZCE and Pardo, ID and Cao, S and Zavodszky, MI and Casey, F and Ferber, K and Luo, Y and Hana, S and Chen, SK and Doherty, J and Costa, R and Cullen, P and Liu, Y and Carlile, TM and Chowdhury, T and Doyle, B and Clarner, P and Mangaudis, K and Guilmette, E and Bourque, S and Koske, D and Nadella, MVP and Trapa, P and Hawes, ML and Raitcheva, D and Lo, SC}, title = {Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {1}, pages = {215-234}, doi = {10.1016/j.ymthe.2024.11.029}, pmid = {39563026}, issn = {1525-0024}, mesh = {Animals ; *Dependovirus/genetics ; Mice ; *MicroRNAs/genetics ; *Ganglia, Spinal/metabolism ; *Genetic Vectors/administration & dosage/genetics ; *RNA Interference ; Superoxide Dismutase-1/genetics ; Humans ; Neurons/metabolism ; Male ; }, abstract = {Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.}, } @article {pmid39562997, year = {2024}, author = {Zheng, W and Xia, T and Zhang, X and Han, J and Li, Y and Tian, N and Zheng, G and Wang, J and Peng, Y and Yao, D and Long, F}, title = {Tailoring Multifunctional Amine Salts Based on Anisole Liquid Soaking for Fabricating Efficient and Stable Perovskite Solar Cells.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {48}, pages = {66643-66654}, doi = {10.1021/acsami.4c12455}, pmid = {39562997}, issn = {1944-8252}, abstract = {The post-treatment based on spin-coating (SC) organic amine salts is commonly used for surface modification of perovskite films to eliminate defects. However, there is still a lack of systematic study and a unified understanding of the functions and mechanisms of different organic amine salts. The SC method is also not conducive to the industrialization of solar cells. In this work, we study three different organic amine salts, and a passivation strategy for perovskite films based on green anisole liquid soaking (ALS) has been developed. Phenylethylammonium iodide (PEAI), diethylamine hydroiodide (DEAI), and guanidine hydroiodide (GAI) organic amine salt passivators are selected to modify perovskite films, and their effect and working mechanism are also systematically estimated. It is found that PEAI passivates shallow-level defects on the surface of perovskite films, while DEAI incorporates into the perovskite lattice to suppress point defects, and GAI eliminates excess PbI2 residuals in perovskite films. These three organic-amine-salt-modified devices achieve enhanced power conversion efficiencies (PCE) of 21.82% (PEAI-ALS), 21.74% (DEAI-ALS), and 22.21% (GAI-ALS), which is much higher than that of the pristine device without treatment (19.95%). The PCE of the PEAI-ALS device retains nearly 94% of the initial efficiency after 1200 h in unpackaged conditions and about 40% ambient humidity, achieving the best stability performance. Particularly, the PEAI-ALS device has the best comprehensive performance in efficiency and stability. And PEAI is estimated by the SC method and ALS method, and it is found that the PEAI-ALS device achieves a higher PCE compared to the PEAI-SC device (21.51%). We believe that the post-treatment based on a combination of appropriate amine salts and ALS enables a universal approach for fabrication of perovskite solar cells with enhanced photovoltaic performance.}, } @article {pmid39562594, year = {2024}, author = {Tahmasebi, BK and Zand, E and Yousefi, A and Babaei, S and Sadeghpour, A}, title = {Surveillance and mapping of tribenuron-methyl-resistant weeds in wheat fields.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28626}, pmid = {39562594}, issn = {2045-2322}, mesh = {*Plant Weeds/drug effects ; *Triticum/drug effects/genetics/growth & development ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; Iran ; Weed Control/methods ; }, abstract = {Tribenuron-methyl (TBM) is among the herbicides that are widely used for controlling broadleaf weeds in wheat fields in Iran due to its low mammalian toxicity and environmental risk, use at low doses, the broad spectrum of weed control, and low price compared to other herbicides. However, wheat farmers' repeated application and dissatisfaction with the optimal and effective control of the TBM herbicide have led to investigating broadleaf weed resistance in Iranian wheat fields. For this purpose, through a national call in 2018, a total of 240 broadleaf weed populations belonging to 13 species and 7 plant families were collected from 153 wheat fields in 72 counties across 14 provinces suspected to be resistant to the TBM herbicide. Then, a screening test was conducted in a completely randomized design with 5 replications of each biotype using the recommended dose of 25 g a.i. ha[- 1] of TBM in the greenhouse. Overall, the results indicated that 124 (51.7%) of the screened populations were resisted to TBM. Specifically, 44 populations (81%) of Sinapis arvensis L., 18 populations (45%) of Malva neglecta Wallr., 25 populations (45%) of Silybum marianum (L.) Gaertn, 2 populations (66.6%) of Ammi majus L., 1 population (50%) of Rapistrum rugosum L., 3 populations (21%) of Descurainia Sophia (L.) Webb ex Prantl, 9 populations (36%) of Vaccaria hispanica Mill., 8 populations (48%) of Galium aparine L., 9 populations (75%) of Melilotus indicus L. According to the Adkins and Maas evaluation, 4 populations (100%) of Raphanus raphanistrum L. were classified as resistant to TBM. This study is the first comprehensive investigation of broadleaf weed resistance to TBM across Iranian wheat fields, providing crucial insights for future herbicide management strategies. Given the high incidence of resistance, continued use of TBM in Iranian wheat fields may lead to increased yield loss and environmental pollution. Additionally, it is necessary to investigate cross-resistance in resistant populations to other ALS-inhibiting herbicides.}, } @article {pmid39561111, year = {2024}, author = {Rohrer, C and Palumbo, A and Paul, M and Reese, E and Basu, S}, title = {Neurotransmitters and neural hormone-based probes for quadruplex DNA sequences associated with neurodegenerative diseases.}, journal = {Nucleosides, nucleotides & nucleic acids}, volume = {}, number = {}, pages = {1-24}, doi = {10.1080/15257770.2024.2431145}, pmid = {39561111}, issn = {1532-2335}, abstract = {The potential of neurotransmitters and neural hormones as possible G-quadruplex DNA binders was analyzed using fluorescence spectroscopy, surface-enhanced Raman spectroscopy (SERS), DNA melting analysis, and molecular docking. G-quadruplex sequences, (GGC)3 and G4C2, with roles in Fragile X syndrome and amyotrophic lateral sclerosis (ALS), respectively, were selected, and their interactions with melatonin, serotonin, and gamma-aminobutyric acid (GABA), were studied. Both melatonin and serotonin demonstrated strong interactions with the DNA sequences with hydrogen bonding being the primary mode of interaction, with some non-intercalative interactions involving the π systems. GABA demonstrated much weaker interactions and may not be a suitable candidate as a probe for low concentrations of G-quadruplex DNA.}, } @article {pmid39560839, year = {2024}, author = {Wu, R and Ramakrishnan, S and Lin, H and Dong, Z and Liu, M and Qiang, L}, title = {Development and validation a novel FEZF2 based fluorescent reporter for corticospinal motor neurons.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {17}, pmid = {39560839}, issn = {1573-7365}, support = {R01 NS115977/NS/NINDS NIH HHS/United States ; 4100083087//the CURE program via Drexel University College of Medicine/ ; 32070725//the National Natural Science Foundation/ ; }, mesh = {Animals ; *Motor Neurons/metabolism ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Pyramidal Tracts/metabolism ; Green Fluorescent Proteins/genetics/metabolism ; Genes, Reporter ; Cells, Cultured ; DNA-Binding Proteins ; }, abstract = {Corticospinal motor neurons (CSMNs), also named upper motor neurons, are the giant pyramidal neurons called Betz cells. In mammals, the majority of CSMNs reside within layer V of the primary motor cortex, where they extend long axon bundles named the pyramidal tract into the brainstem and the spinal cord to control voluntary movement. CSMN lesions are implicated in a variety of neurodegenerative disorders, such Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis and Hereditary Spastic paraplegia. Although FEZF2-CTIP2 genetic axis have been indicated as the cardinal molecular pathway underlying the development of CSMNs, these proteins are transcription factors that are mostly used to label the nuclei of CSMNs in the fixed cells and tissues. Therefore, a fluorescent reporter to mark CSMNs will be invaluable in identifying living CSMNs, including their extended processes, for time-lapse imaging and high-throughput molecular analyses with much more improved specificity. Based on the in-silico analysis, we identified a putative region within the promoter sequence of FEZF2 and assembled it with an indispensable enhancer motif at its downstream of the gene to form a complex promoter that drives the expression of reporter GFP. The plasmid and virus of FEZF2:eGFP reporter constructs were further validated for its use in specifically labeling CSMNs in primary neuronal cultures from the embryonic rat motor cortex, postnatal mouse cortex. This innovative molecular labeling tool has the potential to offer indispensable support in diverse experimental setups, enabling a comprehensive understanding of the susceptibility and specificity of CSMNs in a wide array of neurological disorders.}, } @article {pmid39559551, year = {2024}, author = {Wang, J and Chi, L and Liu, S and Yin, J and Zhang, Y and Shen, J and Wang, X}, title = {Overlooked role of long capping time and environmental factors in the plateau lake for impairing lanthanum-modified-bentonite's immobilization to phosphate.}, journal = {Water research X}, volume = {25}, number = {}, pages = {100272}, pmid = {39559551}, issn = {2589-9147}, abstract = {Lanthanum-modified-bentonite(LMB) has been applied for eutrophication management as a phosphate(P)-binding agent in many lakes. However, re-eutrophication took place several years or decades later after the first practice of capping due to dynamic environmental factors in the plateau lake. Here, we investigated the effect of long-term capping and integrated environmental factors in the plateau lake including alkalinity, organic matter, disturbance and photodegradation to the LMB immobilization. Long-term LMB immobilization exhibited C accumulation(82.3%), La depletion(53.5%) and lager size effect in the sediment particle, indicating the breakage of La-O-P bonds and the formation of La-O-C bonds over immobilization time. Additionally, pH(8-10) in the plateau lake could enhance the P desorption and decrease P adsorption through electrostatic repulsion enhancement with the zeta potential reduction(7.2 mV). Further disturbance experiment indicated a significant releasing trend of active P and DGT-labile P from the solid phase, pore water to the overlying water after disturbances due to resuspended releasing, particle size and amorphous Fe, Mn and Al's redistribution. Moreover, [31]P NMR and EPR results indicated photodegradation after disturbance converted diester phosphate into orthophosphate with long-term LMB immobilization via the oxidation of ·OH in the sediment of the plateau lake. Therefore, management issues for Xingyun Lake may apply to other plateau lakes with low external P input, intermediate depth and intense disturbance.}, } @article {pmid39558635, year = {2024}, author = {Pillai, M and Patil, AD and Das, A and Jha, SK}, title = {Pathological Mutations D169G and P112H Electrostatically Aggravate the Amyloidogenicity of the Functional Domain of TDP-43.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {23}, pages = {4267-4283}, doi = {10.1021/acschemneuro.4c00372}, pmid = {39558635}, issn = {1948-7193}, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; *Static Electricity ; *Amyloid/metabolism/genetics ; Mutation ; Protein Domains/genetics ; Hydrogen-Ion Concentration ; Protein Aggregation, Pathological/genetics/metabolism ; }, abstract = {Aggregation of TDP-43 is linked to the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, electrostatic point mutations such as D169G and P112H, located within the highly conserved functional tandem RNA recognition motif (RRM) domains of the TDP-43 protein (TDP-43[tRRM]), have been identified in diseased patients as well. In this study, we address how the electrostatic mutations alter both the native state stability and aggregation propensity of TDP-43[tRRM]. The mutants D169G and P112H show increased chemical stability compared to the TDP-43[tRRM] at physiological pH. However, at low pH, both the mutants undergo a conformational change to form amyloid-like fibrils, though with variable rates─the P112H mutant being substantially faster than the other two sequences (TDP-43[tRRM] and D169G mutant) showing comparable rates. Moreover, among the three sequences, only the P112H mutant undergoes a strong ionic strength-dependent aggregability trend. These observations signify the substantial contribution of the excess charge of the P112H mutant to its unique aggregation process. Complementary simulated observables with atomistic resolution assign the experimentally observed sequence-, pH-, and ionic strength-dependent aggregability pattern to the degree of thermal lability of the mutation site-containing RRM1 domain and its extent of dynamical anticorrelation with the RRM2 domain whose combination eventually dictate the extent of generation of aggregation-prone partially unfolded conformational ensembles. Our choice of a specific charge-modulated pathogenic mutation-based experiment-simulation-combination approach unravels the otherwise hidden residue-wise contribution to the individual steps of this extremely complicated multistep aggregation process.}, } @article {pmid39557859, year = {2024}, author = {Pamphlett, R and Parkin Kullmann, J}, title = {Early life events may be the first steps on the multistep path to amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28497}, pmid = {39557859}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology/genetics ; Humans ; Female ; Male ; Middle Aged ; Risk Factors ; Adult ; Aged ; Case-Control Studies ; Surveys and Questionnaires ; }, abstract = {A combination of multiple genetic and environmental factors appear to be required to trigger the onset of amyotrophic lateral sclerosis (ALS). Early life environmental exposures have been reported to be risk factors for a variety of adult-onset diseases, so we used data from an online international ALS case-control questionnaire to estimate whether any of these could be risk factors for the clinical onset of ALS. Responses were obtained from 1,049 people aged 40 years or more, 568 with ALS and 481 controls. People with ALS were more likely to have been born and lived longer in a country area than in a city area, to have younger parents, and to have lower educational attainment and fewer years of education. No ALS-control differences were found in sibling numbers, birth order, adult height, birth weight, parent smoking, Cesarean delivery, or age of starting smoking. In conclusion, early life events and conditions may be part of a group of polyenvironmental risk factors that act together with polygenetic variants to trigger the onset of ALS. Reducing exposure to adverse environmental factors in early life could help to lower the risk of later developing ALS.}, } @article {pmid39557152, year = {2025}, author = {Yu, H and Ren, K and Jin, Y and Zhang, L and Liu, H and Huang, Z and Zhang, Z and Chen, X and Yang, Y and Wei, Z}, title = {Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis.}, journal = {Neuropharmacology}, volume = {264}, number = {}, pages = {110217}, doi = {10.1016/j.neuropharm.2024.110217}, pmid = {39557152}, issn = {1873-7064}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; *Neuroinflammatory Diseases/metabolism/immunology/pathology ; Animals ; *Mitochondria/metabolism ; *Alarmins/metabolism ; Inflammasomes/metabolism ; DNA, Mitochondrial/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.}, } @article {pmid39556975, year = {2024}, author = {Yu, Z and Qi, J and Liu, S and Zhao, X and Huang, H}, title = {Evaluating forest aboveground biomass estimation model using simulated ALS point cloud from an individual-based forest model and 3D radiative transfer model across continents.}, journal = {Journal of environmental management}, volume = {372}, number = {}, pages = {123287}, doi = {10.1016/j.jenvman.2024.123287}, pmid = {39556975}, issn = {1095-8630}, mesh = {*Biomass ; *Forests ; Models, Theoretical ; Computer Simulation ; Trees/growth & development ; Algorithms ; }, abstract = {Area-based approach (ABA) has been widely employed for estimating forest aboveground biomass (AGB) using airborne laser scanning (ALS) data. However, its scalability is limited due to challenges in model generalization across different forest types and regions. The selection of sensitive variables from ALS data is crucial for constructing robust forest AGB estimation models, yet this selection varies significantly among forest types and regions. Traditionally, assessing the influence of variable selection is hindered by the lack of accurate reference forest AGB values. Computer simulation-based method provides a perspective for exploring these challenges. This study employs an individual-based forest growth process model, FORMIND, coupled with a 3D radiative transfer model (RTM), LESS, to evaluate the transferability of ABA-based forest AGB estimation models and the generalization of ALS-derived variables. We used six virtual 3D forest scenes and two real-world forest sites, representing a range of global forest types, along with their simulated ALS data, to develop a forest AGB estimation model using the random forest algorithm, which allowed us to analyze the importance of various variables. We assessed model transferability through cross-comparison. Additionally, we validated the model using field plots and ALS data collected from two distinct regions. The results showed that the canopy surface area and volume extracted using the α-shape algorithm and parameters fitted from the Weibull distribution are vital variables when using ALS for forest AGB estimation across forest types and regions. Incorporating these variables into the model significantly improves the accuracy of forest AGB estimation. The optimized model achieved a R[2] of 0.945, a RMSE of 34.22 t/ha, and a MAE of 20.53 t/ha. Our study not only deepens the understanding of the relationship between forest vertical structural metrics and AGB but also highlights the potential of computer simulation as a tool for refining the estimation of forest structural parameters.}, } @article {pmid39556393, year = {2024}, author = {Ishii, J and Nishikimi, M and Kikutani, K and Ohki, S and Ota, K and Anzai, T and Takahashi, K and Okubo, M and Ohshimo, S and Iwami, T and Shime, N}, title = {Resuscitation Attempt and Outcomes in Patients With Asystole Out-of-Hospital Cardiac Arrest.}, journal = {JAMA network open}, volume = {7}, number = {11}, pages = {e2445543}, pmid = {39556393}, issn = {2574-3805}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality/epidemiology ; Male ; Female ; Aged ; Middle Aged ; Japan/epidemiology ; *Cardiopulmonary Resuscitation/methods ; *Registries ; *Emergency Medical Services/statistics & numerical data ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Prospective Studies ; Epinephrine/therapeutic use/administration & dosage ; Treatment Outcome ; Cohort Studies ; }, abstract = {IMPORTANCE: Little is known about the epidemiology of out-of-hospital cardiac arrest (OHCA) in patients with asystole in countries where prehospital resuscitation is not withheld or terminated.

OBJECTIVE: To investigate the secular trends in the patient outcomes and advanced life support (ALS) procedures and evaluate the association of ALS procedures with favorable outcomes among patients with OHCA and asystole.

This cohort study analyzed data from a nationwide prospective OHCA registry in Japan. OHCA occurred from June 1, 2014, to December 31, 2020. Adults with an initial rhythm of asystole and OHCA were included in the analysis, which was conducted between July 29, 2022, and August 24, 2024.

EXPOSURES: Year of OHCA and prehospital ALS procedures (advanced airway management [AAM] and intravenous epinephrine administration).

MAIN OUTCOMES AND MEASURES: Trends in prehospital and in-hospital ALS procedures and patient outcomes were described using the Jonckheere-Terpstra trend test for continuous variables and the Cochran-Armitage trend test for categorical variables. The primary outcome was a favorable neurological outcome at 30 days. The secondary outcomes included a favorable neurological outcome at 90 days and survival at 30 and 90 days. Associations between prehospital procedures and outcomes were analyzed using time-dependent propensity score and risk-set matching.

RESULTS: Of 60 349 patients with OHCA, 35 843 (59.4%) presented with asystole (median age, 77 [IQR, 64-85] years; 20 573 [57.4%] men). Among these, 33 674 patients (93.9%) underwent ALS procedures, with 67 (0.2%) achieving a favorable neurological outcome at 30 days. No significant trends in the outcomes were noted, except for a decline in return of spontaneous circulation (424 of 1848 [22.9%] to 1178 of 5892 [20.0%]; P = .003). Neither AAM (odds ratio [OR], 1.27 [95% CI, 0.76-2.12]; P = .36) nor intravenous epinephrine administration (OR, 0.53 [95% CI, 0.24-1.13]; P = .10) was associated with a favorable neurological outcome at 30 days, although both were associated with survival at 30 days (ORs, 1.45 [95% CI, 1.21-1.74] and 1.81 [95% CI, 1.44-2.27], respectively; P < .001 for both).

CONCLUSIONS AND RELEVANCE: In this cohort study of patients with OHCA presenting with asystole, the proportion with a favorable neurological outcome at 30 days was substantially low, and no prehospital ALS procedure was associated with a favorable neurological outcome. These findings suggest that discussions regarding implementation of a termination of resuscitation rule for such patients are warranted.}, } @article {pmid39556113, year = {2024}, author = {Yeganeh Markid, T and Pourahmadiyan, A and Hamzeh, S and Sharifi-Bonab, M and Asadi, MR and Jalaiei, A and Rezazadeh, M and Ghafouri-Fard, S}, title = {A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnc.16255}, pmid = {39556113}, issn = {1471-4159}, abstract = {Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.}, } @article {pmid39553255, year = {2024}, author = {Zeinali, M and Almasi Dooghaee, M and Ziaee, M and Haghi Ashtiani, B}, title = {Evaluation of Relationship Between Laboratory, Electrodiagnostic, and Functional Parameters in Patients With Amyotrophic Lateral Sclerosis; A Cross Sectional Study.}, journal = {Basic and clinical neuroscience}, volume = {15}, number = {4}, pages = {553-560}, pmid = {39553255}, issn = {2008-126X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a poor prognosis that leads to limb and or bulbar muscle degeneration. Several demographic and biological factors have prognostic importance, but little data exist on the relationship between clinical, electrodiagnostic, and laboratory markers as predictors of disease progression. We aimed to assess the relationships between different aspects of ALS patients' clinical, electrodiagnostic, and laboratory features and their level of functioning.

METHODS: We included 27 ALS patients diagnosed within the last two years. A neurology resident conducted clinical assessment and electrodiagnostic studies. The motor unit number index (MUNIX) and compound motor action potential (CMAP) were used to measure motor unit loss. Serum creatinine, urea, albumin, and creatine kinase were measured as laboratory markers. We used the Persian version of the ALS functional rating scale (ALS-FRS) as the main outcome measure. The Pearson correlation coefficient was calculated to assess the correlations using the SPSS software, version 16.

RESULTS: None of the demographic or laboratory parameters were correlated with ALSFRS. Patients with the onset of disease in the limbs had a higher MUNIX score than those with bulbar onset. Also, increased body mass index (BMI) was associated with lower CMAP and MUNIX scores (P=0.02). Higher serum creatinine levels were significantly associated with higher lower limb MUNIX (P=0.04). Higher lower limb MUNIX was associated with a higher lower limb functional score.

CONCLUSION: Decreased serum creatinine may indicate lower limb motor unit loss in patients with ALS. Also, MUNIX scores may be used as substitutes for ALS-FRS in ALS trials. Further research is needed to elucidate the clinical application of these findings.}, } @article {pmid39552508, year = {2024}, author = {Zhong, R and Dionela, DLA and Kim, NH and Harris, EN and Geisler, JG and Wei-LaPierre, L}, title = {Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27140}, pmid = {39552508}, issn = {1531-8249}, support = {NS117429/NS/NINDS NIH HHS/United States ; NS127858/NS/NINDS NIH HHS/United States ; NS99545/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.

METHODS: hSOD1[G93A] mice were treated with 0.5-1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1[G93A] mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.

RESULTS: DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1[G93A] mice. Strikingly, symptomatic hSOD1[G93A] mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.

INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2024.}, } @article {pmid39552337, year = {2024}, author = {Baindoor, S and Gibriel, HAY and Venø, MT and Su, J and Morrissey, EP and Jirström, E and Woods, I and Kenny, A and Alves, M and Halang, L and Fabbrizio, P and Bilen, M and Engel, T and Hogg, MC and Bendotti, C and Nardo, G and Slack, RS and Kjems, J and Prehn, JHM}, title = {Distinct fingerprints of tRNA-derived small non-coding RNA in animal models of neurodegeneration.}, journal = {Disease models & mechanisms}, volume = {17}, number = {11}, pages = {}, pmid = {39552337}, issn = {1754-8411}, support = {17/JPND/3455//Research Ireland/ ; //European Regional Development Fund/ ; //FutureNeuro/ ; //Precision ALS/ ; 18/CRT/6214//Research Ireland Centre for Research Training in Genomics Data Science/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; CUP E48I20000000007//Regione Lombardia/ ; SG-2018-12366226//Ministero della Salute/ ; //Royal College of Surgeons in Ireland/ ; }, mesh = {Animals ; *Disease Models, Animal ; *RNA, Transfer/genetics/metabolism ; *RNA, Small Untranslated/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Neurodegenerative Diseases/genetics/pathology ; Mice ; Humans ; Mice, Transgenic ; Parkinson Disease/genetics/pathology ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {Transfer RNA-derived small RNAs (tsRNAs) - categorized as tRNA-derived fragments (tRFs), tRNA-derived stress-induced RNAs (tiRNAs) and internal tRF (itRF) - are small non-coding RNAs that participate in various cellular processes such as translation inhibition and responses to cellular stress. We here identified tsRNA profiles within susceptible tissues in animal models of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) to pinpoint disease-specific tsRNAs and those shared across neurodegenerative diseases. We performed small RNA sequencing in the SOD1G93A and TDP43A315T mouse models of ALS (spinal cord), the TauP301S model of FTD (hippocampus), and the parkin/POLG model of PD (substantia nigra). Bioinformatic analysis showed higher expression of 5' tiRNAs selectively in the two ALS models, lower expression of 3' tRFs in both the ALS and FTD mouse models, and lower expression of itRF Arg in the PD model. Experimental validation confirmed the expression of tsRNAs. Gene Ontology analysis of targets associated with validated 3' tRFs indicated functions in the regulation of synaptic and neuronal pathways. Our profiling of tsRNAs indicates disease-specific fingerprints in animal models of neurodegeneration, which require validation in human disease.}, } @article {pmid39551788, year = {2024}, author = {Sadeghdoust, M and Das, A and Kaushik, DK}, title = {Fueling neurodegeneration: metabolic insights into microglia functions.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {300}, pmid = {39551788}, issn = {1742-2094}, support = {MS220110//U.S. Department of Defense/ ; 916184//Multiple Sclerosis Society of Canada/ ; }, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; }, abstract = {Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.}, } @article {pmid39551782, year = {2024}, author = {Labrador, L and Rodriguez, L and Beltran, S and Hernandez, F and Gomez, L and Ojeda, P and Bergmann, C and Calegaro-Nassif, M and Kerr, B and Medinas, DB and Manque, P and Woehlbier, U}, title = {Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1[G93A] ALS mouse model.}, journal = {Biological research}, volume = {57}, number = {1}, pages = {86}, pmid = {39551782}, issn = {0717-6287}, support = {1200459//Agencia Nacional de Investigación y Desarrollo/ ; 1150743//Agencia Nacional de Investigación y Desarrollo/ ; 11160288//Agencia Nacional de Investigación y Desarrollo/ ; 1191538//Agencia Nacional de Investigación y Desarrollo/ ; 1230905//Agencia Nacional de Investigación y Desarrollo/ ; ACT210039//Agencia Nacional de Investigación y Desarrollo/ ; 11240328//Agencia Nacional de Investigación y Desarrollo/ ; 1240176//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Autophagy/genetics/physiology ; Mice ; Humans ; Superoxide Dismutase-1/genetics ; Motor Neurons/pathology ; Superoxide Dismutase/genetics ; Neurons/pathology ; Male ; Female ; Autophagy-Related Proteins/genetics/metabolism ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1[G93A] ALS mouse model. Unexpectedly, PACER/SOD1[G93A] double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1[G93A] mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.}, } @article {pmid39551139, year = {2024}, author = {Liu, C and Chen, IS and Barri, M and Murrell-Lagnado, R and Kubo, Y}, title = {Structural determinants of M2R involved in inhibition by Sigma-1R.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {108006}, pmid = {39551139}, issn = {1083-351X}, mesh = {*Receptors, sigma/metabolism/genetics ; Humans ; *Sigma-1 Receptor ; HEK293 Cells ; *Receptor, Muscarinic M2/metabolism/genetics ; Animals ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism/genetics ; }, abstract = {Sigma-1 receptor (S1R) is a multimodal chaperone protein that is implicated in various pathophysiological conditions including drug addiction, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). S1R interacts with various ion channels and receptors on the endoplasmic reticulum or plasma membrane (PM). It has been reported that S1R colocalizes with the M2-muscarinic acetylcholine receptor (M2R) on the soma of motoneurons, although a functional interaction between these two proteins has not been established. Here, we investigated the regulation of M2R signaling by S1R using electrophysiological recordings of GIRK currents in HEK293T cells. We observed that S1R strongly inhibited M2R-mediated activation of GIRK1/2, but the disease mutant linked to ALS, S1R E102Q, did not. The inhibitory effect of S1R was selective for M2R and wasn't seen when S1R was co-expressed with other Gi/o coupled receptors including M4R. Chimeric and mutant receptors of M2R and M4R were generated and analyzed, and this highlighted Ala401 in the transmembrane 6 domain (TM6) of M2R and Glu172 as well as Glu175 in the extracellular loop 2 regions of M2R, as essential for the inhibition by S1R. Co-immunoprecipitation confirmed the physical interaction between M2R and S1R. Immunocytochemical labeling of M2R and S1R expressed in HeLa cells, HEK293T cells, and cultured hippocampal neurons, showed clear PM expression of M2R throughout the cell which was decreased by coexpression with S1R but was still apparent. Taken together, our results show that S1R interacts with M2R to reduce both its PM expression and function, and this involves TM6 and the extracellular loop 2.}, } @article {pmid39551138, year = {2024}, author = {Yang, C and Leifer, C and Lammerding, J and Hu, F}, title = {Regulation of TAR DNA binding protein 43 (TDP-43) homeostasis by cytosolic DNA accumulation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {107999}, doi = {10.1016/j.jbc.2024.107999}, pmid = {39551138}, issn = {1083-351X}, mesh = {*DNA-Binding Proteins/metabolism/genetics ; *Cytosol/metabolism ; Humans ; Animals ; *Homeostasis ; DNA/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Cytoplasm/metabolism ; beta Karyopherins/metabolism/genetics ; Neurons/metabolism/pathology ; Mice ; Cell Nucleus/metabolism ; Oligodeoxyribonucleotides/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA binding protein predominantly localized in the nucleus under physiological conditions. TDP-43 proteinopathy, characterized by cytoplasmic aggregation and nuclear loss, is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Thus it is crucial to understand the molecular mechanism regulating TDP-43 homeostasis. Here, we show that the uptake of oligodeoxynucleotides (ODNs) from the extracellular space induces reversible TDP-43 cytoplasmic puncta formation in both neurons and glia. ODNs facilitate the liquid-liquid phase separation of TDP-43 in vitro. Importantly, persistent accumulation of DNA in the cytoplasm leads to nuclear depletion of TDP-43 and enhanced production of a short isoform of TDP-43 (sTDP-43). In addition, in response to ODN uptake, the nuclear import receptor karyopherin subunit β1 (KPNB1) is sequestered in the cytosolic TDP-43 puncta. ALS-linked Q331K mutation decreases the dynamics of cytoplasmic TDP-43 puncta and increases the levels of sTDP-43. Moreover, the TDP-43 cytoplasmic puncta are induced by DNA damage and by impaired nuclear envelope integrity due to Lamin A/C deficiency. In summary, our data support that abnormal DNA accumulation in the cytoplasm may be one of the key mechanisms leading to TDP-43 proteinopathy and provides novel insights into molecular mechanisms of ALS caused by TDP-43 mutations.}, } @article {pmid39550606, year = {2024}, author = {Rabadi, MH and Russell, KA and Xu, C}, title = {Analysis of Mortality Causes and Locations in Veterans with ALS: A Decade Review.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {30}, number = {}, pages = {e945816}, pmid = {39550606}, issn = {1643-3750}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; *Veterans ; Male ; Female ; Middle Aged ; Aged ; *Cause of Death ; Retrospective Studies ; United States/epidemiology ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to rapid degeneration of nerves in the brain and spinal cord, with eventual loss of voluntary movements, including breathing. This retrospective study of medical record data from 105 US veterans diagnosed with ALS at the Oklahoma City VA Medical Center between 2010 and 2021 aimed to identify patient demographics, and the causes and places of death for these veterans. MATERIAL AND METHODS Data from 105 US veterans diagnosed with ALS by the El Escorial criteria and supported by neurophysiology testing was reviewed. The information about the place and cause of death was obtained from each patient's care provider and death certificate. Crude mortality rates (per 100 person-years) and standardized mortality ratios (SMRs) were calculated for the causes of death, by sex, age group, and location of death. RESULTS During the 11-year follow-up period, 80 (76.2%) veterans with ALS died. The mean (SD) follow-up time was 4.53 (4.55) years. Most of the deaths were due to respiratory failure and pneumonia (n=43, mortality rate=9.21 per 100 person-years). Most patients died at home (n=71, 88.7%). The annual crude mortality rate was 16.7 and the all-cause death SMR was 25.63 (95% CI, 20.32-31.55). CONCLUSIONS This study's findings are that in veterans with ALS, the main cause of death is respiratory disease (failure). The main location of death was the home, with their family members. The all-cause mortality rate among veterans with ALS was 26 times greater than for the general Oklahoma population.}, } @article {pmid39550435, year = {2024}, author = {Wang, Z and Cao, W and Deng, B and Fan, D}, title = {Lower creatinine-to-cystatin c ratio associated with increased risk of incident amyotrophic lateral sclerosis in the prospective UK biobank cohort.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28289}, pmid = {39550435}, issn = {2045-2322}, support = {81873784//National Natural Science Foundation of China/ ; BYSYDL2019002//Peking University Third Hospital/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/epidemiology ; Humans ; Male ; Female ; *Creatinine/blood ; Middle Aged ; United Kingdom/epidemiology ; Aged ; Incidence ; Prospective Studies ; *Cystatin C/blood ; Risk Factors ; *Biological Specimen Banks ; *Biomarkers/blood ; Proportional Hazards Models ; Adult ; UK Biobank ; }, abstract = {Reduced muscle mass has been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, it remains unclear whether decreased muscle mass is a risk factor for ALS or a consequence of motor neuron degeneration. Recently, serum creatinine-to-cystatin C ratio (CCR) have emerged as promising biomarkers for assessing muscle mass. We aimed to explore the association between CCR and the incidence of ALS using data from the UK Biobank. Between 2006 and 2010, 446,945 participants were included in the baseline. CCR was calculated as the ratio of serum creatinine to cystatin C. Cox regression models were used to analyze the relationship between CCR and ALS incidence. Furthermore, subgroup analyses were conducted to investigate potential covariates in these relationships. After adjusting for all covariates, the multivariate Cox regression analysis revealed a significant association between decreased CCR and an increased risk of ALS (hazard ratio (HR) = 0.990, 95% confidence interval (CI): 0.982-0.999, P = 0.026). Participants were stratified into groups based on CCR tertiles. Compared with participants in the highest tertiles of CCR, those in the lowest (HR = 1.388, 95% CI: 1.032-1.866, P = 0.030) and medium tertiles (HR = 1.348, 95% CI: 1.045-1.739, P = 0.021) had an increased risk of ALS incidence. Subgroup analysis showed that the relationship between CCR and ALS incidence was particularly significant among participants aged < 65 years (CCR tertile 1: HR = 1.916, 95% CI: 1.366-2.688, P < 0.001; CCR tertile 2: HR = 1.699, 95% CI: 1.267-2.278, P < 0.001). The present results demonstrate that lower CCR is significantly associated with a higher risk of ALS.}, } @article {pmid39548852, year = {2024}, author = {Dellar, ER and Vendrell, I and Amein, B and Lester, DG and Edmond, EC and Yoganathan, K and Dharmadasa, T and Sogorb-Esteve, A and Fischer, R and Talbot, K and Rohrer, JD and Turner, MR and Thompson, AG}, title = {Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27133}, pmid = {39548852}, issn = {1531-8249}, support = {Lester/2450/795/MNDA_/Motor Neurone Disease Association/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; MR/Y001095/1/MRC_/Medical Research Council/United Kingdom ; 2018-I2M-2-002//Chinese Academy of Medical Sciences Innovation Fund for Medical Science/ ; }, abstract = {OBJECTIVE: To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.

METHODS: Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.

RESULTS: Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007).

INTERPRETATION: Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.}, } @article {pmid39548731, year = {2024}, author = {Shino, Y and Muraki, N and Kobatake, Y and Kamishina, H and Kato, R and Furukawa, Y}, title = {Disulfide-mediated oligomerization of mutant Cu/Zn-superoxide dismutase associated with canine degenerative myelopathy.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5210}, pmid = {39548731}, issn = {1469-896X}, support = {JP21am0101083//Japan Agency for Medical Research and Development/ ; 19H05765//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22H02768//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22K19389//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 23EXC334//Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences/ ; }, mesh = {Animals ; Dogs ; *Disulfides/chemistry/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Protein Multimerization ; Dog Diseases/genetics ; Spinal Cord Diseases/genetics/metabolism ; Amino Acid Substitution ; Zinc/metabolism/chemistry ; Mutation ; Mutation, Missense ; Copper/metabolism/chemistry ; }, abstract = {A homozygous E40K mutation in the gene coding canine Cu/Zn-superoxide dismutase (cSOD1) causes degenerative myelopathy (DM) in dogs. A pathological hallmark of DM with the cSOD1 mutation is the aggregation of mutant cSOD1 proteins in neurons. The amino acid substitution E40K disrupts a salt bridge between Glu40 and Lys91 and is considered to destabilize the native state of cSOD1; however, the mechanism by which mutant cSOD1 aggregates remains unclear. Here, we show that mutant cSOD1 losing a copper and zinc ion forms oligomers crosslinked via disulfide bonds. The E40K substitution was found to result in the increased solvent exposure of the Cys7 side chain, which then attacked the disulfide bond (Cys57-Cys146) in cSOD1 to form disulfide-linked oligomers. We also successfully prevented the Cys7 exposure and thus the oligomerization of mutant cSOD1 by a fragment antibody that specifically recognizes the region around the mutation site. The fragment antibody covered the β-plug region, reinforcing the interactions compromised by the E40K substitution and thus contributing to the maintenance of the structural integrity of the β-barrel core of cSOD1. Taken together, we propose that the Cys7 exposure in cSOD1 upon the salt bridge disruption plays a central role in the aggregation mechanism of DM-associated mutant cSOD1.}, } @article {pmid39548508, year = {2024}, author = {Panei, FP and Di Rienzo, L and Zacco, E and Armaos, A and Tartaglia, GG and Ruocco, G and Milanetti, E}, title = {Synchronized motion of interface residues for evaluating protein-RNA complex binding affinity: Application to aptamer-mediated inhibition of TDP-43 aggregates.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5201}, pmid = {39548508}, issn = {1469-896X}, support = {855923//ERC-2019-Synergy Grant (ASTRA, 855923)/ ; ivBM4PAP,101098989//EIC-2022-PathfinderOpen/ ; CN00000041//National Center for Gene Therapy and Drugs Based on RNA Technology/ ; CUPj33C22001130001//Potenziamento Strutture di Ricerca e Creazione di Campioni Nazionali Di R&S/ ; }, mesh = {*Aptamers, Nucleotide/chemistry/metabolism ; *Molecular Dynamics Simulation ; Humans ; *DNA-Binding Proteins/chemistry/metabolism ; *Protein Binding ; RNA/chemistry/metabolism ; Molecular Docking Simulation ; }, abstract = {Investigating the binding between proteins and aptamers, such as peptides or RNA molecules, is of crucial importance both for understanding the molecular mechanisms that regulate cellular activities and for therapeutic applications in several pathologies. Here, a new computational procedure, employing mainly docking, clustering analysis, and molecular dynamics simulations, was designed to estimate the binding affinities between a protein and some RNA aptamers, through the investigation of the dynamical behavior of the predicted molecular complex. Using the state-of-the-art software catRAPID, we computationally designed a set of RNA aptamers interacting with the TAR DNA-binding protein 43 (TDP-43), a protein associated with several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We thus devised a computational protocol to predict the RNA-protein molecular complex, so that the structural and dynamical behavior of such a complex can be investigated through extensive molecular dynamics simulation. We hypothesized that the coordinated and synchronized motion of the protein-binding residues, when in contact with RNA molecule, is a critical requisite in order to have a stable binding. Indeed, we calculated the motion covariance exhibited by the interface residues during molecular dynamics simulation: we tested the results against experimental measurements of binding affinity (in this case, the dissociation constant) for six RNA molecules, resulting in a linear correlation of about 0.9. Our findings suggest that the synchronized movement of interface residues plays a pivotal role in ensuring the stability within RNA-protein complexes, moreover providing insights into the contribution of each interface residue. This promising pipeline could thus contribute to the design of RNA aptamers interacting with proteins.}, } @article {pmid39548409, year = {2024}, author = {Ruan, K and Cheng, D and Zhu, X and Sun, S and Bao, F and Zhu, J and Li, F and Shen, M and Ye, Y}, title = {Corneal higher-order aberrations and their relationship with choroid in myopic patients.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {500}, pmid = {39548409}, issn = {1471-2415}, support = {81900910//Innovative Research Group Project of the National Natural Science Foundation of China/ ; LQ19H120003//Natural Science Foundation of Zhejiang Province/ ; Y2023809, Y20190638//Basic Scientific Research Project of Wenzhou/ ; }, mesh = {Humans ; Female ; Male ; *Choroid/pathology/diagnostic imaging/blood supply ; Adult ; *Myopia/physiopathology/complications ; *Corneal Wavefront Aberration/physiopathology ; *Tomography, Optical Coherence/methods ; Young Adult ; *Cornea/pathology/diagnostic imaging ; Axial Length, Eye/pathology/diagnostic imaging ; Refraction, Ocular/physiology ; Visual Acuity/physiology ; Corneal Topography ; Middle Aged ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: To investigate corneal higher-order aberrations (HOAs) and choroidal characteristics in myopic individuals and explore the association between HOAs and choroidal parameters.

METHODS: Myopic participants were categorized into three groups based on axial lengths (ALs). We compared corneal HOAs, including spherical (Z4[0]), comatic (Z3 [- 1] and Z3[1]), and trefoil (Z3 [- 3] and Z3[3]) aberrations, as well as choroidal vascularity index (CVI) and choroidal thickness (CT). Linear regression analysis was used to assess the relationships among corneal HOAs, CVI, CT, spherical equivalent, and AL.

RESULTS: Groups 1, 2, and 3 included 105, 98, and 118 eyes, respectively. Group 3 exhibited lower spherical HOA root mean square and Z4[0] values than group 1(p < 0.05). Group 1 showed lower Z3[1] levels than other groups (p < 0.001). Groups 1 and 2 had higher mean, central, and I2 vertical CVIs than group 3 (p < 0.05). Group 1 had a larger vertical S1 CVI than group 3 (p < 0.05). Group 3 had smaller horizontal CVI values in all regions except N2 (p < 0.05). Both the mean and CT in all regions decreased as AL increased (p < 0.001). The comatic (Z3[1]) and trefoil (Z3[3]) components were predictors of mean horizontal CVI, and the comatic (Z3[1]) component was correlated with both mean vertical and horizontal CT.

CONCLUSION: Longer AL myopic patients exhibited lower absolute values of spherical aberration and horizontal coma. Alterations in choroid in myopic patients correlated with corneal HOAs. Our results suggest a potential connection between the optical quality and ocular perfusion in myopia.}, } @article {pmid39548226, year = {2024}, author = {Qin, J and Wang, X and Fan, G and Zhang, W and Wu, X and Wang, B and Liu, Y}, title = {Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28110}, pmid = {39548226}, issn = {2045-2322}, support = {202103021224405//the Basic Research Project of Shanxi Province/ ; 201903D321049//the Key Research and Development Project Plan of Shanxi Province concerning social advancement/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/cerebrospinal fluid/blood/pathology ; *Diffusion Tensor Imaging/methods ; Middle Aged ; Male ; Female ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; Aged ; Adult ; ROC Curve ; Case-Control Studies ; Anisotropy ; Pyramidal Tracts/diagnostic imaging/pathology ; }, abstract = {To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = - 0.813, p < 0.001), Serum-NFL (r = - 0.493, p = 0.001), CSF-pNFH (r = - 0.637, p < 0.001), and Serum-pNFH (r = - 0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = - 0.562, p < 0.001), CSF-pNFH (r = - 0.506, p = 0.001), and Serum-pNFH (r = - 0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.}, } @article {pmid39547910, year = {2024}, author = {Khamaysa, M and El Mendili, M and Marchand, V and Querin, G and Pradat, PF}, title = {Quantitative spinal cord imaging: Early ALS diagnosis and monitoring of disease progression.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2024.10.005}, pmid = {39547910}, issn = {0035-3787}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. This degeneration leads to muscular weakness, progressively impairing motor functions and ultimately resulting in respiratory failure. The clinical, genetic, and pathological heterogeneity of ALS, combined with the absence of reliable biomarkers, significantly challenge the efficacy of therapeutic trials. Despite these hurdles, neuroimaging, and particularly spinal cord imaging, has emerged as a promising tool. It provides insights into the involvement of both upper and lower motor neurons. Quantitative spinal imaging has the potential to facilitate early diagnosis, enable accurate monitoring of disease progression, and refine the design of clinical trials. In this review, we explore the utility of spinal cord imaging within the broader context of developing spinal imaging biomarkers in ALS. We focus on a both diagnostic and prognostic biomarker in ALS, highlighting its pivotal role in elucidating the disease's underlying pathology. We also discuss the existing limitations and future avenues for research, aiming to bridge the translational gap between academic research and its application in clinical practice and therapeutic trials.}, } @article {pmid39547816, year = {2024}, author = {Salmerón-Mendoza, AN and Aguilar-Vázquez, CA and Aguilar-Castillo, SJ}, title = {[Electromyography in atypical variants of motor neuron disease: a case series].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {4}, pages = {1-6}, doi = {10.5281/zenodo.11397347}, pmid = {39547816}, issn = {2448-5667}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Adult ; Aged, 80 and over ; Motor Neuron Disease/diagnosis/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both the upper and lower motor neurons, it has a heterogeneous clinical presentation, there are atypical variants that differ from the classic form of the disease. The criteria for diagnosis have evolved over time, with the support of electromyography (EMG), we present a patient series with these variants in which EMG was crucial to make the diagnosis.

CLINICAL CASES: Six cases are described with atypical presentation of motor neuron disease, for the isolated bulbar ALS phenotype, three cases are reported: two male patients (68 and 62 years old) and one woman (33 years old), with initial symptoms in the bulbar segment and late progression. to a second segment, corroborating characteristic findings by EMG. For the variant of Vulpian-Bernhardt syndrome (VBS), two male patients aged 82 and 72 years are reported, with initial symptoms in the thoracic segment with electromyographic support for the diagnosis; Finally, a case of amyotrophic diplegia of the legs (APD) is described in a 50-year-old female patient with symptoms isolated to the pelvic limbs, with a slow clinical evolution, corroborated by EMG with involvement of other spinal segments.

CONCLUSIONS: ALS a spectrum of motor neuron disease, a neurodegenerative disease of the CNS, without curative treatment and one with a fatal outcome, the diagnosis of ELA is complex and becomes more complex for atypical phenotypes, as observed in the presented cases EMG is an essential part of the approach and part of the diagnostic criteria.}, } @article {pmid39546178, year = {2024}, author = {Li, N and Zhang, Z and Shen, L and Song, G and Tian, J and Liu, Q and Ni, J}, title = {Selenium metabolism and selenoproteins function in brain and encephalopathy.}, journal = {Science China. Life sciences}, volume = {}, number = {}, pages = {}, pmid = {39546178}, issn = {1869-1889}, abstract = {Selenium (Se) is an essential trace element of the utmost importance to human health. Its deficiency induces various disorders. Se species can be absorbed by organisms and metabolized to hydrogen selenide for the biosynthesis of selenoproteins, selenonucleic acids, or selenosugars. Se in mammals mainly acts as selenoproteins to exert their biological functions. The brain ranks highest in the specific hierarchy of organs to maintain the level of Se and the expression of selenoproteins under the circumstances of Se deficiency. Dyshomeostasis of Se and dysregulation of selenoproteins result in encephalopathy such as Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, and multiple sclerosis. This review provides a summary and discussion of Se metabolism, selenoprotein function, and their roles in modulating brain diseases based on the most currently published literature. It focuses on how Se is utilized and transported to the brain, how selenoproteins are biosynthesized and function physiologically in the brain, and how selenoproteins are involved in neurodegenerative diseases. At the end of this review, the perspectives and problems are outlined regarding Se and selenoproteins in the regulation of encephalopathy.}, } @article {pmid39545975, year = {2024}, author = {Eickhoff, C and Schöne-Seifert, B and Kettemann, D and Bormann, E and Grehl, T and Boentert, M and Koch, JC and Schmitt, C and Schrank, B and Schröter, C and Meyer, T}, title = {[End of life perspectives: a systematic survey of patients with amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {95}, number = {12}, pages = {1131-1138}, pmid = {39545975}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Male ; Female ; Middle Aged ; *Terminal Care/psychology ; Aged ; *Advance Directives/psychology ; Surveys and Questionnaires ; Germany ; Adult ; Aged, 80 and over ; Noninvasive Ventilation ; Palliative Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that still has to be primarily treated symptomatically or palliatively. It is therefore all the more important, in addition to initiating treatment, such as percutaneous endoscopic gastrostomy (PEG), noninvasive ventilation therapy (NIVT) and invasive ventilation therapy via tracheotomy (IVT), to discuss the possible termination of these measures early on.

QUESTION: What is the importance of advance directives for those affected and where are possible deficits in therapy planning for the end of life?

MATERIAL AND METHOD: Between March 2017 and January 2019 patients with a clinically confirmed diagnosis of ALS at six treatment centers were asked to fill out a questionnaire. A total of 328 people returned the completed forms.

RESULTS: Of the participants 72% had already made an advance directive (AD), 25% planned to fill one out and only 3% refused to do so. In composing the AD most patients (90%) had support, although 56% lacked medical counselling and only 18% had drawn up the will together with the doctor and relatives, with the majority of the rest also wanting support from a doctor. A total of 37% of all patients wanted a contact person to talk about their illness but only 40% of them had such a contact person. Of the patients 22% stated that they had considered suicide and of these only 55% stated that they had no contact person for the psychological stress caused by the illness but 31% wished to have such a person.

DISCUSSION AND CONCLUSION: A coordinated care of ALS patients, which also takes the psychosocial aspects into account is urgently needed.}, } @article {pmid39545606, year = {2024}, author = {A Virata, MC and Catahay, JA and Lippi, G and Henry, BM}, title = {Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {6}, pages = {227-239}, pmid = {39545606}, issn = {1758-2032}, mesh = {Humans ; *Biomarkers/blood ; *Neurofilament Proteins/blood ; *Neurodegenerative Diseases/drug therapy ; Genetic Therapy ; }, abstract = {Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.}, } @article {pmid39545045, year = {2024}, author = {Xu, X and Huang, Y and Zhu, Y and Jin, Q}, title = {Association between dietary patterns and the prognosis of amyotrophic lateral sclerosis in China: a cross-sectional study.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1437521}, pmid = {39545045}, issn = {2296-861X}, abstract = {BACKGROUND: Recently, a growing number of studies have specifically examined the impact of dietary variables on the development and progression of amyotrophic lateral sclerosis (ALS). The purpose of this study was to investigate the correlation between different dietary patterns and Chinese ALS patients' prognosis.

METHODS: A retrospective study was conducted by recruiting 590 patients with ALS who attended and were regularly followed at hospitals in Nanjing from 2016 to 2023. Nutrient intake was calculated using dietary information collected through the food frequency questionnaire (FFQ), and patients were divided into a control group and special diet groups, including a high-calorie group (HC), a high-protein group (HP), and a ketogenic diet group (KD), based on their specific intake. And used the Kaplan-Meier product limiting distribution to compare the time required to transition between phases of different dietary patterns and to estimate cumulative survival probabilities.

RESULTS: Patients in the HP had a better nutritional status. And the disease progression rate (ΔFS) was significantly associated with dietary patterns, with the KD group having the lowest ΔFS. Meanwhile, special diets extended the survival time of stage 4 patients but had no effect on the overall survival of the disease.

CONCLUSION: A special diet can be one of effective options for patients with advanced ALS. Patients with poor nutritional status may choose the HP diet, whereas those with underlying conditions should consider the ketogenic diet with caution.}, } @article {pmid39544780, year = {2024}, author = {Silva, JF and de Souza, WM and Mello, JDC and Ceccato, HD and Oliveira, PSP and Ayrizono, MLS and Leal, RF}, title = {Evidence linking gut-brain axis and Crohn's disease, focusing on neurotrophic dysfunctions and radiological imaging analysis - a systematic review.}, journal = {American journal of translational research}, volume = {16}, number = {10}, pages = {6029-6040}, pmid = {39544780}, issn = {1943-8141}, abstract = {OBJECTIVE: To conduct a systematic review (SR) to find evidence for a connection between Crohn's disease (CD) and the gut-brain axis (GBA).

METHODS: This study conducted a systematic review (SR) employing a search strategy and strict inclusion criteria. It was conducted by searching for studies published between 2017 and 2024 in the following databases: PUBMED, PUBMED PMC, BVS-BIREME, SCOPUS, WEB OF SCIENCE, EMBASE, and COCHRANE.

RESULTS: Fifty original research articles were included. Among these, 20 studies addressed neuroimaging methods to evaluate CD patients' functional or structural brain changes. Neurodegenerative diseases were the second most addressed topic in the studies, with 18 articles related to different diseases such as Parkinson's disease, Alzheimer's disease, dementia, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Multiple System Atrophy. Eight articles addressed sleep disorders related to CD; two explored Electroencephalography changes; one investigated Brain-Derived Neurotrophic Factor serum levels and one correlated vagotomy with CD.

CONCLUSION: Interest in the link between CD and GBA is increasing, but studies remain varied and inconclusive, spanning from epidemiology to brain imaging and neglecting to investigate a mechanistic relationship. This SR underscores the need for further research to better understand the potential role of GBA in the prognosis and etiology of CD, highlighting its complexity.}, } @article {pmid39544700, year = {2024}, author = {Parnianpour, P and Steinbach, R and Buchholz, IJ and Grosskreutz, J and Kalra, S}, title = {T1-weighted MRI texture analysis in amyotrophic lateral sclerosis patients stratified by the D50 progression model.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae389}, pmid = {39544700}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis, a progressive neurodegenerative disease, presents challenges in predicting individual disease trajectories due to its heterogeneous nature. This study explores the application of texture analysis on T1-weighted MRI in patients with amyotrophic lateral sclerosis, stratified by the D50 disease progression model. The D50 model, which offers a more nuanced representation of disease progression than traditional linear metrics, calculates the sigmoidal curve of functional decline and provides independent quantifications of disease aggressiveness and accumulation. In this research, a representative cohort of 116 patients with amyotrophic lateral sclerosis was studied using the D50 model and texture analysis on MRI images. Texture analysis, a technique used for quantifying voxel intensity patterns in MRI images, was employed to discern alterations in brain tissue associated with amyotrophic lateral sclerosis. This study examined alterations of the texture feature autocorrelation across sub-groups of patients based on disease accumulation, aggressiveness and the first site of onset, as well as in direct regressions with accumulation/aggressiveness. The findings revealed distinct patterns of the texture-derived autocorrelation in grey and white matter, increase in bilateral corticospinal tract, right hippocampus and left temporal pole as well as widespread decrease within motor and extra-motor brain regions, of patients stratified based on their disease accumulation. Autocorrelation alterations in grey and white matter, in clusters within the left cingulate gyrus white matter, brainstem, left cerebellar tonsil grey matter and right inferior fronto-occipital fasciculus, were also negatively associated with disease accumulation in regression analysis. Otherwise, disease aggressiveness correlated with only two small clusters, within the right superior temporal gyrus and right posterior division of the cingulate gyrus white matter. The findings suggest that texture analysis could serve as a potential biomarker for disease stage in amyotrophic lateral sclerosis, with potential for quick assessment based on using T1-weighted images.}, } @article {pmid39542176, year = {2024}, author = {Tian, Z and Zhang, Q and Wang, L and Li, M and Li, T and Wang, Y and Cao, Z and Jiang, X and Luo, P}, title = {Progress in the mechanisms of pain associated with neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102579}, doi = {10.1016/j.arr.2024.102579}, pmid = {39542176}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Pain/physiopathology/metabolism/etiology ; Animals ; Neuroinflammatory Diseases ; }, abstract = {Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.}, } @article {pmid39542047, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Okhovat, AA and Nafissi, S and Mohammadi, S and Batouli, SAH}, title = {Metabolite alterations in the left dorsolateral prefrontal cortex and its association with cognitive assessments in amyotrophic lateral sclerosis: A longitudinal magnetic resonance spectroscopy study.}, journal = {Brain research bulletin}, volume = {219}, number = {}, pages = {111125}, doi = {10.1016/j.brainresbull.2024.111125}, pmid = {39542047}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Spectroscopy/methods ; Longitudinal Studies ; Aged ; *Cognition/physiology ; *Dorsolateral Prefrontal Cortex/metabolism ; Choline/metabolism ; Creatine/metabolism ; Neuropsychological Tests ; Adult ; Cognitive Dysfunction/metabolism/diagnostic imaging ; Aspartic Acid/analogs & derivatives/metabolism ; Prefrontal Cortex/metabolism/diagnostic imaging ; }, abstract = {OBJECTIVE: To characterize the longitudinal metabolite profile of the left dorsolateral prefrontal cortex (DLPFC) in amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS) and to examine its correlation with cognitive assessments.

METHODS: Thirteen patients at baseline and ten at follow-up, along with 14 age-, sex-, and handedness-matched healthy controls (HCs), were recruited. Three Tesla with a 64-channel coil, Point-RESolved Spectroscopy (PRESS) sequence (TR=1500 ms and TE=140 ms) was used. Metabolites in the left DLPFC were quantified using LCModel. Cognitive performance and functional impairment were assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and Revised ALS Functional Rating Scale (ALSFRS-R), respectively. Group comparisons were adjusted for multiple comparisons (p < 0.05, Bonferroni correction). The links between the brain metabolites and cognitive function were investigated using relevant correlation tests (Pearson's or Spearman's).

RESULTS: Our analysis revealed a significant difference in the choline-to-creatine ratio (tCho/tCr) among the three groups. Baseline ALS patients showed a higher tCho/tCr ratio than HCs (p = 0.033, Bonferroni-corrected). Interestingly, the total N-acetyl aspartate (tNAA)/tCr ratio, a marker of neuronal health, was strongly positively correlated with visuospatial cognitive scores at baseline and follow-up. Furthermore, at follow-up, tNAA/tCr was positively correlated with the total scores and specific sub-scores on the ECAS, encompassing both ALS-specific and non-specific cognitive domains. At follow-up, positive correlations emerged between tNAA/tCr and the total language and executive function scores.

CONCLUSIONS: Metabolite alterations and correlations with cognition were observed in the left DLPFC of ALS patients, supporting extra-motor involvement and its association with cognitive decline.}, } @article {pmid39541975, year = {2025}, author = {Márquez-Moñino, MÁ and Santiveri, CM and de León, P and Camero, S and Campos-Olivas, R and Jiménez, MÁ and Sáiz, M and González, B and Pérez-Cañadillas, JM}, title = {The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {1}, pages = {39-50.e6}, doi = {10.1016/j.str.2024.10.025}, pmid = {39541975}, issn = {1878-4186}, mesh = {*SARS-CoV-2/drug effects/metabolism ; *Antiviral Agents/pharmacology/chemistry ; Binding Sites ; Humans ; *Riluzole/pharmacology/chemistry/metabolism ; *Protein Binding ; Crystallography, X-Ray ; Coronavirus Nucleocapsid Proteins/chemistry/metabolism ; Phosphoproteins/metabolism/chemistry ; Protein Domains ; COVID-19 Drug Treatment ; Models, Molecular ; }, abstract = {Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.}, } @article {pmid39541203, year = {2024}, author = {Russo, A and Maiorano, G and Cortese, B and D'Amone, S and Invidia, A and Quattrini, A and Romano, A and Gigli, G and Palamà, IE}, title = {Optimizing TDP-43 silencing with siRNA-loaded polymeric nanovectors in neuronal cells for therapeutic applications: balancing knockdown and function.}, journal = {Nanoscale}, volume = {16}, number = {48}, pages = {22337-22349}, doi = {10.1039/d4nr03159h}, pmid = {39541203}, issn = {2040-3372}, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; *RNA, Small Interfering/chemistry/metabolism ; Humans ; *Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology/genetics ; Polymers/chemistry ; Nanoparticles/chemistry ; Gene Knockdown Techniques ; Cell Line, Tumor ; Gene Silencing ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA binding protein critical for regulating gene expression, including transcription, splicing, mRNA stability, and protein translation. Aggregation of pathological TDP-43 proteins in the cytoplasm of neurons and glial cells appears to be a common feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as frontotemporal dementia (FTD), contributing to motor neuron degeneration and clinical symptoms. Downregulation of TDP-43 expression to prevent or reduce the formation of pathological aggregates is a potential therapeutic approach for treating TDP-43-related diseases. However, therapeutic strategies to reduce TDP-43 aggregation face significant challenges, as the downregulation of TDP-43 must balance the need to maintain its normal functions, which are essential for RNA metabolism and cellular homeostasis. In this study, we developed novel polymeric nanovectors for the delivery of TDP-43 siRNAs in neuronal cells. These nanovectors were designed to provide adequate TDP-43 silencing to achieve the desired functional reduction of TDP-43 levels, thereby optimizing its impact on cellular functions. Our results demonstrate that the polymeric nanovector formulations effectively reduced TDP-43 mRNA and protein levels to an extent comparable to those observed with traditional lipid-based systems. Concurrently, the polymeric nanovectors exhibited an enhanced capacity to reduce stress granules (SG) formation and facilitate TDP-43-containing SG disassembly, while preserving its essential cellular functions. This study provides the first evidence that polymeric nanovectors may be a valuable tool for developing therapeutic strategies to treat TDP-43 protein diseases, such as ALS and FTD, by directly silencing TDP-43 to reduce its aggregation.}, } @article {pmid39539269, year = {2024}, author = {Risen, S and Sharma, S and Gilberto, VS and Brindley, S and Aguilar, M and Brown, JM and Chatterjee, A and Moreno, JA and Nagpal, P}, title = {Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {11}, pages = {3439-3451}, pmid = {39539269}, issn = {2575-9108}, abstract = {Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood-brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Recent studies have also shown that targeting inflammasomes and specific immune targets can be beneficial for these diseases. Furthermore, our previous studies have shown targeting NF-κB and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) can be therapeutic for several neurodegenerative diseases. Here, we show safety-toxicity studies, followed by pharmacokinetics and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI112. We conducted studies using four different routes of administration: intravenous, subcutaneous, intraperitoneal, and intranasal, and identified the drug concentration over time using inductively coupled plasma mass spectrometry in the blood serum, the brain (including different brain regions), and other target organs such as liver, kidney, and colon. Our results indicate that the Nanoligomer cocktail has a strong safety profile and shows high biodistribution (F ∼ 0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum of ∼30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and prediction of therapeutic dosage between different routes of administration.}, } @article {pmid39538364, year = {2024}, author = {Terra, R and Éthier, V and Busque, L and Morin-Quintal, A and D'Angelo, G and Hébert, J and Wang, X and Lépine, G and LeBlanc, R and Bergeron, J}, title = {Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {}, number = {}, pages = {}, doi = {10.1002/cyto.b.22213}, pmid = {39538364}, issn = {1552-4957}, support = {//BD Biosciences/ ; }, abstract = {Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.}, } @article {pmid39538124, year = {2024}, author = {Sun, Y and Hu, S and Lan, Y and Wang, R and Wei, S and Huang, H and Cui, H and Li, X and Huang, Z}, title = {Investigation of resistance mechanisms to flucarbazone-sodium in wild oat (Avena fatua L.) from China.}, journal = {BMC plant biology}, volume = {24}, number = {1}, pages = {1073}, pmid = {39538124}, issn = {1471-2229}, mesh = {*Avena/genetics/drug effects ; China ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Plant Weeds/genetics/drug effects ; }, abstract = {BACKGROUND: Wild oat (Avena fatua L.) is a self-pollinating, allohexaploid species in the family Gramineae (grasses), which is a malignant weed that mainly harms crops such as wheat. In recent years, a decline in the control efficiency of flucarbazone-sodium against wild oat has occurred in some regions of China.

RESULTS: We identified an ALS-resistant A. fatua population (R population). Whole-plant response assays revealed that the R population exhibited a moderate level of resistance (5.9-fold) to flucarbazone-sodium. Pre-treatment with malathion significantly reduced flucarbazone-sodium resistance in the R population. The known mutation sites and ALS gene relative expression that confer resistance to ALS inhibitor herbicides were not found in R population. Following flucarbazone-sodium treatment, the expression of eight genes related to metabolic enzymes was investigated using quantitative real-time PCR (qRT-PCR). CYP92A6 and the Aldo/keto reductase family were highly expressed in the R population after the application of flucarbazone-sodium.

CONCLUSIONS: The mechanism of flucarbazone-sodium resistance in A. fatua is mediated by NTSR, nor TSR. Two genes, CYP92A6 and the Aldo/keto reductase family, were discovered to be possibly related in the metabolism of NTSR in the A. fatua population, justifying more functional studies. The results will serve as a data resource for further studies on the molecular mechanisms of A. fatua to flucarbazone-sodium.}, } @article {pmid39537536, year = {2024}, author = {Zou, J and Meng, X and Hong, Z and Rao, Y and Wang, K and Li, J and Yu, H and Wang, C}, title = {Cas9-PE: a robust multiplex gene editing tool for simultaneous precise editing and site-specific random mutation in rice.}, journal = {Trends in biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tibtech.2024.10.012}, pmid = {39537536}, issn = {1879-3096}, abstract = {In molecular design breeding, the simultaneous introduction of desired functional genes through specific nucleotide modifications and the elimination of genes regulating undesired phenotypic traits or agronomic components require advanced gene editing tools. Due to limited editing efficiency, even with the use of highly precise editing tools, such as prime editing (PE), simultaneous editing of multiple mutation types poses a challenge. Here, we replaced Cas9 nickase (nCas9) with Cas9 to construct a Cas9-mediated PE (Cas9-PE) system in rice. This system not only enables precise editing, but also allows for site-specific random mutation. Moreover, leveraging the precision of Cas9-PE, we established a transgene-free multiplex gene editing system using a co-editing strategy. This strategy involved the Agrobacterium-mediated transient expression of the precise editing rice endogenous acetolactate synthase gene ALS[S627I] to confer herbicide bispyribac-sodium (BS) resistance as a selection marker. This study provides a versatile and efficient multiplex gene editing tool for molecular design breeding.}, } @article {pmid39536963, year = {2025}, author = {Casiraghi, V and Sorce, MN and Santangelo, S and Invernizzi, S and Bossolasco, P and Lattuada, C and Battaglia, C and Venturin, M and Silani, V and Colombrita, C and Ratti, A}, title = {Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115057}, doi = {10.1016/j.expneurol.2024.115057}, pmid = {39536963}, issn = {1090-2430}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Oxidative Stress/drug effects/physiology ; *Sirolimus/pharmacology ; *TDP-43 Proteinopathies/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined. In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin. Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.}, } @article {pmid39536438, year = {2024}, author = {Henderson, NL and Ortiz-Olguin, E and Bourne, G and Pywell, C and Rose, JB and Williams, GR and Nipp, RD and Rocque, GB}, title = {Implementation of ePROs Into Multidisciplinary Tumor Board Discussions for Patients With Pancreatic Cancer: The INSPIRE Intervention.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {602-609}, doi = {10.6004/jnccn.2024.7052}, pmid = {39536438}, issn = {1540-1413}, mesh = {Humans ; *Pancreatic Neoplasms/therapy ; Female ; Male ; *Patient Reported Outcome Measures ; Aged ; Middle Aged ; Patient Care Team/standards ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The incorporation of electronic patient-reported outcomes (ePROs), such as the Geriatric Assessment (GA) and treatment preferences, into decision-making for pancreatic cancer has been limited by clinician- and system-level barriers concerning workflow. We hypothesized that ePRO inclusion within multidisciplinary tumor boards (MDTBs) would circumvent barriers and provide a venue for systematic consideration of critical patient-provided information.

PATIENTS AND METHODS: The INtegrating Systematic PatIent-Reported Evaluations (INSPIRE) intervention consists of (1) patient survey completion, including GA and patient preferences, and (2) screensharing patient ePROs during MDTBs. Proctor et al's implementation outcomes were assessed, with penetration (the proportion of consented patients who were presented at MDTBs) acting as the primary outcome (considered successful at 70%). Secondary outcomes included adoption, feasibility, acceptability, appropriateness, cost, and sustainability, assessed by clinician post-MDTB exit surveys, clinician postintervention surveys, clinician postintervention semistructured interviews, and time-coding analysis of recorded and transcribed historical (November 2021-February 2022) and intervention (September 2022-June 2023) MDTBs.

RESULTS: A total of 50 patients completed surveys and all were presented at MDTBs (penetration=100%). All eligible clinicians (n=9) enrolled patients (adoption=100%) and reported that ePROs were useful in 90% and led to a change in treatment plan in 30% of cases. In postintervention surveys and interviews, clinicians primarily responded positively to feasibility, acceptability, and appropriateness questions. Time-coding analysis found a modest time cost of an additional 51.1 seconds in mean discussion time-per-patient between preintervention (mean [SD], 172.7 [111.4] seconds) and intervention patients (mean [SD], 223.8 [107.1] seconds); 86% of clinicians reported the intervention did not take too much time. All surveyed clinicians reported interest in continuing the intervention and suggested adaptations to further promote sustainability.

CONCLUSIONS: The integration of ePROs into pancreatic MDTBs was feasible and acceptable, providing a potential approach to increase the utilization of ePROs by clinical teams in their management of patients with pancreatic cancer.}, } @article {pmid39535960, year = {2024}, author = {Soares, RV and Pedrosa, RBDS and Sandars, J and Cecilio-Fernandes, D}, title = {The importance of combined use of spacing and testing effects for complex skills training: A quasi-experimental study.}, journal = {Medical teacher}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/0142159X.2024.2427735}, pmid = {39535960}, issn = {1466-187X}, abstract = {INTRODUCTION: A major challenge is retention of complex clinical skills. Spacing training and testing have been demonstrated to increase knowledge and skill retention but the combination has not been previously investigated in complex clinical skills. The aim of our study was to compare the effectiveness of combined spacing and testing for Basic Life Support (BLS) and Advance Life Support (ALS) simulation training in one group (intervention group), with combined spacing and testing, and another group (control) that received simulation training in a single-session simulation training without testing.

METHODS: A quasi-experimental study.

RESULTS: Thirteen nursing students were in the intervention group and 18 in the control group. After three months, there was no significant reduction in retention of BLS knowledge (p > 0.05) or BLS skills (p < 0.05) in the intervention group, but there was a significant reduction in both (p < 0.05) in the control group. We found no significant reduction in retention of ALS knowledge in the control group (p > 0.05), but there was a significant reduction in the intervention group (p < 0.05). There was no significant decay of ALS skills in both groups (p < 0.05).

DISCUSSION: This is the first study to demonstrate that combined spacing and testing could be highly effective for complex skills simulation training to increase retention after three months.}, } @article {pmid39535924, year = {2024}, author = {Hannestad, J and Smith, S and Lam, A and Hurt, J and Harada, N and Kim, R and Das, A and Brunello, J and Whitaker, G and Chalmers, D and Senjoti, F and Lin, W and Coghill, J and Bansal, Y and Sidhu, S and Zann, V and Liu, E}, title = {A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.}, journal = {Clinical and translational science}, volume = {17}, number = {11}, pages = {e70064}, pmid = {39535924}, issn = {1752-8062}, mesh = {Humans ; Male ; *Food-Drug Interactions ; Adult ; Administration, Oral ; *Healthy Volunteers ; Young Adult ; Middle Aged ; Area Under Curve ; Double-Blind Method ; Dose-Response Relationship, Drug ; Methylcellulose/administration & dosage/analogs & derivatives/chemistry ; Spray Drying ; Suspensions ; Cross-Over Studies ; Placebos/administration & dosage ; }, abstract = {TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.}, } @article {pmid39534418, year = {2024}, author = {Wang, WL and Tam, PKH and Chen, Y}, title = {Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth.}, journal = {World journal of gastroenterology}, volume = {30}, number = {41}, pages = {4490-4495}, pmid = {39534418}, issn = {2219-2840}, mesh = {Humans ; *Carcinoma, Hepatocellular/pathology/metabolism ; *Liver Neoplasms/pathology/metabolism ; *Tumor-Associated Macrophages/metabolism/immunology ; *Cell Proliferation ; *Wnt Signaling Pathway ; *Tumor Microenvironment ; Cell Movement ; Animals ; Disease Progression ; Macrophage Activation ; }, abstract = {In this article, we comment on the article by Huang et al. The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer. Tumor-associated macrophages (TAMs), primarily of the M2 subtype, are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways, including the wingless/integrated (Wnt) pathway. Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization, which in turn can exacerbate hepatocarcinoma cell proliferation and migration. This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer, highlighting the potential therapeutic benefits of inhibiting the Wnt pathway. Lastly, we point out areas in Huang et al's study that require further research, providing guidance and new directions for similar studies.}, } @article {pmid39525702, year = {2024}, author = {Ravichandran, VV and Coleman, E and Brown, A and Boh, E}, title = {Response to Rodríguez-Cuadrado et al's "Clinical, histopathologic, immunohistochemical, and electron microscopic findings in cutaneous monkeypox: A multicenter retrospective case series in Spain".}, journal = {JAAD case reports}, volume = {53}, number = {}, pages = {149-150}, pmid = {39525702}, issn = {2352-5126}, } @article {pmid39524179, year = {2024}, author = {Trinh, QD and Mai, HN and Pham, DT}, title = {Application of mesenchymal stem cells for neurodegenerative diseases therapy discovery.}, journal = {Regenerative therapy}, volume = {26}, number = {}, pages = {981-989}, pmid = {39524179}, issn = {2352-3204}, abstract = {Neurodegenerative diseases are central or peripheral nervous system disorders associated with progressive brain cell degeneration. Common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis have been widely studied. However, current therapeutics only reduce the symptoms and do not ameliorate the pathogenesis of these diseases. Recent studies suggested the roles of neuroinflammation, apoptosis, and oxidative stress in neurodegenerative diseases. Mesenchymal stem cells (MSCs) exert anti-apoptotic, anti-inflammatory, and antioxidative effects. Therefore, investigating the effects of MSCs and their applications may lead to the discovery of more effective therapies for neurodegenerative diseases. In this study, we review different approaches used to identify therapies for neurodegenerative diseases using MSCs.}, } @article {pmid39534515, year = {2024}, author = {Watanabe, S and Sekiguchi, K and Suehiro, H and Yoshikawa, M and Noda, Y and Kamiyama, N and Matsumoto, R}, title = {Decreased diaphragm moving distance measured by ultrasound speckle tracking reflects poor prognosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {252-260}, pmid = {39534515}, issn = {2467-981X}, abstract = {OBJECTIVE: Decreased cephalocaudal diaphragm movement may indicate respiratory dysfunction in amyotrophic lateral sclerosis (ALS). We aimed to evaluate diaphragm function in ALS using ultrasound speckle tracking, an image-analysis technology that follows similar pixel patterns.

METHODS: We developed an offline application that tracks pixel patterns of recorded ultrasound video images using speckle-tracking methods. Ultrasonography of the diaphragm movement during spontaneous quiet respiration was performed on 19 ALS patients and 21 controls to measure the diaphragm moving distance (DMD) in the cephalocaudal direction during a single respiration. We compared respiratory function measures and analyzed the relationship between the clinical profiles and DMD.

RESULTS: DMD was significantly lower in ALS patients than in the control group (0.6 ± 1.4 mm vs 2.2 ± 2.2 mm, p < 0.01) and positively correlated with phrenic nerve compound motor action potential amplitude (R = 0.63, p = 0.01). DMD was negatively correlated with the change in the ALS Functional Rating Scale-Revised scores per month after the exam (R = -0.61, p = 0.02), and those with a larger rate of decline had a significantly lower DMD (p = 0.03).

CONCLUSIONS: Diaphragm ultrasound speckle tracking enabled the detection of diaphragm dysfunction in ALS.

SIGNIFICANCE: Diaphragm ultrasound speckle tracking may be useful for predicting prognosis.}, } @article {pmid39534483, year = {2024}, author = {Sbarigia, C and Rome, S and Dini, L and Tacconi, S}, title = {New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the 'dying back' hypothesis.}, journal = {Journal of extracellular biology}, volume = {3}, number = {11}, pages = {e70019}, pmid = {39534483}, issn = {2768-2811}, abstract = {Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, and is characterized by muscle weakness, paralysis and ultimately, respiratory failure. The exact causes of ALS are not understood, though it is believed to combine genetic and environmental factors. Until now, it was admitted that motor neurons (MN) in the brain and spinal cord degenerate, leading to muscle weakness and paralysis. However, as ALS symptoms typically begin with muscle weakness or stiffness, a new hypothesis has recently emerged to explain the development of the pathology, that is, the 'dying back hypothesis', suggesting that this degeneration starts at the connections between MN and muscles, resulting in the loss of muscle function. Over time, this damage extends along the length of the MN, ultimately affecting their cell bodies in the spinal cord and brain. While the dying back hypothesis provides a potential framework for understanding the progression of ALS, the exact mechanisms underlying the disease remain complex and not fully understood. In this review, we are positioning the role of extracellular vesicles as new actors in ALS development.}, } @article {pmid39534022, year = {2024}, author = {Li, Y and Bhinge, A and Inoue, S and Garcia, G}, title = {Editorial: Noncoding RNAs in neurodegenerative disorders: from current insights and future directions to translational modeling and therapeutic approaches.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1497673}, pmid = {39534022}, issn = {1662-4548}, } @article {pmid39531950, year = {2025}, author = {Kacem, I and Sghaier, I and Ben Rhouma, H and Ratti, A and Ticozzi, N and Silani, V and Gouider-Khouja, N and Gouider, R}, title = {Association of Amyotrophic Lateral Sclerosis and Dopa-responsive dystonia in a Tunisian patient.}, journal = {Parkinsonism & related disorders}, volume = {130}, number = {}, pages = {107171}, doi = {10.1016/j.parkreldis.2024.107171}, pmid = {39531950}, issn = {1873-5126}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Dystonic Disorders/genetics/drug therapy ; Tunisia ; Male ; GTP Cyclohydrolase/genetics ; Female ; Adult ; }, abstract = {Dopa-responsive dystonia (DRD) is an autosomal dominant disease with parkinsonian and dystonic symptoms caused by GCH1 gene pathogenic variants affecting dopamine synthesis. The present case report is the first to link DRD with childhood-onset with ALS, suggesting that complex inheritance patterns in the North African population may contribute to multiple disorders.}, } @article {pmid39531940, year = {2024}, author = {Pioro, EP and Brooks, BR and Liu, Y and Zhang, J and Apple, S}, title = {Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial.}, journal = {Journal of the neurological sciences}, volume = {467}, number = {}, pages = {123290}, doi = {10.1016/j.jns.2024.123290}, pmid = {39531940}, issn = {1878-5883}, mesh = {Humans ; *Edaravone/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Middle Aged ; Aged ; Treatment Outcome ; Double-Blind Method ; Free Radical Scavengers/therapeutic use/administration & dosage ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups.

METHODS: Disease trajectories of MCI186-19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories.

RESULTS: ALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186-19 double-blind period. Latent classes 2-4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects.

CONCLUSIONS: This post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.}, } @article {pmid39529471, year = {2025}, author = {Trojsi, F and Canna, A and Sharbafshaaer, M and di Nardo, F and Canale, F and Passaniti, C and Pirozzi, MA and Silvestro, M and Orologio, I and Russo, A and Cirillo, M and Tessitore, A and Siciliano, M and Esposito, F}, title = {Brain neurovascular coupling in amyotrophic lateral sclerosis: Correlations with disease progression and cognitive impairment.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16540}, pmid = {39529471}, issn = {1468-1331}, support = {NRRP project MNESYS (PE0000006, to NT)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Disease Progression ; Middle Aged ; *Cognitive Dysfunction/physiopathology/etiology/diagnostic imaging ; Aged ; *Magnetic Resonance Imaging ; *Neurovascular Coupling/physiology ; Adult ; *Brain/physiopathology/diagnostic imaging/blood supply ; Nerve Net/diagnostic imaging/physiopathology ; Default Mode Network/physiopathology/diagnostic imaging ; }, abstract = {BACKGROUND AND PURPOSE: 'Neurovascular coupling' (NVC) alterations, assessing the interplay between local cerebral perfusion and neural activity within a given brain region or network, may reflect neurovascular unit impairment in amyotrophic lateral sclerosis (ALS). The aim was to explore NVC as a correlation between the functional connectivity and cerebral blood flow within the large-scale resting-state functional magnetic resonance imaging brain networks in a sample of ALS patients compared to healthy controls (HCs).

METHODS: Forty-eight ALS patients (30 males; mean age 60.64 ± 9.62 years) and 32 HC subjects (14 males; mean age 55.06 ± 16 years) were enrolled and underwent 3 T magnetic resonance imaging. ALS patients were screened by clinical and neuropsychological scales and were retrospectively classified as very fast progressors (VFPs), fast progressors and slow progressors (SPs).

RESULTS: Neurovascular coupling reduction within the default mode network (DMN) (p = 0.005) was revealed in ALS patients compared to HCs, observing, for this network, significant NVC differences between VFP and SP groups. Receiver operating characteristic curve analysis showed that impaired NVC in the DMN at baseline best discriminated VFPs and SPs (area under the curve 75%). Significant correlations were found between NVC and the executive (r = 0.40, p = 0.01), memory (r = 0.32, p = 0.04), visuospatial ability (r = 0.40, p = 0.01) and non-ALS-specific (r = 0.40, p = 0.01) subscores of the Edinburgh Cognitive and Behavioural ALS Screen.

CONCLUSIONS: The reduction of brain NVC in the DMN may reflect largely distributed abnormalities of the neurovascular unit. NVC alterations in the DMN could play a role in anticipating a faster clinical progression in ALS patients, aiding patient selection and monitoring during clinical trials.}, } @article {pmid39528814, year = {2024}, author = {Ovchinnikova, LA and Dzhelad, SS and Simaniv, TO and Zakharova, MN and Lomakin, YA and Gabibov, AG and Illarioshkin, SN}, title = {Development of a Panel of Biomarkers for Differential Diagnosis of Multiple Sclerosis.}, journal = {Doklady. Biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {39528814}, issn = {1608-3091}, abstract = {Demyelinating diseases are a group of heterogeneous pathologies that affect the nervous system and reduce the quality of life. One of such diseases is multiple sclerosis (MS), an inflammatory autoimmune neurodegenerative disease of the central nervous system (CNS). At the initial stages, MS can mimic some infectious, neoplastic, genetic, metabolic, vascular, and other pathologies. Accurate differential diagnosis of this disease is important to improve the quality of life of patients and reduce possible irreversible damage to the central nervous system. In this work, we confirmed the possibility of using our previously proposed candidate panel of MS biomarkers to distinguish MS from neuromyelitis optica spectrum disorder (NMOSD) and amyotrophic lateral sclerosis (ALS). We have shown that our proposed panel (SPTAN1601-644 + PRX451-494 + PTK6301-344 + LMP1285-330) allows us to distinguish MS from ALS (AUC = 0.796) and NMOSD (AUC = 0.779).}, } @article {pmid39526716, year = {2024}, author = {Šljivo, A and Jevtić, T and Siručić, I and Terzić-Salihbašić, S and Abdulkhaliq, A and Reiter, L and Salihbašić, F and Bečar-Alijević, A and Alijević, A and Dadić, I and Gavrankapetanović, F}, title = {Out-of-hospital cardiac arrest (OHCA) in Bosnia and Herzegovina in the period 2018-2022: current trends, usage of automated external defibrillators (AED) and bystanders' involvement.}, journal = {Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina}, volume = {21}, number = {2}, pages = {267-273}, doi = {10.17392/1719-21-2}, pmid = {39526716}, issn = {1840-2445}, abstract = {AIM: To investigate out-of-hospital cardiac arrest (OHCA) trend, provided advanced life support (ALS) measures, automated external defibrillator (AEDs) utilization and bystanders' involvement in cardiopulmonary resuscitation (CPR) during OHCA incidents.

METHODS: This cross-sectional study encompassed data pertaining to all OHCA incidents attended to by the Emergency Medical Service of Canton Sarajevo, Bosnia and Herzegovina, covering the period from January 2018 to December 2022.

RESULTS: Among a total of 1131 OHCA events, 236 (20.8 %) patients achieved return of spontaneous circulation (ROSC); there were 175 (74.1%) males and 61 (25.9%) females. The OHCA incidence was 54/100,000 inhabitants per year. After a 30-day period post-ROSC, 146 (61.9%) patients fully recovered, while 90 (38.1%) did not survive during this timeframe. Younger age (p<0.05), initial rhythm of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) (p<0.05), and faster emergency medical team (EMT) response time (p<0.05) were significantly associated with obtaining ROSC. Only 38 (3.3%) OHCA events were assisted by bystanders, who were mostly medical professionals, 25 (65.7%), followed by close family members, 13 (34.3%). There was no report of AED usage.

CONCLUSION: This follow-up study showed less ROSC achievement, similar bystanders' involvement, similar factors associated with achieving ROSC (age, EMT response time), and a decline in OHCA events (especially in year 2021 and 2022) compared to our previous study (2015-2019). There was an extremely low rate of bystander engagement and no AEDs usage. Governments and health organizations must swiftly improve public awareness, promote better practice (basic life support), and actively encourage bystander participation.}, } @article {pmid39523617, year = {2024}, author = {Iguchi, Y and Katsuno, M}, title = {[Current Status of Drug Development for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1241-1249}, doi = {10.11477/mf.1416202766}, pmid = {39523617}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; Clinical Trials as Topic ; Animals ; Riluzole/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease of motor neuron. Although riluzole and edaravone have been approved for the treatment of ALS, it remains a lethal disease that causes rapid motor impairment, and there is an urgent need to develop more effective treatments. Advances in understanding the pathomechanisms of ALS, efficient clinical trial design, and research support programs have led to many clinical trials for ALS both domestically and internationally.}, } @article {pmid39523616, year = {2024}, author = {Ishiguro, T and Nagata, T and Yokota, T}, title = {[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1233-1239}, doi = {10.11477/mf.1416202765}, pmid = {39523616}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.}, } @article {pmid39523615, year = {2024}, author = {Ogino, M}, title = {[Palliative Care for Persons with Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1225-1232}, doi = {10.11477/mf.1416202764}, pmid = {39523615}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Analgesics, Opioid/administration & dosage ; Japan ; *Palliative Care ; }, abstract = {Palliative care in Japan is available mainly for patients with cancer, and palliative care specialists do not have sufficient experience with management of palliation in persons with amyotrophic lateral sclerosis (ALS). Treatment of ALS symptoms is an important component of palliative care, and it is important that neurologists and home care physicians familiarize themselves with palliative care for ALS in consultation with palliative care specialists. Notably, the use of opioids at the end of life differs from that of pain relief for cancer. Physicians should be mindful that opioids are not a perfect solution for palliative care of persons with ALS.}, } @article {pmid39523614, year = {2024}, author = {Yamakawa, I and Urushitani, M}, title = {[Gold Coast Criteria: A New Diagnostic Paradigm in the Era of Disease-Modifying Therapy for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1217-1223}, doi = {10.11477/mf.1416202763}, pmid = {39523614}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Humans ; }, abstract = {Significant progress has been made in the development of disease-modifying drugs for amyotrophic lateral sclerosis (ALS), with the introduction of tofersen, an antisense oligonucleotide drug for familial ALS, marking a turning point in the treatment. These drugs are most effective when administered early in the disease course, highlighting the need for improved diagnostic sensitivity. The 2020 Gold Coast Diagnostic Criteria allow ALS diagnosis in cases without upper motor neuron symptoms, potentially increasing early detection rates. However, careful differential diagnoses are necessary when applying these criteria to maintain diagnostic specificity. This review outlines the key points to consider when using the Gold Coast Criteria, balancing the need for an early diagnosis with caution to avoid overdiagnosis.}, } @article {pmid39523613, year = {2024}, author = {Fukutake, T}, title = {[Diagnosis, Notification, and Managements of ALS: A Personal Perspective from 40 years of Experience as a Clinical Neurologist].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1205-1216}, doi = {10.11477/mf.1416202762}, pmid = {39523613}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; *Neurologists ; Female ; Middle Aged ; Male ; Aged ; }, abstract = {This narrative summary presents the author's 40-year experience as a clinical neurologist who treated patients with amyotrophic lateral sclerosis (ALS). Five representative cases from the author's first 20 years at Chiba University Hospital and its affiliated hospitals were selected, including a patient of respiratory-onset who was ignorantly extubated by a female relative for patient's distress to the intratracheal tube. Based on the latter 20 years of experience at the author's current hospital, the author first describes a famous patient with ALS who was being treated at this medical center before the author was assigned to this hospital and fought against ALS for 31 years before eventually succumbing to total locked-in syndrome. Thereafter, the author has summarized the ages, sex, phenotypes, comorbidities, responses to the available treatment options, and total number of years that have elapsed for the 24 patients that the author initially examined in the outpatient clinic. In terms of diagnostic delay, the author describes "foot drop" in patients who developed lower limb symptoms, and hoarseness in those who developed bulbar palsy. Furthermore, the author discusses issues regarding family caregiving capacity, patient's and families' understanding of notification, and medical management (i.e., medications, rehabilitation for ADL, nutrition and respiration, complications of frontotemporal dementia, and medical cooperation with other clinics and hospitals).}, } @article {pmid39522728, year = {2024}, author = {Lauck, KC and Narayanan, D and Tolkachjov, SN}, title = {Regarding response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.10.059}, pmid = {39522728}, issn = {1097-6787}, } @article {pmid39522725, year = {2024}, author = {Tsai, SY}, title = {Response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.08.085}, pmid = {39522725}, issn = {1097-6787}, } @article {pmid39522723, year = {2024}, author = {Nardone, V and Esposito, A and D'Ippolito, E and Argenziano, G and Reginelli, A and Troiani, T}, title = {Response to Sajid et al's "Response to Valerio Nardone et al's 'Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.10.058}, pmid = {39522723}, issn = {1097-6787}, } @article {pmid39522697, year = {2024}, author = {Gao, L and Yang, XN and Dong, YX and Han, YJ and Zhang, XY and Zhou, XL and Liu, Y and Liu, F and Fang, JS and Ji, JL and Gao, ZR and Qin, XM}, title = {The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products.}, journal = {Pharmacology & therapeutics}, volume = {264}, number = {}, pages = {108751}, doi = {10.1016/j.pharmthera.2024.108751}, pmid = {39522697}, issn = {1879-016X}, mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.}, } @article {pmid39522672, year = {2025}, author = {Shapiro, O and Woods, C and Gleixner, AM and Sannino, S and Ngo, M and McDaniels, MD and Wipf, P and Hukriede, NA and Donnelly, CJ and Brodsky, JL}, title = {Assays to measure small molecule Hsp70 agonist activity in vitro and in vivo.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115712}, doi = {10.1016/j.ab.2024.115712}, pmid = {39522672}, issn = {1096-0309}, mesh = {*HSP70 Heat-Shock Proteins/metabolism/agonists ; Animals ; *Zebrafish ; Humans ; Small Molecule Libraries/pharmacology/chemistry ; Optogenetics/methods ; DNA-Binding Proteins/agonists/metabolism ; }, abstract = {Hsp70 prevents protein aggregation and is cytoprotective, but sustained Hsp70 overexpression is problematic. Therefore, we characterized small molecule agonists that augment Hsp70 activity. Because cumbersome assays were required to assay agonists, we developed cell-based and in vivo assays in which disease-associated consequences of Hsp70 activation can be quantified. One assay uses an optogenetic system in which the formation of TDP-43 inclusions can be controlled, and the second assay employs a zebrafish model for acute kidney injury (AKI). These complementary assays will facilitate future work to identify new Hsp70 agonists as well as optimized agonist derivatives.}, } @article {pmid39521994, year = {2024}, author = {Liang, H and Zhou, X and Zhang, J and Xu, W and Liu, Y and Wang, X and Hu, Y and Xu, R and Li, X}, title = {The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {206}, pmid = {39521994}, issn = {1528-3658}, support = {81960244//National Natural Science Foundation of China/ ; 20212BAB216026//Jiangxi Natural Science Foundation/ ; 202110016//Science and Technology Plan of Jiangxi Provincial Health Commission/ ; 2022B975//Science and Technology Plan of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Animals ; *Apigenin/pharmacology/therapeutic use ; Mice ; *Signal Transduction/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; *NF-E2-Related Factor 2/metabolism/genetics ; Oxidative Stress/drug effects ; Aldehyde Dehydrogenase 1 Family/metabolism/genetics ; Humans ; Apoptosis/drug effects ; Retinal Dehydrogenase/metabolism/genetics ; Cell Line ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.

METHODS: We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.

RESULTS: APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.

CONCLUSIONS: Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.}, } @article {pmid39520580, year = {2024}, author = {Hyldgaard Andersen, S and Harsløf, S and Tøttrup, A}, title = {Laparoscopic ileopexy for afferent loop syndrome after restorative proctocolectomy-a retrospective case series.}, journal = {International journal of colorectal disease}, volume = {39}, number = {1}, pages = {180}, pmid = {39520580}, issn = {1432-1262}, mesh = {Humans ; *Proctocolectomy, Restorative/adverse effects ; *Laparoscopy/adverse effects ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Afferent Loop Syndrome/surgery/etiology ; *Ileum/surgery ; Aged ; Treatment Outcome ; Postoperative Complications/etiology/surgery ; }, abstract = {BACKGROUND: To study the effect of laparoscopic ileopexy in patients with afferent-loop syndrome (ALS) after restorative proctocolectomy (RP).

METHOD: Ileopexy has been the treatment of choice in patients with ALS for the last 5 years at our department. All patients who had undergone ileopexy for ALS between January 2019 and August 2023 were identified. Data were extracted from the medical records. All patients were contacted and asked standardized questions regarding symptoms of ALS. A symptom score was calculated and compared before surgery and at the last follow-up.

RESULTS: Ten patients, who had undergone ileopexy for ALS, were identified. Eight of these (80%) had been admitted with small bowel obstruction due to ALS. The remaining 2 patients had other symptoms indicative of ALS. In all patients, ileopexy was immediately effective in reducing symptoms. Symptoms recurred after 16.5 weeks (2-80) in 8 patients. Repeat laparoscopy showed that the ileopexy had slipped in 6 of these. Six had a new ileopexy with mesh. Later, one of these developed recurrent symptoms and had a new mesh ileopexy performed. No mesh complications were seen. Symptom score was reduced from 6.5 (1-9) to 2 (0-7) (p = 0.02) at the last follow-up.

CONCLUSIONS: In this study, ileopexy is effective in reducing symptoms of ALS after RP. In a high proportion of patients, it is necessary to use mesh to ensure long-term fixation of the ileum.}, } @article {pmid39520508, year = {2024}, author = {Larose, A and Miller, CCJ and Mórotz, GM}, title = {The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {447}, pmid = {39520508}, issn = {1420-9071}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/enzymology ; Animals ; *Neurons/metabolism/pathology ; Cyclin-Dependent Kinase 5/metabolism/genetics ; Signal Transduction ; Synapses/metabolism/pathology ; Protein-Tyrosine Kinases/metabolism/genetics ; Phosphorylation ; Axonal Transport ; Glycogen Synthase Kinase 3 beta/metabolism ; }, abstract = {The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.}, } @article {pmid39519213, year = {2024}, author = {Bova, V and Mannino, D and Capra, AP and Lanza, M and Palermo, N and Filippone, A and Esposito, E}, title = {CK and LRRK2 Involvement in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519213}, issn = {1422-0067}, mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Mutation ; Phosphorylation ; Autophagy/genetics ; }, abstract = {Neurodegenerative diseases (NDDs) are currently the most widespread neuronal pathologies in the world. Among these, the most widespread are Alzheimer's disease (AD), dementia, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)-all characterized by a progressive loss of neurons in specific regions of the brain leading to varied clinical symptoms. At the basis of neurodegenerative diseases, an emerging role is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alteration of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal death. Important in the neurodegeneration process is the upregulation of casein kinase (CK), which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in PD and HD, and increasing the accumulation of the amyloid-β protein (Aβ) for AD. Recent research has identified CK of the kinases upstream of LRRK2 as a regulator of the stability of the LRRK2 protein. Based on this evidence, this review aims to understand the direct involvement of individual kinases in NDDs and how their crosstalk may impact the pathogenesis and early onset of neurodegenerative diseases.}, } @article {pmid39519209, year = {2024}, author = {Firdaus, Z and Li, X}, title = {Epigenetic Explorations of Neurological Disorders, the Identification Methods, and Therapeutic Avenues.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519209}, issn = {1422-0067}, support = {DK129241 DK126662/GF/NIH HHS/United States ; }, mesh = {Humans ; *Epigenesis, Genetic ; *DNA Methylation ; Neurodegenerative Diseases/genetics/therapy ; Animals ; Nervous System Diseases/genetics/therapy ; Histones/metabolism/genetics ; Epigenomics/methods ; Histone Code/genetics ; }, abstract = {Neurodegenerative disorders are major health concerns globally, especially in aging societies. The exploration of brain epigenomes, which consist of multiple forms of DNA methylation and covalent histone modifications, offers new and unanticipated perspective into the mechanisms of aging and neurodegenerative diseases. Initially, chromatin defects in the brain were thought to be static abnormalities from early development associated with rare genetic syndromes. However, it is now evident that mutations and the dysregulation of the epigenetic machinery extend across a broader spectrum, encompassing adult-onset neurodegenerative diseases. Hence, it is crucial to develop methodologies that can enhance epigenetic research. Several approaches have been created to investigate alterations in epigenetics on a spectrum of scales-ranging from low to high-with a particular focus on detecting DNA methylation and histone modifications. This article explores the burgeoning realm of neuroepigenetics, emphasizing its role in enhancing our mechanistic comprehension of neurodegenerative disorders and elucidating the predominant techniques employed for detecting modifications in the epigenome. Additionally, we ponder the potential influence of these advancements on shaping future therapeutic approaches.}, } @article {pmid39518442, year = {2024}, author = {Laucius, O and Drūteika, J and Balnytė, R and Palačionytė, J and Ališauskienė, M and Petrikonis, K and Vaitkus, A}, title = {Phrenic Nerve Sonography Alterations in Patients with ALS: Insight with Clinical and Neurophysiological Findings.}, journal = {Journal of clinical medicine}, volume = {13}, number = {21}, pages = {}, pmid = {39518442}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, and although the diagnosis is primarily based on clinical criteria, ENMG, as the "gold standard", does not always show detectable changes. Therefore, our study suggests that alterations in echogenicity and heterogeneity of the phrenic nerve (PN) may serve as potential additional diagnostic tools for ALS. Methods: Our study included 32 patients in the ALS group and 64 individuals in the control group. Each participant underwent an interview and completed questionnaires to collect clinical and demographic data, including age, gender, height, body mass index (BMI), hip and waist circumference, duration of illness, ALS-FRS-R score, comorbidities, and medication use. Ultrasound examinations of the PN were performed by two authors using a high-resolution "Philips EPIQ 7" ultrasound machine equipped with a linear 4-18 MHz transducer. The ALS group participants underwent PN sonography and conduction examinations, arterial blood gas (ABG) analysis, respiratory function tests (RFT), and electroneuromyography (ENMG). Results: The study demonstrated that the phrenic nerve is significantly smaller on both sides in patients with ALS compared to the control group (p < 0.01). Changes in the homogeneity and echogenicity of the PN were also observed on both sides. On the right side, 43.8% of the nerves showed heterogeneity, 40.6% were isoechoic, and 21.9% were hyperechoic. On the left side, 59.4% of the nerves exhibited heterogeneity, 34.4% were isoechoic, and 28.1% were hyperechoic. Moreover, sonography on both sides showed significant correlation with ALS-FRS-R, COMPASS-31, and ENMG results. Conclusions: Our study highlights the importance of phrenic nerve ultrasound as a promising supplementary diagnostic tool for ALS. The significant differences in phrenic nerve size, echogenicity, and homogeneity between patients with ALS and the control group demonstrate that ultrasound imaging can detect morphological changes in the phrenic nerve. Incorporating phrenic nerve ultrasound into routine diagnostic protocols could improve early detection, enhance disease monitoring, and offer a more comprehensive understanding of the neurodegenerative processes in ALS.}, } @article {pmid39517754, year = {2024}, author = {Ciou, TS and Lin, CH and Wang, CK}, title = {Airborne LiDAR Point Cloud Classification Using Ensemble Learning for DEM Generation.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {21}, pages = {}, pmid = {39517754}, issn = {1424-8220}, abstract = {Airborne laser scanning (ALS) point clouds have emerged as a predominant data source for the generation of digital elevation models (DEM) in recent years. Traditionally, the generation of DEM using ALS point clouds involves the steps of point cloud classification or ground point filtering to extract ground points and labor-intensive post-processing to correct the misclassified ground points. The current deep learning techniques leverage the ability of geometric recognition for ground point classification. However, the deep learning classifiers are generally trained using 3D point clouds with simple geometric terrains, which decrease the performance of model inferencing. In this study, a point-based deep learning model with boosting ensemble learning and a set of geometric features as the model inputs is proposed. With the ensemble learning strategy, this study integrates specialized ground point classifiers designed for different terrains to boost classification robustness and accuracy. In experiments, ALS point clouds containing various terrains were used to evaluate the feasibility of the proposed method. The results demonstrated that the proposed method can improve the point cloud classification and the quality of generated DEMs. The classification accuracy and F1 score are improved from 80.9% to 92.2%, and 82.2% to 94.2%, respectively, by using the proposed methods. In addition, the DEM generation error, in terms of mean squared error (RMSE), is reduced from 0.318-1.362 m to 0.273-1.032 m by using the proposed ensemble learning.}, } @article {pmid39515011, year = {2024}, author = {Mauri, L and Taccaliti, F and Lingua, E}, title = {Modeling the interaction between wildfires and windthrows: A pilot case study for Italian Alps.}, journal = {Journal of environmental management}, volume = {371}, number = {}, pages = {123150}, doi = {10.1016/j.jenvman.2024.123150}, pmid = {39515011}, issn = {1095-8630}, mesh = {*Wildfires ; Italy ; *Forests ; Pilot Projects ; Models, Theoretical ; Ecosystem ; Wind ; }, abstract = {Wildland fires and windthrows represent relevant disturbances for forest ecosystems worldwide. In this context, especially for Italian catchments, the interaction between windthrows and changes in wildfire behaviour starting from ALS data processing is scarcely investigated. Therefore, this research aims to compute a multi-temporal analysis of the interaction between windthrows and wildfire behaviour in a forested area (Veneto region, northern Italy), recently affected by the renamed Vaia windstorm. The semi-empirical FlamMap model was applied, starting from ALS data processing implemented in R for mapping the spatial distribution of forest attributes and fuels within the catchment. The role of windthrows in altering wildfire behaviour was investigated considering ALS point clouds acquired before and after the occurrence of the storm Vaia. Digital Terrain Models (DTMs), Canopy Height Models (CHMs), topographic data and metrics describing forest structure were extracted from ALS data for both scenarios at 5 m resolution, to compare changes in wildfire behaviour over time. Differences in Rate of Spread (RoS), flame length (FL), midflame windspeed (WS) and arrival time (AT) were assessed, and their correlation with windstorm damages was investigated at the catchment detail. , An increase of RoS, FL, and WS greater than 30 m/min, 3 m and 1.1 m/s were respectively estimated in windthrown areas, as well as a decrease of AT greater than 30 min, attesting the key role of windthrows in altering wildfire behaviour over time. The correlation between windthrows and changes in wildfire attributes was finally modeled by computing regression analysis, with R[2] of 0.86, 0.93, 0.62, and 0.91 resulted for RoS, FL, WS and AT. This research represents a pilot case study for better detecting changes in wildfires behaviour due to windthrows occurrence, therefore proposing and carrying out effective planning and management strategies for disturbed forest stands over time.}, } @article {pmid39514515, year = {2024}, author = {Ohnari, K and Mafune, K and Adachi, H}, title = {Fasciculation potentials are related to the prognosis of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0313307}, pmid = {39514515}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/diagnosis ; Male ; Female ; Middle Aged ; Prognosis ; *Fasciculation/physiopathology/diagnosis ; *Electromyography ; Aged ; Retrospective Studies ; Disease Progression ; Adult ; Biomarkers/blood ; }, abstract = {Some prognostic biomarkers of amyotrophic lateral sclerosis (ALS) have been described; however, they are inadequate for satisfactorily predicting individual patient outcomes. Fasciculation potentials (FPs) on electromyography (EMG) are useful for the early diagnosis of ALS, and complex FPs are associated with shorter survival in ALS. In this study, we investigated the relationship between the proportion of muscles with FPs, biochemical markers, and the prognosis of ALS. 89 Patients with ALS were retrospectively classified into three groups based on the interval from onset to death or tracheostomy (less than 1 year: fast progression; from 1 year to less than 3 years: average progression; 3 years or more: slow progression). We performed statistical analysis of the electrophysiological findings, including the percentage of examined muscles with FPs, and biochemical markers evaluated on admission. Patients with fast ALS progression had a higher percentage of muscles with FPs (93.1% vs. 37.9%, P<0.001) and lower uric acid (UA) levels (male: 4.19 mg/dl vs 5.55 mg/dl, P<0.001; female: 3.71 mg/dl vs 5.41 mg/dl, P<0.001) than patients with slow progression. Survival curves demonstrated a relationship between these factors and the survival time in patients with ALS. Furthermore, UA levels were correlated with the percentage of muscles with FPs. Our electrophysiological findings suggest that ALS presents with multisystem neurological manifestations, and these manifestations differed among the groups classified by disease progression. The percentage of muscles with FPs on EMG and serum UA levels were especially associated with the prognosis of ALS.}, } @article {pmid39513379, year = {2024}, author = {Simkins, TJ and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and Shefner, JM and Bowser, R}, title = {Plasma neurofilament analysis in VITALITY-ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2423707}, pmid = {39513379}, issn = {2167-9223}, abstract = {Objective: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS). Methods: Plasma was collected at baseline and every 8 weeks thereafter. Results were compared between treatment groups and evaluated by clinical characteristics and over time. Pearson's correlation coefficients (r) were calculated to evaluate associations between Nf concentrations and slow vital capacity (SVC), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and pre-study/in-study rates of disease progression (psRDP/isRDP). Results: Nf measurements were available from 101 placebo- and 161 tirasemtiv-treated people with ALS (pALS). There were no significant differences in Nf between placebo and tirasemtiv groups at any time point; further analyses grouped all samples. At baseline, Nf concentration did not differ by multiple clinical characteristics. Baseline Nf light chain (NfL) concentration correlated with the psRDP (r = 0.50, p < 0.001) and isRDP (r = 0.53, p < 0.0001). Phosphorylated Nf heavy chain (pNfH) demonstrated a similar, but less robust, pattern of results. Baseline Nf concentration correlated with change in SVC and ALSFRS-R score over time. Plasma pNfH concentration continuously decreased over time. There was no meaningful change in plasma NfL concentration over the study period. Conclusions: In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression.}, } @article {pmid39513316, year = {2024}, author = {Yadav, H and Malviya, R and Kaushik, N and Sridhar, SB}, title = {Therapeutic Potential of Quercetin Analogous: Prospective and Advances.}, journal = {Recent advances in food, nutrition & agriculture}, volume = {}, number = {}, pages = {}, doi = {10.2174/012772574X332803240930065210}, pmid = {39513316}, issn = {2772-5758}, abstract = {The purpose of the article is to investigate the therapeutic potential of quer-cetin and related compounds by elucidating their pharmacological characteristics and molecular mechanisms of action. The potential benefits of quercetin and its analogs for cardiovascular health, disorders of the brain, metabolic disorders, and more are discussed in the discussion part of this page. Concerns about their clinical efficacy due to issues with bioavailability and distribution are also discussed. This region of the paper emphasizes the importance of researchers and clinicians working together to maximize the incorporation of these chemicals into real-world therapeutic approaches. In conclusion, quercetin, along with related substances, shows great potential in a wide range of therapeutic settings. Potentially useful for the management of a wide variety of illnesses, their multiple methods of action include the regulation of pathways for cell signaling and interaction with different enzymes. However, additional clinical tri-als are needed to verify their efficacy and safety.}, } @article {pmid39512134, year = {2025}, author = {Pattee, GL}, title = {Gastrostomy in Amyotrophic Lateral Sclerosis: Timing Enhances Survival.}, journal = {Muscle & nerve}, volume = {71}, number = {1}, pages = {3-5}, doi = {10.1002/mus.28294}, pmid = {39512134}, issn = {1097-4598}, } @article {pmid39512085, year = {2024}, author = {White, CG and Hancewicz, TM and Fasasi, A and Wright, J and Lavine, BK}, title = {Alternating and Modified Alternating Least Squares Applied to Raman Spectra of Finished Gasolines.}, journal = {Applied spectroscopy}, volume = {}, number = {}, pages = {37028241292649}, doi = {10.1177/00037028241292649}, pmid = {39512085}, issn = {1943-3530}, abstract = {Extraction of components from individual refinery streams (e.g., reformates and alkylates) in finished gasoline was undertaken using Raman spectroscopy to characterize the chemical content of the finished product. Modified alternating least squares (MALS) was used for separating Raman spectroscopic data sets of the finished product into its pure individual components. The advantages of MALS over alternating least squares (ALS) for multicomponent resolution are highlighted in this study using three Raman spectroscopic data sets which provide a suitable benchmark for comparing the performance of these two methods. MALS is superior to ALS in terms of accuracy and can better resolve components than ALS, and it is also more robust toward collinear data. Finally, components near the noise level usually cannot be extracted by ALS because of instability when inverting the covariance structure which inflates the noise present in the data. However, these same components can be extracted by MALS due to the stabilization of the least squares regression with respect to the matrix inversion using modified techniques from ridge regression.}, } @article {pmid39511965, year = {2025}, author = {Bhai, S and Levine, T and Moore, D and Bowser, R and Heim, AJ and Walsh, M and Shibani, A and Simmons, Z and Grogan, J and Goyal, NA and Govindarajan, R and Hussain, Y and Papsdorf, T and Schwasinger-Schmidt, T and Olney, N and Goslin, K and Pulley, M and Kasarskis, E and Weiss, M and Katz, SW and Moser, S and Jabari, D and Jawdat, O and Statland, J and Dimachkie, MM and Barohn, R and , }, title = {A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {71}, number = {1}, pages = {63-72}, pmid = {39511965}, issn = {1097-4598}, support = {R01 FD003937/FD/FDA HHS/United States ; R01FD003937//FDA-OPD/ ; //U.S. Food and Drug Administration/ ; }, mesh = {Humans ; *Memantine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; *Disease Progression ; Treatment Outcome ; Young Adult ; Excitatory Amino Acid Antagonists/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.

AIMS: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.

METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis.

RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline.

DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.}, } @article {pmid39511939, year = {2024}, author = {Eisen, A and Vucic, S and Kiernan, MC}, title = {Amyotrophic lateral sclerosis represents corticomotoneuronal system failure.}, journal = {Muscle & nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28290}, pmid = {39511939}, issn = {1097-4598}, abstract = {Several decades have passed since the anterograde corticomotoneuronal hypothesis for amyotrophic lateral sclerosis (ALS) was proposed. The intervening years have witnessed its emergent support based on anatomical, pathological, physiological, neuroimaging, and molecular biological studies. The evolution of an extensive corticomotoneuronal system appears restricted to the human species, with ALS representing a uniquely human disease. While some, very select non-human primates have limited corticomotoneuronal projections, these tend to be absent in all other animals. From a general perspective, the early clinical features of ALS may be considered to reflect failure of the corticomotoneuronal system. The characteristic loss of skilled motor dexterity involving the limbs, and speech impairment through progressive bulbar dysfunction specifically involve those motor units having the strongest corticomotoneuronal projections. A similar explanation likely underlies the unique "split phenotypes" that have now been well characterized in ALS. Large Betz cells and other pyramidal corticomotoneuronal projecting neurons, with their extensive dendritic arborization, are particularly vulnerable to the elements of the ALS exposome such as aging, environmental stress and lifestyle changes. Progressive failure of the proteosome impairs nucleocytoplasmic shuffling and induces toxic but soluble TDP-43 to aggregate in corticomotoneurons. Betz cell failure is further accentuated through dysfunction of its profuse dendritic arborizations. Clarification of system specific genomes and neural networks will likely promote the initiation of precision medicine approaches directed to support the key structure that underlies the neurological manifestations of ALS, the corticomotoneuronal system.}, } @article {pmid39511821, year = {2025}, author = {Grady, A and Lorch, R and Giles, L and Lamont, H and Anderson, A and Pearson, N and Romiti, M and Lum, M and Stuart, A and Leigh, L and Yoong, SL}, title = {The impact of early childhood education and care-based interventions on child physical activity, anthropometrics, fundamental movement skills, cognitive functioning, and social-emotional wellbeing: A systematic review and meta-analysis.}, journal = {Obesity reviews : an official journal of the International Association for the Study of Obesity}, volume = {26}, number = {2}, pages = {e13852}, pmid = {39511821}, issn = {1467-789X}, support = {APP1170042//National Health and Medical Research Council/ ; Heart Foundation Postdoctoral Fellowship 102518//National Heart Foundation of Australia/ ; Heart Foundation Future Leader Fellowship 106654//National Heart Foundation of Australia/ ; }, mesh = {Humans ; *Cognition ; Child, Preschool ; *Exercise/psychology ; Child ; Infant ; Motor Skills/physiology ; Pediatric Obesity/psychology/prevention & control ; Anthropometry ; Early Intervention, Educational ; }, abstract = {This review assessed the effectiveness of ECEC-based interventions to improve child physical activity, and intervention impact on child weight-based anthropometrics, fundamental movement skills (FMS), cognitive functioning, and social-emotional wellbeing. Adverse effects and costs were assessed. Finch et al's 2014 systematic review was updated. Electronic databases were searched 10 September 2014 to 27 October 2022. Included studies were randomized controlled trials of ECEC interventions targeting physical activity among children aged 0-6 years. The methodological quality of studies was assessed using Cochrane's Risk of Bias tool v2. Standardized mean differences (SMD) were calculated for each outcome with meta-analysis undertaken; otherwise, findings were described narratively. Fifty-three studies were included. ECEC-based interventions were found to significantly improve child physical activity (SMD 0.193, 95% confidence interval [CI] 0.09 to 0.3; p < 0.001) and FMS (SMD 0.544, 95% CI 0.1 to 0.98; p = 0.015), compared to control. Small positive, but non-significant, effects were found for weight-based anthropometrics, cognitive functioning, and social-emotional wellbeing. Few studies reported adverse effects (n = 10), and no studies reported formal economic analyses. While ECEC-based interventions can significantly improve child physical activity and FMS, further evidence of their impact on cognitive functioning, social-emotional wellbeing, and the cost-effectiveness of such interventions is required to inform policy and practice.}, } @article {pmid39511709, year = {2024}, author = {Fontaine, M and Horowitz, K and Anoja, N and Genge, A and Salmon, K}, title = {How the prospect of a clinical trial impacts decision-making for predictive genetic testing in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2423718}, pmid = {39511709}, issn = {2167-9223}, abstract = {Objective: Genetic testing practices are rapidly evolving for people living with, or at-risk for, amyotrophic lateral sclerosis (ALS), due to emerging genotype-driven therapies. This study explored how individuals at-risk for familial ALS (fALS) perceive the opportunity to participate in a clinical trial, and to better understand how that may influence the decision-making process for predictive genetic testing. Methods: This study used both quantitative and qualitative data analyses. Data were collected through an online questionnaire, followed by semi-structured interviews conducted with twelve (n = 12) individuals at-risk for either SOD1- or C9orf72-ALS who had predictive testing prior to study participation. Interview data were analyzed using reflexive thematic analysis. Results: Three overarching themes were conceptualized from the data: i) the psychosocial impact of fALS; ii) perspectives of at-risk individuals on research involvement; and iii) predictive genetic counseling and testing considerations. These results contribute perspectives of the lived experience to inform predictive genetic counseling and testing practices for individuals at-risk for fALS. Conclusion: Individuals at-risk for fALS view potential participation in a presymptomatic clinical trial as an actionable measure that may increase their desire for predictive genetic testing. Genetic counseling was identified as a critical component of the predictive testing process given the life-changing implications associated with a positive result. Increased access to predictive genetic counseling, and in a timely manner, is a significant need in the ALS population given potential access to gene-specific therapies in the presymptomatic stage.}, } @article {pmid39511225, year = {2024}, author = {Silvestri, B and Mochi, M and Mawrie, D and de Turris, V and Colantoni, A and Borhy, B and Medici, M and Anderson, EN and Garone, MG and Zammerilla, CP and Simula, M and Ballarino, M and Pandey, UB and Rosa, A}, title = {HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9618}, pmid = {39511225}, issn = {2041-1723}, support = {CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; 2022BYB33L//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; CN00000041//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; RP123188EC9F2349//Sapienza Università di Roma (Sapienza University of Rome)/ ; RM12117A5DE7A45B//Sapienza Università di Roma (Sapienza University of Rome)/ ; LT0024/2022-L//Human Frontier Science Program (HFSP)/ ; }, mesh = {Humans ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Apoptosis/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; *Disease Models, Animal ; *ELAV-Like Protein 4/metabolism/genetics ; Mutation ; Oxidative Stress ; Drosophila Proteins/metabolism/genetics ; Drosophila melanogaster/genetics ; Female ; Male ; Drosophila ; }, abstract = {Defects at the neuromuscular junction (NMJ) are among the earliest hallmarks of amyotrophic lateral sclerosis (ALS). According to the "dying-back" hypothesis, NMJ disruption not only precedes but also triggers the subsequent degeneration of motoneurons in both sporadic (sALS) and familial (fALS) ALS. Using human induced pluripotent stem cells (iPSCs), we show that the RNA-binding protein HuD (ELAVL4) contributes to NMJ defects and apoptosis in FUS-ALS. HuD overexpression mimics the severe FUS[P525L] mutation, while its knockdown rescues the FUS[P525L] phenotypes. In Drosophila, neuronal overexpression of the HuD ortholog, elav, induces motor dysfunction, and its knockdown improves motor function in a FUS-ALS model. Finally, we report increased HuD levels upon oxidative stress in human motoneurons and in sALS patients with an oxidative stress signature. Based on these findings, we propose that HuD plays a role downstream of FUS mutations in fALS and in sALS related to oxidative stress.}, } @article {pmid39510899, year = {2024}, author = {Kaul, M and Mukherjee, D and Weiner, HL and Cox, LM}, title = {Gut microbiota immune cross-talk in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00469}, pmid = {39510899}, issn = {1878-7479}, support = {R01 NS115951/NS/NINDS NIH HHS/United States ; R21 NS126866/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/microbiology ; *Gastrointestinal Microbiome/immunology/physiology ; Humans ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 % of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.}, } @article {pmid39510439, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {BRD7 regulates cellular senescence and apoptosis in ALS by modulating p21 expression and p53 mitochondrial translocation respectively.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {51-62}, doi = {10.1016/j.neuroscience.2024.11.004}, pmid = {39510439}, issn = {1873-7544}, mesh = {*Cellular Senescence/physiology ; *Apoptosis/physiology ; *Tumor Suppressor Protein p53/metabolism/genetics ; Humans ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; *Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Motor Neurons/metabolism/pathology ; Chromosomal Proteins, Non-Histone/metabolism/genetics ; Male ; Female ; Middle Aged ; Aged ; Bromodomain Containing Proteins ; }, abstract = {Cellular senescence is involved in the progression of neurodegenerative diseases. Motor neurons exhibit senescence-like alterations in ALS. BRD7, identified as a regulatory factor associated with cellular senescence, its function in ALS remains unclear. This study aims to investigate the potential role and mechanisms of BRD7 in ALS. We analyzed RNA levels using qRT-PCR, protein levels through immunofluorescence and western blot, and apoptosis via TUNEL staining. Cell transfection was conducted for in vitro experiments. The level of β-galactosidase was measured by β-galactosidase activity detection kit. ALS motor neurons exhibited senescence-like alterations, characterized by increased activity of p53, p21, and β-galactosidase, as well as reduced lamin B1 staining. Additionally, the expression of BRD7 was upregulated and induced cellular senescence and apoptosis. Downregulation of BRD7 alleviates the cellular senescence by inhibiting p21 rather than p53. Knockdown of BRD7 inhibited p53 mitochondrial translocation, leading to reduced apoptosis. Our results suggest that BRD7 plays an important role in the survival of ALS motor neurons. BRD7 knockdown can reduce cellular senescence and apoptosis by inhibiting p21 and p53 mitochondrial translocation.}, } @article {pmid39509425, year = {2024}, author = {Deng, YC and Liu, JW and Ting, HC and Kuo, TC and Chiang, CH and Lin, EY and Harn, HJ and Lin, SZ and Chang, CY and Chiou, TW}, title = {n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0311573}, pmid = {39509425}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Calcium/metabolism ; *Homeostasis/drug effects ; *Superoxide Dismutase-1/genetics/metabolism ; *Phthalic Anhydrides/pharmacology ; Cell Differentiation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development.}, } @article {pmid39508675, year = {2024}, author = {}, title = {DSP-01 conversion from PLS to ALS: a Dutch cohort study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {262-279}, doi = {10.1080/21678421.2024.2403307}, pmid = {39508675}, issn = {2167-9223}, } @article {pmid39508663, year = {2024}, author = {}, title = {Platform Communications: Abstract Book 35th International Symposium on ALS/MND (Complete printable file).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {1-92}, doi = {10.1080/21678421.2024.2403293}, pmid = {39508663}, issn = {2167-9223}, } @article {pmid39508354, year = {2024}, author = {Bhatele, P and Pai, AR}, title = {Wine Glass Sign in Bulbar Onset Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27131}, pmid = {39508354}, issn = {1531-8249}, } @article {pmid39506867, year = {2024}, author = {Ishihara, T and Koyama, A and Atsuta, N and Tada, M and Toyoda, S and Kashiwagi, K and Hirokawa, S and Hatano, Y and Yokoseki, A and Nakamura, R and Tohnai, G and Izumi, Y and Kaji, R and Morita, M and Tamura, A and Kano, O and Aoki, M and Kuwabara, S and Kakita, A and Sobue, G and Onodera, O}, title = {SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {263}, pmid = {39506867}, issn = {1755-8794}, support = {17K09750//Scientific Research from the Japan Society for the Promotion of Science/ ; 21K07272//Scientific Research from the Japan Society for the Promotion of Science/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 26117006//Scientific Research on Innovative Areas from MEXT/ ; JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; }, mesh = {Humans ; *Survival of Motor Neuron 2 Protein/genetics ; Male ; Japan/epidemiology ; Middle Aged ; Female ; Prognosis ; *Motor Neuron Disease/genetics ; *Gene Dosage ; Incidence ; Amyotrophic Lateral Sclerosis/genetics ; Aged ; Adult ; Case-Control Studies ; DNA Copy Number Variations ; }, abstract = {BACKGROUND: The copy number status (CNS) of the survival motor neuron (SMN) gene may influence the risk and prognosis of amyotrophic lateral sclerosis (ALS) and lower motor neuron diseases (LMND) other than spinal muscular atrophy (SMA). However, previous studies of this association, mainly from Europe, have yielded controversial results, suggesting possible regional differences. Here, we investigated the effect of the SMN gene in Japanese patients with ALS and LMND.

METHODS: We examined the SMN copy numbers and clinical histories of 487 Japanese patients with sporadic ALS (281 men; mean age at onset 61.5 years), 50 with adult LMND (50 men; mean age at onset 58.4 years) and 399 Japanese controls (171 men; mean age 62.2 years). Patients with pathogenic mutations in ALS-causing genes were excluded. SMN1 and SMN2 copy numbers were determined using the droplet digital polymerase chain reaction.

RESULTS: The frequency of a copy number of one for the SMN2 gene was higher in patients with ALS (38.0%) than in healthy controls (30.8%) (odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.04-1.82, p < 0.05). The SMN2 copy number affected the survival time of patients with ALS (median time: 0 copies, 34 months; 1 copy, 39 months; 2 copies, 44 months; 3 copies, 54 months; log-rank test, p < 0.05). Cox regression analysis revealed that the SMN2 copy number was associated with increased mortality (hazard ratio = 0.84, 95% CI = 0.72-0.98, p < 0.05). Also, null SMN2 cases were significantly more frequent in the LMND group (12.0%) than in the control group (4.8%) (OR = 2.73, 95% CI = 1.06-6.98, p < 0.05).

CONCLUSIONS: Our findings suggest that SMN2 copy number reduction may adversely affect the onset and prognosis of MND, including ALS and LMND, in Japanese.}, } @article {pmid39506789, year = {2024}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1[G93A] mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {174}, pmid = {39506789}, issn = {2051-5960}, support = {SG-2019-12371083//Italian Ministry of Health/ ; PE0000006//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; }, mesh = {Animals ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/microbiology/pathology ; Mice ; *Mice, Transgenic ; *Lipid Metabolism/genetics ; Inflammation/metabolism/pathology ; Mice, Inbred C57BL ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1[G93A] mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.}, } @article {pmid39508106, year = {2024}, author = {Gao, XF and Chen, AQ and Tang, HY and Kong, XQ and Zhang, H and Wang, ZM and Lu, W and Wang, LG and Wang, F and Zhou, WY and Gu, Y and Zuo, GF and Ge, Z and Zhang, JJ and Chen, SL}, title = {m[6]A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {44}, number = {12}, pages = {2543-2559}, pmid = {39508106}, issn = {1524-4636}, mesh = {Animals ; *Neointima ; *Muscle, Smooth, Vascular/metabolism/pathology ; *Hyperplasia ; *Phenotype ; *STAT3 Transcription Factor/metabolism/genetics ; *Myocytes, Smooth Muscle/metabolism/pathology ; *Signal Transduction ; *Disease Models, Animal ; *Proto-Oncogene Mas ; Male ; *Profilins/metabolism/genetics ; *Mice, Knockout ; *Adenosine/metabolism/analogs & derivatives ; Humans ; Mice ; Mice, Inbred C57BL ; Rats ; Cells, Cultured ; Rats, Sprague-Dawley ; Phosphorylation ; Coronary Restenosis/metabolism/pathology/genetics/etiology ; Carotid Stenosis/metabolism/pathology/genetics ; Cell Proliferation ; }, abstract = {BACKGROUND: In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia.

METHODS: Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia.

RESULTS: Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1[SMC-IKO] (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1[SMC-IKO] mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N[6]-methyladenosine methyltransferase) and YTHDF3 (YTH N6-methyladenosine RNA binding protein F3; N[6]-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N[6]-methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src (SRC proto-oncogene, nonreceptor tyrosine kinase), promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), a typical transcription factor known to induce VSMC phenotype switching.

CONCLUSIONS: This study unveils the significance of PFN1 N[6]-methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway.}, } @article {pmid39505881, year = {2024}, author = {Li, J and Jaiswal, MK and Chien, JF and Kozlenkov, A and Jung, J and Zhou, P and Gardashli, M and Pregent, LJ and Engelberg-Cook, E and Dickson, DW and Belzil, VV and Mukamel, EA and Dracheva, S}, title = {Author Correction: Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9588}, doi = {10.1038/s41467-024-53972-1}, pmid = {39505881}, issn = {2041-1723}, } @article {pmid39505319, year = {2024}, author = {Lee, J and Kim, A and Choi, SJ and Cho, E and Seo, J and Oh, SI and Jung, J and Kim, JS and Sung, JJ and Abrahams, S and Hong, YH}, title = {Erratum: Development and Validation of the Korean Version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS-K).}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {6}, pages = {637}, doi = {10.3988/jcn.2022.0403e}, pmid = {39505319}, issn = {1738-6586}, abstract = {This corrects the article on p. 454 in vol. 19, PMID: 37488957.}, } @article {pmid39505137, year = {2024}, author = {Abbasi, H and Jourabchi-Ghadim, N and Asgarzade, A and Mirshekari, M and Ebrahimi-Mameghani, M}, title = {Unveiling the veil of adipokines: A meta-analysis and systematic review in amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {1-9}, doi = {10.1016/j.neuroscience.2024.11.003}, pmid = {39505137}, issn = {1873-7544}, mesh = {*Amyotrophic Lateral Sclerosis/blood/metabolism ; Humans ; *Adipokines/blood ; Ghrelin/blood ; Leptin/blood ; Adiponectin/blood ; Disease Progression ; }, abstract = {BACKGROUND: Adipokines are proposed to be associated with ALS progression through assorted pathways. Therefore, The present meta-analysis explored the link between various adipokines and ALS progression.

METHOD: International database like PubMed, Scopus, and Web of Science databases were searched to achieve eligible papers published before December 2023. The following PICO structure was utilized: Population (patients with ALS); Intervention (serum concentrations of ghrelin, leptin, and adiponectin), Comparison (with or without controls), and Outcome (ALS progression). the risk of bias of selected papers was assessed through the Newcastle-Ottawa Scale (NOS) tool.

RESULTS: 11 out of 240 papers were selected for this study which were published between 2010 and 2024. Lower serum leptin concentrations were detected in the ALS compared to control groups (WMD: -0.91, 95% CI:-1.77, -0.05). Serum concentrations of adiponectin were higher in ALS compared to control groups (WMD: 0.41, 95% CI:-0.7, 0.89). Ultimately, The serum concentrations of ghrelin in the ALS groups were lower than control groups (WMD: -1.21, 95% CI: -2.95, 0.53).

CONCLUSION: Our findings revealed that serum concentrations of ghrelin and leptin were higher in ALS patients compared to control, unlike adiponectin.}, } @article {pmid39503426, year = {2025}, author = {Shimizu, M and Okuno, T}, title = {Disruption of neuronal actin barrier promotes the entry of disease-implicated proteins to exacerbate amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2589-2590}, doi = {10.4103/NRR.NRR-D-24-00661}, pmid = {39503426}, issn = {1673-5374}, } @article {pmid39503423, year = {2025}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Translational challenges in amyotrophic lateral sclerosis therapy with macrophage migration inhibitory factor.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2583-2584}, doi = {10.4103/NRR.NRR-D-24-00616}, pmid = {39503423}, issn = {1673-5374}, } @article {pmid39503319, year = {2024}, author = {Bedlack, R and Li, X and Evangelista, BA and Panzetta, ME and Kwan, J and Gittings, LM and Sattler, R}, title = {The Scientific and Therapeutic Rationale for Off-Label Treatments in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {1}, pages = {15-27}, pmid = {39503319}, issn = {1531-8249}, support = {//ALS Association/ ; }, abstract = {There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease with multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by a group called ALSUntangled to identify 8 alternative and off-label treatments that target ≥1 of these mechanisms, and have ≥1 human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms of the highlighted products, we suggest that combinations of these treatments targeting diverse mechanisms might be worthwhile for future amyotrophic lateral sclerosis therapy development. ANN NEUROL 2024.}, } @article {pmid39503018, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Hepatobiliary anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {70}, pmid = {39503018}, issn = {2415-1289}, abstract = {BACKGROUND AND OBJECTIVE: Hepatobiliary diseases are a longstanding and significant medical challenge which, despite advances in surgical techniques, still carry risks for postoperative complications such as anastomotic leaks (ALs), which can include both postoperative pancreatic fistula (POPF) and bile leaks (BL). These complications incur significant human and economic costs on all those involved, including the patient, healthcare providers, and hospital systems. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs in the context of hepato-pancreato-biliary (HPB) procedures, and consequences of POPF and BL.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following search criteria: (((((((anastomosis) OR (anastomotic leak*)) OR (postoperative pancreatic fistula)) OR (bile leak*)) OR (pancreaticoduodenectomy)) OR (whipple)) AND ((hepatobiliary) OR (hepato-pancreato-biliary)) AND ((definition) OR (grading system*) OR (consequences) OR (outcomes) OR (risk factor*) OR (morbidity) OR (mortality))). Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

KEY CONTENT AND FINDINGS: A universally accepted definition and grading system for POPF and BL continues to be lacking, leading to variability in reported incidence in the literature. Various groups have worked to publish guidelines for defining and grading POPF and BL, with the International Study Group in Pancreatic Surgery (ISGPS) and International Study Group for Liver Surgery (ISGLS) definitions the current most recommended definitions for POPF and BL, respectively. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: AL remains a significant challenge in HPB surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid39502740, year = {2024}, author = {Nishiyama, A and Niihori, T and Suzuki, N and Izumi, R and Akiyama, T and Kato, M and Funayama, R and Nakayama, K and Warita, H and Aoki, Y and Aoki, M}, title = {Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200196}, pmid = {39502740}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease. Approximately 10% of ALS cases are familial, and more than 20 causative genes have been identified. As we have previously reported, SOD1 variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for SOD1-linked ALS are being used in practical applications, the types of variants and the clinical features of patients need to be updated.

METHODS: We consecutively recruited 160 families with familial ALS in Japan. We performed genetic analyses, focusing on SOD1-linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes.

RESULTS: A total of 26 SOD1 variants in 56 patients and 49 families (30.6%) were collected, with the 3 most common (p.His47Arg [the conventional numbering; H46R], p.Leu127Ser [L126S], p.Asn87Ser [N86S]) accounting for 38.8% of all families. We also identified 2 novel variants (p.Ile36Phe [I35F] and p.Asn132Argfs*3 [N131Rfs*3]). The mean age at onset was 48.9 ± 12.2 (mean ± SD) years for all patients with SOD1-linked ALS. Lower limb onset comprised 70% of cases. The mean disease duration was 64.7 ± 82 months, and the median survival was 71.5 months. Some variants led to a relatively homogeneous phenotype, although clinical characteristics differed among types of variants and families. Patients with p.His47Arg (H46R) showed slower progression with lower limb onset and a predominance of lower motor neuron involvement. The p.Leu127Ser (L126S) variant led to varying degrees of progression in heterozygous or homozygous states and presented incomplete penetrance. Intrafamilial phenotypic differences were observed in families carrying p.Asn87Ser (N86S). Four variants (p.Cys7Gly [C6G], p.His44Arg [H43R], p.Leu85Val [L84V], and p.Cys147Arg [C146R]) were found to be associated with rapid disease progression.

DISCUSSION: The genetic basis of familial ALS, at least for SOD1 variants, still differed by geographic and ethnic background. Understanding these clinical profiles will help optimize evaluation in targeted gene therapy worldwide and benefit efficient diagnosis, leading to precise application in clinical practice.}, } @article {pmid39501538, year = {2024}, author = {Bampton, A and McHutchison, C and Talbot, K and Benatar, M and Thompson, AG and Turner, MR}, title = {The Basis of Cognitive and Behavioral Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {14}, number = {11}, pages = {e70115}, pmid = {39501538}, issn = {2162-3279}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Jan20/952-795//Motor Neurone Disease Association Lady Edith Wolfson Clinician Scientist Fellowship/ ; //Foulkes Foundation/ ; //National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Cognitive Dysfunction/etiology/physiopathology ; }, abstract = {OBJECTIVE: To summarize and evaluate evidence pertaining to the clinical, genetic, histopathological, and neuroimaging correlates of cognitive and behavioral dysfunction in amyotrophic lateral sclerosis (ALS).

METHODOLOGY: We comprehensively reviewed the literature on cognitive and behavioral manifestations of ALS, narrating findings from both cross-sectional and longitudinal studies. We discussed knowledge gaps in the evidence base and key limitations affecting studies to date, before formulating a framework for future research paradigms aimed at investigating clinicopathological correlates of neuropsychological dysfunction in ALS.

RESULTS: Studies have demonstrated clinical associations with cognitive dysfunction in ALS e.g., bulbar-onset of symptoms, pathological associations (extramotor TDP-43 deposition), and imaging associations (frontotemporal involvement). The most common behavioral deficit, apathy, is highly associated with verbal fluency, but longitudinal studies assessing behavioral dysfunction in ALS are comparatively lacking.

CONCLUSION: Longitudinal studies have been helpful in identifying several potential correlates of cognitive and behavioral dysfunction but have frequently been confounded by selection bias and inappropriate testing platforms. This review provides a framework for more robust assessment of clinicopathological associations of neuropsychological abnormalities in ALS in the future, advocating for greater utilization of pre-symptomatic C9orf72 repeat expansion-carrying cohorts.}, } @article {pmid39501102, year = {2025}, author = {Howard, J and Chaouch, A and Douglas, AGL and MacLeod, R and Roggenbuck, J and McNeill, A}, title = {Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members.}, journal = {European journal of human genetics : EJHG}, volume = {33}, number = {1}, pages = {7-13}, pmid = {39501102}, issn = {1476-5438}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/methods/standards ; Motor Neuron Disease/genetics/diagnosis ; Genetic Counseling ; Family ; }, abstract = {Motor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. Increasing numbers of people with MND are requesting genetic testing, and indeed receiving a genetic diagnosis. Consequently, requests for genetic counselling and predictive testing (i.e. of unaffected family members) are similarly expected to rise, alongside pre-symptomatic clinical trials. Despite this, there is no evidence-based guideline for predictive genetic testing in MND. This paper provides an overview of the genomic basis of MND, focusing specifically on the most common monogenic causes of MND. It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. Additionally, there is limited research on the psychosocial impact of predictive genetic testing for MND, with studies suggesting potential difficulty in adjusting to the news, in part due to a lack of support and follow-up. This underscores a case for evidence-based, disease-specific guidance for predictive testing in MND.}, } @article {pmid39500920, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {NPJ systems biology and applications}, volume = {10}, number = {1}, pages = {128}, pmid = {39500920}, issn = {2056-7189}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; RF1NS133812//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; U01 AG073323/AG/NIA NIH HHS/United States ; U01AG073323//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG082118//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG066707//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG066707/AG/NIA NIH HHS/United States ; R01AG076448//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R21AG083003//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG076448/AG/NIA NIH HHS/United States ; RF1AG082211//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG084250//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; Humans ; *Quantitative Trait Loci/genetics ; Genome-Wide Association Study/methods ; Drug Repositioning/methods ; Genomics/methods ; Protein Interaction Maps/genetics/drug effects ; Multiomics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, } @article {pmid39500483, year = {2024}, author = {Piotrkiewicz, M}, title = {Possible changes in motor neuron discharge characteristics in presymptomatic amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {24}, pages = {6631-6635}, doi = {10.1113/JP287788}, pmid = {39500483}, issn = {1469-7793}, } @article {pmid39496878, year = {2024}, author = {Yang, T and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Li, C and Shang, H}, title = {Mutation Screening of ATXN1, ATXN2, and ATXN3 in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39496878}, issn = {1559-1182}, support = {82371430//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; }, abstract = {Emerging evidence suggests potential disease modifying roles of ATXN1, ATXN2, and ATXN3 in amyotrophic lateral sclerosis (ALS). We aimed to provide a comprehensive variants profile of the ATXN1, ATXN2, and ATXN3 genes and examine the association of these variants with the risk and clinical characteristics of ALS. We screened and analyzed the rare variants in a cohort of 2220 ALS patients from Southwest China, using controls from the Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP). The over-representation of rare variants and their association with disease risk in ALS patients were assessed using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis was employed to explore the relationship between the distribution of variants and survival. A total of 62 eligible rare missense variants were identified, comprising 32 from ATXN1, 21 from ATXN2, and 9 from ATXN3. Allelic association testing revealed a significant enrichment of the ATXN1 (c.2122C > G, p.Leu708Val) variant and the ATXN2 (c.3778C > G, p.Pro1260Ala) variant in ALS. Gene burden analysis indicated that variants in the ATXN1 and ATXN3 genes had a higher burden in ALS. Substantial heterogeneity in survival time was observed among patients carrying different variants within the same gene. However, there were no significant differences in survival between ALS patients grouped by N-terminal or C-terminal distribution. Our results provided a genetic variation profile of ATXN1, ATXN2, and ATXN3 in ALS patients, along with the clinical characteristics of individuals carrying these variations. This information might offer valuable insights for the ongoing ALS disease-modifying treatments.}, } @article {pmid39496465, year = {2024}, author = {Baker, MR and Maitland, S}, title = {Response to: 'Cortical Inexcitability in ALS: Correlating a Clinical Phenotype'.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334587}, pmid = {39496465}, issn = {1468-330X}, } @article {pmid39496035, year = {2024}, author = {Xu, W and Zhao, X and Wang, J and Guo, Y and Ren, Z and Cai, L and Wu, S and Zhou, M}, title = {Different intensities of physical activity for amyotrophic lateral sclerosis and Parkinson disease: A Mendelian randomization study and meta-analysis.}, journal = {Medicine}, volume = {103}, number = {44}, pages = {e40141}, pmid = {39496035}, issn = {1536-5964}, support = {ZYYLJRC201911//the Anhui Province Traditional Chinese Medicine Leading Talents Construction Project/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Amyotrophic Lateral Sclerosis/genetics ; *Parkinson Disease/genetics/epidemiology ; *Exercise ; Genome-Wide Association Study ; }, abstract = {BACKGROUND: The causal relationships between amyotrophic lateral sclerosis (ALS), Parkinson disease and different intensities of physical activity (PA) are still inconclusive. To evaluate the causal impact of PA on ALS and Parkinson disease (PD), this study integrates evidence from Mendelian randomization (MR) using a meta-analysis approach.

METHODS: MR analyses on genetically predicted levels of PA (compose of self-reported moderate-to-vigorous physical activity [MVPA], self-reported vigorous physical activity [VPA], and strenuous sports or other exercises [SSOE]) regarding ALS and PD published up to July 27, 2024, were obtained from PubMed, Scopus, Web of Science, and Embase. De novo MR studies were analyzed utilizing publicly accessible datasets from genome-wide association studies and then meta-analyses were performed to pool the results.

RESULTS: Meta-analyses of results of 12 de novo MR studies analyses and 2 published MR studies indicated that genetic predicted levels of MVPA (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.08-1.38), VPA (OR: 1.32, 95% CI: 1.08-1.60), and SSOE (OR: 1.35, 95% CI: 1.07-1.70) were related to a raised risk of ALS, but not causally with PD.

CONCLUSION: Our findings showed no causal relationships between MVPA, VPA, SSOE, and PD, while MVPA, VPA, and SSOE were associated with increased ALS risk, highlighting the need for targeted PA recommendations for disease management.}, } @article {pmid39495912, year = {2024}, author = {Wheeler, HB and Madrigal, AA and Chaim, IA}, title = {Mapping the future of oxidative RNA damage in neurodegeneration: Rethinking the status quo with new tools.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {46}, pages = {e2317860121}, pmid = {39495912}, issn = {1091-6490}, support = {R00 NS121511/NS/NINDS NIH HHS/United States ; 4R00NS121511-03//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *RNA/metabolism/genetics ; *Oxidation-Reduction ; Oxidative Stress ; RNA-Binding Proteins/metabolism/genetics ; Proteomics/methods ; Animals ; }, abstract = {Over two decades ago, increased levels of RNA oxidation were reported in postmortem patients with ALS, Alzheimer's, Parkinson's, and other neurodegenerative diseases. Interestingly, not all cell types and transcripts were equally oxidized. Furthermore, it was shown that RNA oxidation is an early phenomenon, altogether indicating that oxidative RNA damage could be a driver, and not a consequence, of disease. Despite all these exciting observations, the field appears to have stagnated since then. We argue that this is a consequence of the shortcomings of technologies to model these diseases, limiting our understanding of which transcripts are being oxidized, which RNA-binding proteins are interacting with these RNAs, what their implications are in RNA processing, and as a result, what their potential role is in disease onset and progression. Here, we discuss the limits of previous technologies and propose ways by which advancements in iPSC-derived disease modeling, proteomics, and sequencing technologies can be combined and leveraged to answer new and decades-old questions.}, } @article {pmid39494889, year = {2024}, author = {Ito, SI and Tanaka, Y}, title = {Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, doi = {10.3791/67385}, pmid = {39494889}, issn = {1940-087X}, mesh = {*Extracellular Vesicles/metabolism ; Humans ; *Microtubule-Associated Proteins/metabolism/genetics ; Autophagy/physiology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {(Macro)autophagy represents a fundamental cellular degradation pathway. In this process, double-membraned vesicles known as autophagosomes engulf cytoplasmic contents, subsequently fusing with lysosomes for degradation. Beyond the canonical role, autophagy-related genes also modulate a secretory pathway involving the release of inflammatory molecules, tissue repair factors, and extracellular vesicles (EVs). Notably, the process of disseminating pathological proteins between cells, particularly in neurodegenerative diseases affecting the brain and spinal cord, underscores the significance of understanding this phenomenon. Recent research suggests that the transactive response DNA-binding protein 43 kDa (TDP-43), a key player in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, is released in an autophagy-dependent manner via EVs enriched with the autophagosome marker microtubule-associated proteins 1A/1B light chain 3B-II (LC3-II), especially when autophagosome-lysosome fusion is inhibited. To elucidate the mechanism underlying the formation and release of LC3-II-positive EVs, it is imperative to establish an accessible and reproducible method for evaluating both intracellular and extracellular LC3-II-positive vesicles. This study presents a detailed protocol for assessing LC3-II levels via immunoblotting in cellular and EV fractions obtained through differential centrifugation. Bafilomycin A1 (Baf), an inhibitor of autophagosome-lysosome fusion, serves as a positive control to enhance the levels of intracellular and extracellular LC3-II-positive vesicles. Tumor susceptibility gene 101 (TSG101) is used as a marker for multivesicular bodies. Applying this protocol, it is demonstrated that siRNA-mediated knockdown of syntaxin-6 (STX6), a genetic risk factor for sporadic Creutzfeldt-Jakob disease, augments LC3-II levels in the EV fraction of cells treated with Baf while showing no significant effect on TSG101 levels. These findings suggest that STX6 may negatively regulate the extracellular release of LC3-II via EVs, particularly under conditions where autophagosome-lysosome fusion is impaired. Combined with established methods for evaluating autophagy, this protocol provides valuable insights into the role of specific molecules in the formation and release of LC3-II-positive EVs.}, } @article {pmid39494653, year = {2025}, author = {Springer, SA}, title = {Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.}, journal = {Addiction (Abingdon, England)}, volume = {120}, number = {1}, pages = {21-22}, pmid = {39494653}, issn = {1360-0443}, support = {DP1 DA056106/DA/NIDA NIH HHS/United States ; NIDA DP1DA056106/DA/NIDA NIH HHS/United States ; }, abstract = {Provision of buprenorphine treatment for opioid use disorder is often stymied by clinicians’ concerns for precipitated opioid withdrawal. Gregory et al’s systematic review identified a low level of precipitated withdrawal with buprenorphine induction even among persons who reported fentanyl use. Evidence, not fear should guide treatment.}, } @article {pmid39494632, year = {2024}, author = {Uzunçakmak-Uyanık, H and Tan, E and Temuçin, ÇM and Yıldız, FG}, title = {Lack of habituation in somatosensory cortex but not in visual cortex of ALS patients.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2421747}, pmid = {39494632}, issn = {2167-9223}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease with extra-motor components. In ALS, there is also hyperexcitability of extra-motor areas. Habituation is defined as ''a response decrement" caused by repeated stimulations. Studies on evoked potential habituation can be conducted to detect cortical excitability. This study aimed to explore lack of habituation in non-motor cortical structures in ALS.

METHODS: Twenty-one ALS patients and 14 controls were enrolled. Recordings were obtained in 3 and 10 consecutive blocks (each containing 100 responses) during right median somatosensory evoked potential (SEP) and bilateral visual evoked potential (VEP), respectively. "Habituation" and "lack of habituation" were defined as the amount of increase or decrease in the average N20 or N75-P100 amplitude of the last blocks compared to the first blocks, respectively. Comparative analyses were performed between patient and control groups, as well as the first and last block within groups.

RESULTS: Paired sample t-test showed that in control group N20 peak amplitude of last blocks were significantly lower than first block values (p = 0.025) that indicate the physiological habituation as expected. On the other hand, there was not such a difference in ALS group (p = 0.239) which indicated lack of habituation.

CONCLUSIONS: Our study results suggest somatosensory hyperexcitability in line with cortical reorganization in ALS patients.}, } @article {pmid39494512, year = {2024}, author = {Donohoe, MN and Upadhyay, A and Pratt, DA}, title = {Ligand-Based Radical Reactivity of Metal Thiosemicarbazones Prompts the Identification of Platinum(II)-Based Cytoprotectants.}, journal = {Journal of the American Chemical Society}, volume = {146}, number = {45}, pages = {31307-31320}, doi = {10.1021/jacs.4c12713}, pmid = {39494512}, issn = {1520-5126}, mesh = {*Thiosemicarbazones/chemistry/pharmacology ; Ligands ; *Platinum/chemistry/pharmacology ; *Coordination Complexes/chemistry/pharmacology/chemical synthesis ; Humans ; Antioxidants/chemistry/pharmacology ; Lipid Peroxidation/drug effects ; Molecular Structure ; Copper/chemistry ; Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; }, abstract = {CuATSM, a copper(II) complex of a bis(thiosemicarbazone) of diacetyl, prevents oxidative cell death and acts as a neuroprotectant in vivo, prompting its evaluation to treat amyotrophic lateral sclerosis and other neurodegenerative conditions in the clinic. We recently demonstrated that CuATSM functions as a potent radical-trapping antioxidant (RTA), inhibiting lipid peroxidation and associated ferroptotic cell death by a noncanonical mechanism based on radical addition to the ligand backbone. Herein we report our investigations of the generality of this reactivity, which include studies of corresponding complexes of various other metals, including Co, Ru, Ni, Pd, Pt, and Au. Inhibited autoxidations of styrene and dioxane reveal that most of these complexes exhibit RTA activity, consistent with ligand-based reactivity, but the identity of the metal atom nevertheless plays a role. In particular, analyses of the electronic structures of the complexes of metals within the same group (i.e., the group 10 metals Ni, Pd and Pt) highlight how the metal atom can modulate the ligand-based reactivity by enabling spin delocalization to the other thiosemicarbazone moiety. The RTA activity determined in organic solution largely translates to phospholipid bilayers and mammalian cells, where most complexes inhibited lipid peroxidation and associated ferroptotic cell death. A preliminary structure-activity study revealed Pt complexes with potencies eclipsing those of archetype ferroptosis inhibitors ferrostatin-1 and liproxstatin-1, suggesting that Pt (and to a lesser extent Ni) bis(thiosemicarbazone)s may be better suited to optimization for therapeutic development than those based on Cu.}, } @article {pmid39494508, year = {2024}, author = {Mariani, D and Setti, A and Castagnetti, F and Vitiello, E and Stufera Mecarelli, L and Di Timoteo, G and Giuliani, A and D'Angelo, A and Santini, T and Perego, E and Zappone, S and Liessi, N and Armirotti, A and Vicidomini, G and Bozzoni, I}, title = {ALS-associated FUS mutation reshapes the RNA and protein composition of stress granules.}, journal = {Nucleic acids research}, volume = {52}, number = {21}, pages = {13269-13289}, pmid = {39494508}, issn = {1362-4962}, support = {ERC-2019-SyG 855923-ASTRA//ERC/ ; IG 2019 Id. 23053//Associazione Italiana per la Ricerca sul Cancro/ ; CN00000041//NextGenerationEU/ ; //Istituto Italiano di Tecnologia/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Mutation ; *Stress Granules/metabolism/genetics ; Cell Line, Tumor ; Transcriptome ; RNA/metabolism/genetics ; RNA, Messenger/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Cytoplasmic Granules/metabolism/genetics ; }, abstract = {Stress granules (SG) are part of a cellular protection mechanism where untranslated messenger RNAs and RNA-binding proteins are stored upon conditions of cellular stress. Compositional variations due to qualitative or quantitative protein changes can disrupt their functionality and alter their structure. This is the case of different forms of amyotrophic lateral sclerosis (ALS) where a causative link has been proposed between the cytoplasmic de-localization of mutant proteins, such as FUS (Fused in Sarcoma), and the formation of cytotoxic inclusions. Here, we describe the SG transcriptome in neuroblastoma cells and define several features for RNA recruitment in these condensates. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of mutant FUS, switching to a more unstructured, AU-rich SG transcriptome. Moreover, we show that mutant FUS, together with its protein interactors and their target RNAs, are responsible for the reshaping of the mutant SG transcriptome with alterations that can be linked to neurodegeneration. Our data describe the molecular differences between physiological and pathological SG in ALS-FUS conditions, showing how FUS mutations impact the RNA and protein composition of these condensates.}, } @article {pmid39494098, year = {2024}, author = {Xu, AX and Zhao, ZF and Zhu, L and Zhang, YH and Li, Y and Wei, YF and Zhang, BY and Jiang, B and Gao, TZ and Li, MS and Liu, JY}, title = {Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment.}, journal = {World journal of gastroenterology}, volume = {30}, number = {40}, pages = {4380-4385}, pmid = {39494098}, issn = {2219-2840}, mesh = {Humans ; Drugs, Chinese Herbal/therapeutic use ; *Liver Neoplasms/therapy/pathology/mortality ; *Medicine, Chinese Traditional/methods ; Neoplasm Staging ; Quality of Life ; Treatment Outcome ; }, abstract = {Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis, enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.}, } @article {pmid39493687, year = {2024}, author = {Kato, N and Hashida, G and Kobayashi, M and Sahara, W}, title = {Characteristics and factors associated with independence in the activities of daily living of patients with amyotrophic lateral sclerosis at diagnosis.}, journal = {Journal of physical therapy science}, volume = {36}, number = {11}, pages = {692-698}, pmid = {39493687}, issn = {0915-5287}, abstract = {[Purpose] To investigate the characteristics and factors associated with independence in the activities of daily living in patients with amyotrophic lateral sclerosis at diagnosis based on clinical phenotypes. [Participants and Methods] Fifty-seven participants diagnosed with amyotrophic lateral sclerosis were assessed using the Barthel Index. Participants were classified into three clinical phenotypes (bulbar-onset, upper limb-onset, and lower limb-onset), and the total and subitem scores were compared. To statistically examine factors associated with independence in the activities of daily living, the participants were divided into two groups: Barthel Index of 100 and ≤95. [Results] The total, bulbar-onset, upper limb-onset, and lower limb-onset Barthel Index scores were 87.9 ± 17.7, 96.7 ± 5.9, 92.5 ± 11.9, and 70.0 ± 22.2, respectively. The Total Barthel Index and lower limb-related activities of daily living scores were significantly lower in the lower limb-onset group, and knee extension muscle strength was identified as a factor associated with independence, with a cutoff value of 32.0%. [Conclusion] Patients with lower limb onset had more impairments in lower limb-related activities of daily living than those with other clinical phenotypes. To maintain independence in patients with amyotrophic lateral sclerosis at diagnosis, it is necessary to improve knee extension muscle strength through exercise and perform environment adjustments using the cutoff values as indicators.}, } @article {pmid39492846, year = {2024}, author = {Matera, AG and Steiner, RE and Mills, CA and McMichael, BD and Herring, LE and Garcia, EL}, title = {Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.}, journal = {Frontiers in RNA research}, volume = {2}, number = {}, pages = {}, pmid = {39492846}, issn = {2813-7116}, support = {P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM136435/GM/NIGMS NIH HHS/United States ; }, abstract = {INTRODUCTION: Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an assembly chaperone and serves as a paradigm for studying how specific RNAs are identified and paired with their client substrate proteins to form RNPs. SMN is the eponymous component of a large complex, required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs), that localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN protein forms the oligomeric core of this complex, and missense mutations in the human SMN1 gene are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known. However, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood.

METHODS: Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. We carried out affinity purification mass spectrometry (AP-MS) of Drosophila SMN complexes using fly lines exclusively expressing either wildtype or SMA-causing missense alleles.

RESULTS: Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially associated with SMA-causing alleles of SMN.

DISCUSSION: Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.}, } @article {pmid39492487, year = {2023}, author = {Xu, L and Ma, Y and Ji, Y and Ma, Y and Wang, Y and Zhao, X and Ge, S}, title = {Obesity exacerbates postoperative cognitive dysfunction by activating the PARP1/NAD[+]/SIRT1 axis through oxidative stress.}, journal = {Experimental gerontology}, volume = {}, number = {}, pages = {112320}, doi = {10.1016/j.exger.2023.112320}, pmid = {39492487}, issn = {1873-6815}, abstract = {The purposes of this study were to explore the impact of obesity on postoperative cognitive dysfunction (POCD) and to investigate the underlying mechanism by which obesity exacerbates POCD. In this study, fifteen-month-old male C57BL/6 J mice were fed a High-fat diet for three months to establish obesity models. Internal fixation of tibial fractures under isoflurane inhalation was performed to construct a POCD animal model. Three days after surgery, mice were subjected to the Morris water maze (MWM) experiment to evaluate their learning and memory abilities. The findings from the MWM experiment revealed that in comparison to the Ad Libitum Surgical group (ALS), mice in the High-fat Surgical group (HFS) exhibited prolonged escape latencies and reduced platform crossings. These outcomes suggest the potential exacerbating role of obesity in cognitive impairment within the POCD mouse models. Immunofluorescence (IF) findings demonstrate that obesity intensifies anesthesia and surgery-induced oxidative stress levels within the hippocampus. Compared to the Ad Libitum Control group (ALC), an elevation in PARP1 expression and a reduction in the NAD[+]/NADH ratio and SIRT1 expression were observed in the hippocampus of mice from the ALS. Moreover, when contrasting the HFS group with the ALS group, increased PARP1 expression along with decreased NAD[+]/NADH ratio and SIRT1 expression were evident. In vitro studies found that compared with the Control group (CON), oil red staining and BODIPY probe staining showed significant lipid droplet aggregation in the palmitic acid (PA) group. IF results demonstrated that HT22 cells in the PA group experienced oxidative stress and activation of the PARP1/NAD[+]/SIRT1 axis in contrast to the CON group. Moreover, manipulation of PARP1 expression in HT22 cells through PARP1 lentivirus-based silencing or overexpression revealed a converse relationship between PARP1 expression levels and the NAD[+]/NADH ratio as well as SIRT1 expression levels. This study concludes that obesity may exacerbate POCD by triggering activation of the oxidative stress-induced PARP1/NAD[+]/SIRT1 axis.}, } @article {pmid39492438, year = {2023}, author = {Hamzeh, O and Rabiei, F and Shakeri, M and Parsian, H and Saadat, P and Rostami-Mansoor, S}, title = {Mitochondrial dysfunction and inflammasome activation in neurodegenerative diseases: Mechanisms and therapeutic implications.}, journal = {Mitochondrion}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mito.2023.10.003}, pmid = {39492438}, issn = {1872-8278}, abstract = {Impaired mitochondrial function is crucial to the pathogenesis of several neurodegenerative diseases. It causes the release of mitochondrial DNA (mtDNA), mitochondrial reactive oxygen species (mtROS), ATP, and cardiolipin, which activate the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. NLRP3 inflammasome is an important innate immune system element contributing to neuroinflammation and neurodegeneration. Therefore, targeting the NLRP3 inflammasome has become an interesting therapeutic approach for treating neurodegenerative diseases. This review describes the role of mitochondrial abnormalities and over-activated inflammasomes in the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA). We also discuss the therapeutic strategies focusing on signaling pathways associated with inflammasome activation, which potentially alleviate neurodegenerative symptoms and impede disease progression.}, } @article {pmid39492095, year = {2023}, author = {Mohammadi, S and Mohammadi, M and Ghaderi, S}, title = {Sleep-related regions in neurodegenerative diseases by central nervous system localization using magnetic resonance imaging.}, journal = {Psychiatry research. Neuroimaging}, volume = {336}, number = {}, pages = {111727}, doi = {10.1016/j.pscychresns.2023.111727}, pmid = {39492095}, issn = {1872-7506}, abstract = {Sleep disruptions associated with neurodegenerative diseases (NDDs) damage the brain's sleep-regulating regions. Advanced magnetic resonance imaging (MRI) techniques can characterize the signature of each neurodegenerative pathology. We performed an evaluation of sleep-related regions in NDDs using MRI to localize the central nervous system (CNS). In the initial search, 61 related papers were discovered using predetermined inclusion and exclusion criteria. Finally, 30 articles were included in this study. The study included patients with Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), rapid eye movement (REM) sleep behavior disorder (RBD), idiopathic RBD (iRBD), amyotrophic lateral sclerosis (ALS), and mild cognitive impairment (MCI). Sleep-related regions recognized by CNS localization in NDDs can be linked to important regions. MRI also revealed cortical thinning, GM atrophy, WM, and tract loss, changes in diffusion tensor imaging (DTI) biomarkers (fractional anisotropy (FA), axial diffusivity (Da), and radial diffusivity (Dr)), a decrease in DMN connectivity, a reduction in functional connectivity (FC), and amplitude of low-frequency fluctuation (ALFF) alterations. Sleep plays an important role in predicting future risks for the development of NDDs. Other neuroimaging, cognitive-behavioral, and clinical research can use the information found in this research about the brain regions, MRI biomarker changes, and their relationships.}, } @article {pmid39491718, year = {2024}, author = {Sharma, R and Khan, Z and Mehan, S and Das Gupta, G and Narula, AS}, title = {Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons.}, journal = {Mutation research. Reviews in mutation research}, volume = {794}, number = {}, pages = {108518}, doi = {10.1016/j.mrrev.2024.108518}, pmid = {39491718}, issn = {1388-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Animals ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, primarily impairs upper and lower motor neurons, leading to debilitating motor dysfunction and eventually respiratory failure, widely known as Lou Gehrig's disease. ALS presents with diverse symptomatology, including dysarthria, dysphagia, muscle atrophy, and hyperreflexia. The prevalence of ALS varies globally, with incidence rates ranging from 1.5 to 3.8 per 100,000 individuals, significantly affecting populations aged 45-80. A complex interplay of genetic and environmental factors underpins ALS pathogenesis. Key genetic contributors include mutations in chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase type 1 (SOD1), Fusedin sarcoma (FUS), and TAR DNA-binding protein (TARDBP) genes, accounting for a considerable fraction of both familial (fALS) and sporadic (sALS) cases. The disease mechanism encompasses aberrant protein folding, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation, contributing to neuronal death. This review consolidates current insights into ALS's multifaceted etiology, highlighting the roles of environmental exposures (e.g., toxins, heavy metals) and their interaction with genetic predispositions. We emphasize the polygenic nature of ALS, where multiple genetic variations cumulatively influence disease susceptibility and progression. This aspect underscores the challenges in ALS diagnosis, which currently lacks specific biomarkers and relies on symptomatology and familial history. Therapeutic strategies for ALS, still in nascent stages, involve symptomatic management and experimental approaches targeting molecular pathways implicated in ALS pathology. Gene therapy, focusing on specific ALS mutations, and stem cell therapy emerge as promising avenues. However, effective treatments remain elusive, necessitating a deeper understanding of ALS's genetic architecture and the development of targeted therapies based on personalized medicine principles. This review aims to provide a comprehensive understanding of ALS, encouraging further research into its complex genetic underpinnings and the development of innovative, effective treatment modalities.}, } @article {pmid39491634, year = {2024}, author = {Tedeschi, V and Nele, V and Valsecchi, V and Anzilotti, S and Vinciguerra, A and Zucaro, L and Sisalli, MJ and Cassiano, C and De Iesu, N and Pignataro, G and Canzoniero, LMT and Pannaccione, A and De Rosa, G and Secondo, A}, title = {Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107491}, doi = {10.1016/j.phrs.2024.107491}, pmid = {39491634}, issn = {1096-1186}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Animals ; *Transient Receptor Potential Channels/metabolism ; *Lysosomes/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; *Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Humans ; Mice ; Phosphatidylinositols/metabolism ; Phosphatidylinositol Phosphates/metabolism ; Male ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca[2+] dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models. Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1[G93A] ALS mice, thereby establishing its therapeutic profile. F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca[2+]]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1[G93A] mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level. Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.}, } @article {pmid39491419, year = {2023}, author = {Talebi, M and Sadoughi, MM and Ayatollahi, SA and Ainy, E and Kiani, R and Zali, A and Miri, M}, title = {Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {168}, number = {}, pages = {115805}, doi = {10.1016/j.biopha.2023.115805}, pmid = {39491419}, issn = {1950-6007}, abstract = {Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits. This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington's disease, Alzheimer's disease, Parkinson's disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.}, } @article {pmid39491120, year = {2023}, author = {Stachel, SJ and Wang, D and Ginnetti, AT and Niroomand, S and Ma, L and Hu, Y and Fay, JF and Lemaire, W and Krosky, DJ and Ramirez, AD and Zariwala, HA and Coleman, PJ}, title = {Virtual screening for early identification of potent and selective histone deacetylase 6 inhibitor series.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {}, number = {}, pages = {129537}, doi = {10.1016/j.bmcl.2023.129537}, pmid = {39491120}, issn = {1464-3405}, abstract = {Virtual screening was leveraged to identify novel series of histone deacetylase 6 (HDAC6) inhibitors prior to conducting a high-throughput screen. The virtual screen was designed to augment and expand on chemical matter that would otherwise be unavailable for high-throughput screening. Through this effort we succeeded in identifying four novel, potent and highly selective HDAC6 inhibitor series. These series displayed favorable ligand binding efficiencies and good potential for further optimization. The virtual design specifications and results are discussed herein.}, } @article {pmid39490684, year = {2024}, author = {Liu, YJ and Lee, CW and Liao, YC and Huang, JJ and Kuo, HC and Jih, KY and Lee, YC and Chern, Y}, title = {The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106715}, doi = {10.1016/j.nbd.2024.106715}, pmid = {39490684}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Adiponectin/metabolism ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; *AMP-Activated Protein Kinases/metabolism ; Aged ; Motor Neurons/metabolism ; Severity of Illness Index ; }, abstract = {Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.}, } @article {pmid39490682, year = {2024}, author = {Leykam, L and Forsberg, KME and Nordström, U and Hjertkvist, K and Öberg, A and Jonsson, E and Andersen, PM and Marklund, SL and Zetterström, P}, title = {Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106718}, doi = {10.1016/j.nbd.2024.106718}, pmid = {39490682}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Male ; *Mutation ; Female ; Middle Aged ; Superoxide Dismutase/genetics/cerebrospinal fluid ; Adult ; Aged ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a cause of hereditary amyotrophic lateral sclerosis (ALS) through a gain-of-function mechanism involving unfolded mutant SOD1. Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduce SOD1 expression delays disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for inactivating SOD1 mutations developing the SOD1 Deficiency Syndrome (ISODDES) with injury to the motor system suggests that a too low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3. We here present a sensitive method to assess SOD1 activity by removing SOD3 from CSF samples using highly specific immobilized antibodies and subsequent measurement of the SOD activity. We validated the method on 171 CSF samples from ALS patients with and without mutations and controls and used paired erythrocyte samples for comparison. We found that in ALS patients with wildtype SOD1, the SOD1 activity in CSF was equal to controls, but patients with mutant SOD1 show lower activity in CSF, even for patients with mutants previously reported to have full activity in erythrocytes. Activity variation in CSF was large among patients carrying the same SOD1 mutation and larger than in erythrocytes and in post-mortem nervous tissue. Additionally, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies used for SOD1 ELISA-quantification are raised against the natively folded wildtype SOD1, the concentration of mutant SOD1s may be underestimated. Analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering drugs.}, } @article {pmid39490400, year = {2024}, author = {Zhang, Y and Zou, M and Wu, H and Zhu, J and Jin, T}, title = {The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106710}, doi = {10.1016/j.nbd.2024.106710}, pmid = {39490400}, issn = {1095-953X}, mesh = {Humans ; *Nucleotidyltransferases/metabolism ; *Membrane Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; *Signal Transduction/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.}, } @article {pmid39489870, year = {2024}, author = {Van Weehaeghe, D and Devrome, M and de Vocht, J and Masrori, P and Schramm, G and Deckers, W and Baete, K and De Weerdt, C and Van Damme, P and Koole, M and Van Laere, K}, title = {Combined brain and spinal FDG PET in the differentiation between ALS and ALS mimics - correction and additional validation study.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {52}, number = {1}, pages = {109-112}, pmid = {39489870}, issn = {1619-7089}, } @article {pmid39489397, year = {2024}, author = {Desouky, MA and Michel, HE and Elsherbiny, DA and George, MY}, title = {Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation.}, journal = {Life sciences}, volume = {359}, number = {}, pages = {123206}, doi = {10.1016/j.lfs.2024.123206}, pmid = {39489397}, issn = {1879-0631}, mesh = {*Proteasome Endopeptidase Complex/metabolism ; Humans ; Animals ; Neurodegenerative Diseases/metabolism/drug therapy ; Nervous System Diseases/drug therapy/metabolism ; Proteolysis/drug effects ; Signal Transduction/drug effects ; Proteostasis/drug effects ; Ubiquitin/metabolism ; }, abstract = {Protein homeostasis (proteostasis) refers to the plethora of mechanisms that safeguard the proper folding of the newly synthesized proteins. It entails various intricately regulated cues that demolish the toxic protein species to prevent their aggregation. The ubiquitin-proteasome system (UPS) is recognized as a salient protein degradation system, with a substantial role in maintaining proteostasis. However, under certain circumstances the protein degradation capacity of the UPS is overwhelmed, leading to the accumulation of misfolded proteins. Several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis are characterized with the presence of protein aggregates and proteinopathy. Accordingly, enhancing the 26S proteasome degradation activity might delineate a pioneering approach in targeting various proteotoxic disorders. Regrettably, the exact molecular approaches that enhance the proteasomal activity are still not fully understood. Therefore, this review aimed to underscore several signaling cascades that might restore the degradation capacity of this molecular machine. In this review, we discuss the different molecular components of the UPS and how 26S proteasomes are deleteriously affected in many neurodegenerative diseases. Moreover, we summarize different signaling pathways that can be utilized to renovate the 26S proteasome functional capacity, alongside currently known druggable targets in this circuit and various classes of proteasome activators.}, } @article {pmid39487163, year = {2024}, author = {Cai, S and Venugopalan, S and Seaver, K and Xiao, X and Tomanek, K and Jalasutram, S and Morris, MR and Kane, S and Narayanan, A and MacDonald, RL and Kornman, E and Vance, D and Casey, B and Gleason, SM and Nelson, PQ and Brenner, MP}, title = {Using large language models to accelerate communication for eye gaze typing users with ALS.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9449}, pmid = {39487163}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Communication Aids for Disabled ; Female ; Male ; Pilot Projects ; *Fixation, Ocular/physiology ; Language ; Adult ; User-Computer Interface ; Middle Aged ; Communication ; }, abstract = {Accelerating text input in augmentative and alternative communication (AAC) is a long-standing area of research with bearings on the quality of life in individuals with profound motor impairments. Recent advances in large language models (LLMs) pose opportunities for re-thinking strategies for enhanced text entry in AAC. In this paper, we present SpeakFaster, consisting of an LLM-powered user interface for text entry in a highly-abbreviated form, saving 57% more motor actions than traditional predictive keyboards in offline simulation. A pilot study on a mobile device with 19 non-AAC participants demonstrated motor savings in line with simulation and relatively small changes in typing speed. Lab and field testing on two eye-gaze AAC users with amyotrophic lateral sclerosis demonstrated text-entry rates 29-60% above baselines, due to significant saving of expensive keystrokes based on LLM predictions. These findings form a foundation for further exploration of LLM-assisted text entry in AAC and other user interfaces.}, } @article {pmid39486809, year = {2024}, author = {Van Loon, FT and Seitidis, G and Mavridis, D and van Unnik, JWJ and Weemering, DN and van den Berg, LH and Bethani, I and Nikolakopoulos, S and van Eijk, RPA}, title = {Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e087970}, pmid = {39486809}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Clinical Trials as Topic ; Disease Progression ; Network Meta-Analysis ; Research Design ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials.

METHODS AND ANALYSIS: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.

ETHICS AND DISSEMINATION: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.}, } @article {pmid39484239, year = {2024}, author = {Leinders, S and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Geukes, SH and Schippers, A and Verberne, MSW and van den Boom, M and van der Vijgh, B and Crone, NE and Denison, T and Ramsey, NF and Vansteensel, MJ}, title = {DO NOT LOSE SLEEP OVER IT: IMPLANTED BRAIN-COMPUTER INTERFACE FUNCTIONALITY DURING NIGHTTIME IN LATE-STAGE AMYOTROPHIC LATERAL SCLEROSIS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39484239}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Brain-computer interfaces (BCIs) hold promise as augmentative and alternative communication technology for people with severe motor and speech impairment (locked-in syndrome) due to neural disease or injury. Although such BCIs should be available 24/7, to enable communication at all times, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an individual with amyotrophic lateral sclerosis (ALS) who was implanted with an electrocorticography-based BCI that enabled the generation of click-commands for spelling words and call-caregiver signals.

METHODS: We investigated nocturnal dynamics of neural signal features used for BCI control, namely low (LFB: 10-30Hz) and high frequency band power (HFB: 65-95Hz). Additionally, we assessed the nocturnal performance of a BCI decoder that was trained on daytime data by quantifying the number of unintentional BCI activations at night. Finally, we developed and implemented a nightmode decoder that allowed the participant to call a caregiver at night, and assessed its performance.

RESULTS: Power and variance in HFB and LFB were significantly higher at night than during the day in the majority of the nights, with HFB variance being higher in 88% of nights. Daytime decoders caused 245 unintended selection-clicks and 13 unintended caregiver-calls per hour when applied to night data. The developed nightmode decoder functioned error-free in 79% of nights over a period of ±1.5 years, allowing the user to reliably call the caregiver, with unintended activations occurring only once every 12 nights.

DISCUSSION: Reliable nighttime use of a BCI requires decoders that are adjusted to sleep-related signal changes. This demonstration of a reliable BCI nightmode and its long-term use by an individual with advanced ALS underscores the importance of 24/7 BCI reliability.

TRIAL REGISTRATION: This trial is registered in clinicaltrials.gov under number NCT02224469 (https://clinicaltrials.gov/study/NCT02224469?term=NCT02224469&rank=1). Date of submission to registry: August 21, 2014. Enrollment of first participant: September 7, 2015.}, } @article {pmid39483635, year = {2024}, author = {Murakami, Y and Ando, M and Imamura, A and Oketani, R and Leproux, P and Honjoh, S and Kano, H}, title = {Molecular Fingerprinting of Mouse Brain Using Ultrabroadband Coherent Anti-Stokes Raman Scattering (CARS) Microspectroscopy Empowered by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS).}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {10}, pages = {689-697}, pmid = {39483635}, issn = {2832-3637}, abstract = {The Raman fingerprint spectral region provides abundant structural information on molecules. However, analyzing vibrational images within this region using coherent Raman imaging remains challenging due to the small Raman cross section and congested spectral features. In this study, we combined ultrabroadband coherent anti-Stokes Raman scattering (CARS) microspectroscopy across the spectral range of 500-4000 cm[-1] with multivariate curve resolution-alternating least-squares (MCR-ALS) to reveal hidden Raman bands in the fingerprint region. Applying this method to mouse brain tissue, we extracted information on cholesterol and collagen, leveraging their distinctive molecular signatures, as well as on key molecules such as lipids, proteins, water, and nucleic acids. Moreover, the simultaneous detection of second harmonic generation facilitated label-free visualization of organelles, including arachnoid membrane and Rootletin filaments.}, } @article {pmid39483234, year = {2024}, author = {Fujimoto, A and Kinjo, M and Kitamura, A}, title = {Short Repeat Ribonucleic Acid Reduces Cytotoxicity by Preventing the Aggregation of TDP-43 and Its 25 KDa Carboxy-Terminal Fragment.}, journal = {JACS Au}, volume = {4}, number = {10}, pages = {3896-3909}, pmid = {39483234}, issn = {2691-3704}, abstract = {TAR DNA/RNA-binding protein 43 kDa (TDP-43) proteinopathy is a hallmark of neurodegenerative disorders, such as amyotrophic lateral sclerosis, in which cytoplasmic aggregates containing TDP-43 and its C-terminal fragments, such as TDP-25, are observed in degenerative neuronal cells. However, few reports have focused on small molecules that can reduce their aggregation and cytotoxicity. Here, we show that short RNA repeats of GGGGCC and AAAAUU are aggregation suppressors of TDP-43 and TDP-25. TDP-25 interacts with these RNAs, as well as TDP-43, despite the lack of major RNA-recognition motifs using fluorescence cross-correlation spectroscopy. Expression of these RNAs significantly decreases the number of cells harboring cytoplasmic aggregates of TDP-43 and TDP-25 and ameliorates cell death by TDP-25 and mislocalized TDP-43 without altering the cellular transcriptome of molecular chaperones. Consequently, short RNA repeats of GGGGCC and AAAAUU can maintain proteostasis by preventing the aggregation of TDP-43 and TDP-25.}, } @article {pmid39488863, year = {2024}, author = {Lopes, M and Swash, M and de Carvalho, M}, title = {F-waves responses derived from low-intensity electrical stimulation: A method to explore split-hand pathogenesis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {54}, number = {6}, pages = {103018}, doi = {10.1016/j.neucli.2024.103018}, pmid = {39488863}, issn = {1769-7131}, mesh = {Humans ; Male ; Female ; *Hand/physiopathology ; Adult ; *Muscle, Skeletal/physiopathology/physiology ; *Electric Stimulation/methods ; Middle Aged ; Motor Neurons/physiology ; Electromyography ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Young Adult ; Evoked Potentials, Motor/physiology ; Aged ; }, abstract = {OBJECTIVES: The "split-hand syndrome" is a common clinical sign in amyotrophic lateral sclerosis (ALS), being characterized by more severe atrophy of the hand muscles on the radial side of the hand compared to the ulnar side. We aimed to investigate possible physiological differences between relevant hand muscles using low-intensity F-wave stimulation to assess spinal motoneuron excitability.

METHODS: We recruited 36 healthy volunteers. F-waves were recorded from the abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digiti minimi (ADM), using 20 supramaximal stimuli followed by 20 stimuli at a low-intensity required to obtain M-waves with 10 % amplitude of maximal CMAP. We evaluated the following F-wave parameters: F-M latency, chronodispersion, persistence, amplitude, F/CMAP amplitude ratio and number of F-wave repeaters (with low-intensity). In 10 subjects, low-intensity stimulation F-waves were compared after 20 and 50 stimuli in each muscle.

RESULTS: Low-intensity stimulation resulted in lower F-wave amplitude and persistence and higher F/CMAP amplitude ratios. There were no significant differences in F-wave latencies and chronodispersion. When comparing the three muscles, we found higher F-wave persistence and F/CMAP amplitude ratios when recording over the ADM and APB compared to the FDI. We also found a higher number of F-wave repeaters in the ADM with low-intensity stimulation. Results from 20 to 50 low-intensity stimuli were similar.

DISCUSSION: A small number of low-intensity stimuli is appropriate to study F-wave latencies and chronodispersion. We found differences in some physiological properties of the ADM spinal motoneuron pool compared to other hand muscles.}, } @article {pmid39480764, year = {2024}, author = {Perrin, S and Ladha, S and Maragakis, N and Rivner, MH and Katz, J and Genge, A and Olney, N and Lange, D and Heitzman, D and Bodkin, C and Jawdat, O and Goyal, NA and Bornstein, JD and Mak, C and Appel, SH and Paganoni, S}, title = {Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.}, journal = {PLoS medicine}, volume = {21}, number = {10}, pages = {e1004469}, pmid = {39480764}, issn = {1549-1676}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Male ; Middle Aged ; Female ; Aged ; Adult ; CD40 Ligand/blood ; Biomarkers/blood ; Antibodies, Monoclonal, Humanized/adverse effects/administration & dosage/therapeutic use/pharmacokinetics ; Antibodies, Monoclonal/adverse effects/administration & dosage/therapeutic use ; Neurofilament Proteins/blood ; Dose-Response Relationship, Drug ; Treatment Outcome ; Disease Progression ; Imidazoles ; Pyrazines ; }, abstract = {BACKGROUND: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).

METHODS AND FINDINGS: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.

CONCLUSIONS: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.

TRIAL REGISTRATION: Clintrials.gov ID:NCT04322149.}, } @article {pmid39480562, year = {2025}, author = {Cao, G and Wang, S and Yu, J and Wang, X and Shi, X and Yang, L and Zhang, X and Tong, P and Tan, H}, title = {Outcomes of combined single-bundle anterior cruciate ligament reconstruction and anterolateral structure reconstruction through a modified single femoral tunnel.}, journal = {International orthopaedics}, volume = {49}, number = {1}, pages = {83-91}, pmid = {39480562}, issn = {1432-5195}, support = {82104896//National Natural Science Foundation of China/ ; 242102310025//Henan Provincial Science and Technology Research Project/ ; 2024HLTJ17//Heluo Youth Talent Support Program/ ; }, mesh = {Humans ; Male ; Female ; *Anterior Cruciate Ligament Reconstruction/methods ; Adult ; Middle Aged ; Young Adult ; Adolescent ; *Femur/surgery ; *Anterior Cruciate Ligament Injuries/surgery ; Treatment Outcome ; Arthroscopy/methods ; Hamstring Tendons/transplantation ; Transplantation, Autologous/methods ; }, abstract = {PURPOSE: To explore the clinical outcomes of combining anterior cruciate ligament (ACL) reconstruction and anterolateral structure (ALS) reconstruction through a modified single femoral tunnel in patients with high risk of clinical failure.

METHODS: From December 2018 to August 2022, a total of 62 patients with ACL injury in our institution were enrolled in this study. All patients were associated with high risk of clinical failure, meeting the indications of ALS reconstruction. All patients accepted arthroscopic single-bundle ACL reconstruction and ALS reconstruction using hamstring autograft through a modified single femoral tunnel. Perioperative clinical outcome measurements consisted of functions, stability and safety evaluation at different time points (preoperative, postoperative three month, six month, one year, two year, three year and more). Functional evaluation included Lysholm score, Tegner activity scale, subjective and objective International Knee Documentation Committee (IKDC) score.

RESULTS: All patients, including 47 males and 15 females, aged 16-52 years with an average age of 29.3 ± 9.2 years, were followed up for 12-58 months. At the last follow-up, the Lysholm, subjective IKDC and Tegner activity scale (93.8 ± 7.0, 88.8 ± 10.7 and 5.8 ± 1.4 respectively) were significantly higher than those before surgery (65.0 ± 20.8, 51.2 ± 21.1 and 2.3 ± 1.3 respectively)(P < 0.05). Postoperative pivot shift and Lachman test were markedly improved (P < 0.05). One patient still had grade II pivot shift, defined as clinical failure. During follow-up, no graft rupture occurred according to magnetic resonance imaging and physical examination, no lateral compartment osteoarthritis were found in all patients.

CONCLUSIONS: Combined single bundle ACL reconstruction and ALS reconstruction through a modified single femoral tunnel could significantly improve knee function and stability with low related risk in patients with high risk of failure in ACL injury.}, } @article {pmid39487710, year = {2024}, author = {van Veenhuijzen, K and Tan, HHG and Nitert, AD and van Es, MA and Veldink, JH and van den Berg, LH and Westeneng, HJ}, title = {Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27116}, pmid = {39487710}, issn = {1531-8249}, support = {//Stichting ALS Nederland/ ; 772376-EScORIAL//Horizon 2020 Framework Programme/ ; }, abstract = {OBJECTIVE: We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

METHODS: We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.

RESULTS: Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters.

INTERPRETATION: Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2024.}, } @article {pmid39487328, year = {2024}, author = {Paganoni, S and Harkey, B and Giacomelli, E and Cudkowicz, M and , }, title = {Lessons from the HEALEY adaptive platform trial in amyotrophic lateral sclerosis.}, journal = {Nature aging}, volume = {4}, number = {11}, pages = {1512-1515}, pmid = {39487328}, issn = {2662-8465}, } @article {pmid39486621, year = {2024}, author = {Stephani, C and Krämer, H and Chakalov, I and Bähr, M and Paulus, W and Antal, A and Koch, JC}, title = {Static transcranial magnetic stimulation does not alter cortical excitability in patients with amyotrophic lateral sclerosis on riluzole.}, journal = {Brain stimulation}, volume = {17}, number = {6}, pages = {1244-1246}, doi = {10.1016/j.brs.2024.10.013}, pmid = {39486621}, issn = {1876-4754}, } @article {pmid39486473, year = {2024}, author = {Wang, HE and Daya, MR and Schmicker, R and Nassal, M and Okubo, M and Aramendi, E and Alonso, E and Idris, A and Panchal, AR and Jaureguibeitia, X and Aufderheide, T and Carlson, J and Nichol, G}, title = {Vasopressor or advanced airway first in cardiac arrest?.}, journal = {Resuscitation}, volume = {205}, number = {}, pages = {110422}, doi = {10.1016/j.resuscitation.2024.110422}, pmid = {39486473}, issn = {1873-1570}, mesh = {Humans ; *Vasoconstrictor Agents/therapeutic use/administration & dosage ; Male ; Female ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; *Cardiopulmonary Resuscitation/methods ; Middle Aged ; Aged ; *Airway Management/methods ; Epinephrine/administration & dosage ; Return of Spontaneous Circulation ; Intubation, Intratracheal/methods ; Vasopressins/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND: While resuscitation guidelines emphasize early vasopressor administration and advanced airway management, their optimal sequence remains unclear. We sought to determine the associations between vasopressor-airway resuscitation sequence and out-of-hospital cardiac arrest (OHCA) outcomes in the Pragmatic Airway Resuscitation Trial (PART).

METHODS: We analyzed data from the PART trial. For each patient we determined times of first vasopressor administration (epinephrine or vasopressin), and successful advanced airway insertion (laryngeal tube or endotracheal tube). We classified each case as vasopressor-first or advanced airway-first. We used Generalized Estimating Equations to determine associations between vasopressor-airway sequence and outcomes (72-hour survival, return of spontaneous circulation (ROSC) on emergency department arrival, survival to hospital discharge, hospital survival with favorable neurologic status) and CPR outside of recommended parameters (chest compression fraction <0.8, chest compression rate <100 or >120 per min, or ventilation rate <8 or >12 breaths/min), adjusting for confounders.

RESULTS: Of 3,004 patients in the parent trial, we analyzed 2,404, including 1,821 vasopressor-first and 583 advanced airway-first. Median intervention times: ALS arrival-to-vasopressor 8 min (IQR 6-11) and ALS arrival-to-airway 11 min (8-15). Compared with airway-first, vasopressor-first sequence was not associated with 72-hour survival (adjusted OR 0.96; 95% CI: 0.71-1.31), ROSC (0.83; 0.66-1.06), hospital survival (1.09; 0.68-1.73), or hospital survival with favorable neurologic status (0.97; 0.53-1.78). Vasopressor-first sequence was not associated with non-compliance with recommended CPR performance parameters.

CONCLUSIONS: Vasopressor-airway resuscitation sequence was not associated with OHCA outcomes or CPR quality.}, } @article {pmid39486415, year = {2024}, author = {Al-Azzam, N and To, JH and Gautam, V and Street, LA and Nguyen, CB and Naritomi, JT and Lam, DC and Madrigal, AA and Lee, B and Jin, W and Avina, A and Mizrahi, O and Mueller, JR and Ford, W and Schiavon, CR and Rebollo, E and Vu, AQ and Blue, SM and Madakamutil, YL and Manor, U and Rothstein, JD and Coyne, AN and Jovanovic, M and Yeo, GW}, title = {Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes.}, journal = {Neuron}, volume = {112}, number = {24}, pages = {4033-4047.e8}, doi = {10.1016/j.neuron.2024.10.007}, pmid = {39486415}, issn = {1097-4199}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *RNA Splicing ; *Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Cell Nucleus/metabolism ; Phenotype ; Active Transport, Cell Nucleus ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.}, } @article {pmid39478664, year = {2024}, author = {Ropert, B and Bannwarth, S and Genin, EC and Vaillant-Beuchot, L and Lacas-Gervais, S and Hounoum, BM and Bernardin, A and Dinh, N and Mauri-Crouzet, A and D'Elia, MA and Augé, G and Lespinasse, F and Di Giorgio, A and Meira, W and Bonnefoy, N and Monassier, L and Schiff, M and Sago, L and Kilinc, D and Brau, F and Redeker, V and Bohl, D and Tribouillard-Tanvier, D and Procaccio, V and Azoulay, S and Ricci, JE and Delahodde, A and Paquis-Flucklinger, V}, title = {Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae348}, pmid = {39478664}, issn = {1460-2156}, abstract = {The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.}, } @article {pmid39478194, year = {2024}, author = {Yang, M and You, D and Liu, G and Lu, Y and Yang, G and O'Brien, T and Henshall, DC and Hardiman, O and Cai, L and Liu, M and Shen, S}, title = {Polyethyleneimine facilitates the growth and electrophysiological characterization of iPSC-derived motor neurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {26106}, pmid = {39478194}, issn = {2045-2322}, support = {16/RC/3948/SFI_/Science Foundation Ireland/Ireland ; C2024205026//Natural Science Foundation of Hebei Province/ ; L2024B36//Doctoral Research Initiation Fund Project of Hebei Normal University/ ; GJHZ20200731095005016//International Scientific and Technological Cooperation Foundation of Shenzhen/ ; 00000326//Medical-Engineering Interdisciplinary Research Foundation of ShenZhen University/ ; }, mesh = {*Induced Pluripotent Stem Cells/cytology ; *Motor Neurons/physiology/cytology ; Humans ; *Polyethyleneimine/chemistry/pharmacology ; *Cell Differentiation ; Electrophysiological Phenomena ; Cells, Cultured ; Cell Proliferation ; }, abstract = {Induced pluripotent stem cell (iPSC) technology, in combination with electrophysiological characterization via multielectrode array (MEA), has facilitated the utilization of iPSC-derived motor neurons (iPSC-MNs) as highly valuable models for underpinning pathogenic mechanisms and developing novel therapeutic interventions for motor neuron diseases (MNDs). However, the challenge of MN adherence to the MEA plate and the heterogeneity presented in iPSC-derived cultures raise concerns about the reproducibility of the findings obtained from these cellular models. We discovered that one novel factor modulating the electrophysiological activity of iPSC-MNs is the extracellular matrix (ECM) used in the coating to support in vitro growth, differentiation and maturation of iPSC-MNs. The current study showed that two coating conditions, namely, Poly-L-ornithine/Matrigel (POM) and Polyethyleneimine (PEI) strongly promoted attachment of iPSC-MNs on MEA culture dishes compared to three other coating conditions, and both facilitated the maturation of iPSC-MNs as characterized by the detection of extensive electrophysiological activities from the MEA plates. POM coating accelerated the maturation of the iPSC-MNs for up to 5 weeks, which suits modeling of neurodevelopmental disorders. However, the application of PEI resulted in more even distribution of the MNs on the culture dish and reduced variability of electrophysiological signals from the iPSC-MNs in 7-week cultures, which permitted the detection of enhanced excitability in iPSC-MNs from patients with amyotrophic lateral sclerosis (ALS). This study provides a comprehensive comparison of five coating conditions and offers POM and PEI as favorable coatings for in vitro modeling of neurodevelopmental and neurodegenerative disorders, respectively.}, } @article {pmid39475611, year = {2024}, author = {Wang, LQ and Ma, Y and Zhang, MY and Yuan, HY and Li, XN and Xia, W and Zhao, K and Huang, X and Chen, J and Li, D and Zou, L and Wang, Z and Le, W and Liu, C and Liang, Y}, title = {Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations.}, journal = {Science advances}, volume = {10}, number = {44}, pages = {eado8499}, pmid = {39475611}, issn = {2375-2548}, mesh = {*Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Amyloid/metabolism ; *Mutation ; *Ferroptosis/genetics ; Cryoelectron Microscopy ; Models, Molecular ; Mitochondria/metabolism ; }, abstract = {Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid-101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS.}, } @article {pmid39475283, year = {2025}, author = {Ziser, L and van Eijk, RPA and Kiernan, MC and McRae, A and Henderson, RD and Schultz, D and Needham, M and Mathers, S and McCombe, P and Talman, P and Vucic, S}, title = {Amyotrophic lateral sclerosis established as a multistep process across phenotypes.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16532}, pmid = {39475283}, issn = {1468-1331}, support = {//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Middle Aged ; *Phenotype ; Male ; Female ; Aged ; *Registries ; *Age of Onset ; Australia/epidemiology ; Disease Progression ; Incidence ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes.

METHODS: Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005-2016), and age-specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age-specific incidence and log age of onset, with McFadden's R[2] used to assess the goodness of fit of the model.

RESULTS: In total, 2647 ALS patients were included, with mean disease-onset age being 62.2 ± 12.1 years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6-5.6); cervical 2.7 (95% CI 2.3-3.0); lumbar 3.5 (95% CI 3.2-3.9); flail arm 4.7 (95% CI 3.9-5.5); flail leg 3.6 (95% CI 2.6-4.5); primary lateral sclerosis 2.7 (95% CI 1.8-3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R[2] values were >0.4 for all phenotypes indicating excellent model fit.

DISCUSSION: A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance.}, } @article {pmid39475135, year = {2024}, author = {Jackowski, T and Horodnicka-Józwa, A and Berus, E and Walczak, M and Petriczko, E}, title = {An analysis of acid-labile subunit (ALS) levels in children with short stature born with normal weight.}, journal = {Endokrynologia Polska}, volume = {75}, number = {5}, pages = {548-557}, doi = {10.5603/ep.100285}, pmid = {39475135}, issn = {2299-8306}, mesh = {Humans ; Child ; Female ; Male ; *Glycoproteins ; Growth Disorders/diagnosis ; Carrier Proteins ; Child, Preschool ; Insulin-Like Growth Factor I/metabolism/analysis ; Insulin-Like Growth Factor Binding Protein 3/blood ; Body Height ; }, abstract = {INTRODUCTION: The acid-labile subunit (ALS) is a protein best known for its function in stabilising the insulin like growth factor-1/2-insulin-like growth factor-1 binding protein 3/5 (IGF-1/2-IGFBP3/5) binary complex by creating the ternary complex and in consequence regulating the biological activity of IGF-1. The aim of the study was to assess ALS concentrations in a chosen population of children with short stature taking into account their clinical diagnosis.

MATERIAL AND METHODS: A total of 109 prepubertal children were involved in the study - 85 children in the study group and 24 in controls. In all the children IGF-1, IGFBP3, and ALS were measured. The study group was divided according to diagnosis into groups: growth hormone deficiency (GHD), constitutional delay of growth and puberty (CDGP), idiopathic short stature (ISS), and familial short stature (FSS).

RESULTS: In the control group the ALS concentration ranged from 4.81 to 13.66 μg/mL. In the whole study group the ALS concentration ranged from 2.73 to 15.81 μg/mL. The difference between both groups was statistically significant (p < 0.0001, R = 0.39). A strong, statistically significant correlation between ALS levels and age was observed, but only in the study group (p < 0.0001, r = 0.59). The ALS standard deviation score (SDS) was not significantly different between the control and CDGP children (p = 0.0644). The ALS concentration was significantly lower in children with short stature. There was, however, no difference between the subgroups of the study group.

CONCLUSION: There was no significant difference in ALS SDS between the control group and children with constitutional delay of growth and development. The usefulness of ALS in routine short stature diagnostics is uncertain, but it might play a role in the diagnosis of children with ISS and CDGP in the future.}, } @article {pmid39474398, year = {2024}, author = {Goyal, O and Goyal, MK}, title = {Critical analysis of the effects of proton pump inhibitors on inflammatory bowel disease: An updated review.}, journal = {World journal of gastroenterology}, volume = {30}, number = {37}, pages = {4160-4162}, pmid = {39474398}, issn = {2219-2840}, mesh = {Humans ; *Colitis, Ulcerative/drug therapy/immunology/diagnosis ; *Crohn Disease/diagnosis/drug therapy/immunology ; *Proton Pump Inhibitors/therapeutic use/adverse effects ; Treatment Outcome ; Review Literature as Topic ; }, abstract = {This letter critically evaluates the effects of proton pump inhibitors (PPIs) on inflammatory bowel disease, particularly focusing on Crohn's disease (CD) and ulcerative colitis (UC), as discussed in Liang et al's recent review. While the review provides significant insights, it relies heavily on cross-sectional and observational studies, which limits the ability to draw causal inferences. The heterogeneous study populations and inconsistent definitions of long-term PPI use further complicate the findings. This letter also highlights the need for rigorous control of confounding factors and considers the potential publication bias in the existing literature. The implications of these issues are discussed in the context of both CD and UC, and future research directions are proposed to address these shortcomings.}, } @article {pmid39474168, year = {2024}, author = {Sandler, AB and Wells, ME and Tran, C and Arakawa, R and Klahs, KJ and Scanaliato, JP and Green, CK and Hettrich, CM and Dunn, JC and Adler, A and Parnes, N}, title = {High rates of return to sport after suprascapular nerve decompression: an updated systematic review.}, journal = {JSES reviews, reports, and techniques}, volume = {4}, number = {4}, pages = {654-661}, pmid = {39474168}, issn = {2666-6391}, abstract = {BACKGROUND: Suprascapular nerve decompression (SSND) remains a controversial procedure. In 2018, Momaya et al published the first systematic review of SSND noting satisfactory outcomes with low rates of complications; however, numerous studies published since have noted no benefit in routinely adding SSND to other arthroscopic surgeries, contributing to existing contention regarding the procedure. The purpose of this study is to provide an updated assessment of outcomes after SSND.

METHODS: To conduct this updated systematic review, a search of PubMed (MEDLINE) for relevant studies published prior to January 21, 2023 was conducted. Outcomes including patient-reported clinical outcomes, return to sport, preoperative and postoperative electrodiagnostic testing, and adverse events were collected and pooled for assessment. Studies were eligible for inclusion if they met Momaya et al's inclusion criteria and/or reported outcomes following SSND at either the suprascapular notch or spinoglenoid notch.

RESULTS: In total, 730 patients from 33 studies were eligible for inclusion. All patient-reported outcome measure scores including American Shoulder Elbow Surgeon Standardized Shoulder Assessment; Constant-Murley score; Disabilities of the Arm, Shoulder, and Hand; Subjective Shoulder Value; University of California-Los Angeles shoulder; and visual analog scale pain scores improved significantly postoperatively, with improvements ranging from 53.5% to 102.6% of preoperative values. Ultimately, 98% (n = 90/92) of patients returned to sport or military duty and 96% of these patients returned at their previous level of activity (n = 48/50) without heterogeneity among rates between studies (P = .176, P = .238, respectively). Preoperative electrodiagnostic testing was conducted in 93% of patients, and 90% had associated abnormal findings. Continued symptoms were noted among 12% of patients (n = 39/322) with significantly different rates observed between studies. Complications from operative management not limited to SSND occurred in 11% of patients (n = 64/576) and reoperations occurred in 3.3% of patients (n = 15/455).

CONCLUSION: Suprascapular neuropathy treated with SSND significantly improves patient-reported outcomes and is noninferior to similar procedures without SSND. Appropriate clinical diagnosis of suprascapular neuropathy is required as opposed to a routine adjunct procedure with other arthroscopic shoulder surgery. Ultimately, SSND is associated with high rates of return to sport and relatively low rates of adverse events; however, the risk of continued symptoms and electrodiagnostic test-related complications is an important point on preoperative counseling.}, } @article {pmid39473991, year = {2024}, author = {Hobro, AJ and Sakaguchi, T and Akira, S and Smith, NI}, title = {Correlative Quantitative Raman Chemical Imaging and MCR-ALS in Mouse NASH Model Reveals Direct Relationships between Diet and Resultant Liver Pathology.}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {8}, pages = {577-583}, pmid = {39473991}, issn = {2832-3637}, abstract = {Raman imaging has the capability to provide unlabeled, spatially aware analysis of chemical components, with no a priori assumptions. Several lifestyle diseases such as nonalcoholic steatohepatitis (NASH) can appear in the liver as changes in the nature, abundance, and distribution of lipids, proteins, and other biomolecules and are detectable by Raman imaging. In order to identify which of these liver-associated changes occur as a direct result of the diet and which are secondary effects, we developed correlative imaging and analysis of diet and liver samples. Oleic acid was found to be a direct contributor to NASH liver composition, whereas protein and collagen distributions were found to be affected in a manner consistent with early fibrotic transformation, as a secondary consequence of the high-fat diet.}, } @article {pmid39473807, year = {2024}, author = {Oliveira, GC and Ngo, QC and Passos, LA and Oliveira, LS and Stylianou, S and Papa, JP and Kumar, D}, title = {Video Assessment to Detect Amyotrophic Lateral Sclerosis.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {171-180}, pmid = {39473807}, issn = {2504-110X}, abstract = {INTRODUCTION: Weakened facial movements are early-stage symptoms of amyotrophic lateral sclerosis (ALS). ALS is generally detected based on changes in facial expressions, but large differences between individuals can lead to subjectivity in the diagnosis. We have proposed a computerized analysis of facial expression videos to detect ALS.

METHODS: This study investigated the action units obtained from facial expression videos to differentiate between ALS patients and healthy individuals, identifying the specific action units and facial expressions that give the best results. We utilized the Toronto NeuroFace Dataset, which includes nine facial expression tasks for healthy individuals and ALS patients.

RESULTS: The best classification accuracy was 0.91 obtained for the pretending to smile with tight lips expression.

CONCLUSION: This pilot study shows the potential of using computerized facial expression analysis based on action units to identify facial weakness symptoms in ALS.}, } @article {pmid39473490, year = {2024}, author = {Fei, Y and Ding, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1475934}, pmid = {39473490}, issn = {1662-5102}, abstract = {Ferroptosis represents an iron[-] and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.}, } @article {pmid39473462, year = {2024}, author = {Zhang, Y and Xu, N and Yan, C and Zhou, X and Qiao, Q and Miao, L and Xu, Z}, title = {Live-Cell Imaging to Resolve Salt-Induced Liquid-Liquid Phase Separation of FUS Protein by Dye Self-Labeling.}, journal = {Chemical & biomedical imaging}, volume = {2}, number = {1}, pages = {70-80}, pmid = {39473462}, issn = {2832-3637}, abstract = {The aggregation of fusion in sarcoma (FUS) in the cytoplasm and nucleus is a pathological feature of Amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD). Genetic mutations, abnormal protein synthesis, environmental stress, and aging have all been implicated as causative factors in this process. Salt ions are essential to many physiological processes in the body, and the imbalance of them is an important environmental stress factor in cells. However, their effect on liquid-liquid phase separation (LLPS) of FUS proteins in living cells is not well understood. Here, we map the various salt-induced LLPS of FUS in living cells by genetically coding and self-labeling FUS with organic dyes. The brightness and photostability of the dyes enable long-term imaging to track the mechanism of the assembly and disappearance of FUS phase separation. The FUS protein showed a better phase separation tendency under 0.3 M salt stimulation, and there was a large amount of FUS shuttling from the nucleus to the cytoplasm. At this concentration, various salt solutions displayed different effects on the phase separation of FUS protein, following the Hofmeister effects. We further observed that the assembly of FUS droplets underwent a process of rapid formation of small droplets, plateaus, and mutual fusion. Strikingly, The CsCl-stimulated FUS droplets were not completely reversible after washing, and some solid-like granules remained in the nucleus. Taken together, these results help broaden our understanding of the LLPS of FUS proteins in cellular stress responses.}, } @article {pmid39473221, year = {2024}, author = {Ito, D and Okada, K}, title = {Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {12}, pages = {3054-3063}, pmid = {39473221}, issn = {2328-9503}, support = {21H02812//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Oligonucleotides, Antisense/administration & dosage/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.}, } @article {pmid39472924, year = {2024}, author = {Stikvoort García, DJL and Sleutjes, BTHM and Mugge, W and Plouvier, JJ and Goedee, HS and Schouten, AC and van der Helm, FCT and van den Berg, LH}, title = {Instrumented assessment of lower and upper motor neuron signs in amyotrophic lateral sclerosis using robotic manipulation: an explorative study.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {193}, pmid = {39472924}, issn = {1743-0003}, support = {AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Robotics/instrumentation/methods ; *Electromyography/methods/instrumentation ; Aged ; *Motor Neurons/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Torque ; Wrist Joint/physiopathology ; Adult ; Muscle Strength/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal progressive neurodegenerative disease characterized by upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Their varying degree of involvement results in a clinical heterogenous picture, making clinical assessments of UMN signs in patients with ALS often challenging. We therefore explored whether instrumented assessment using robotic manipulation could potentially be a valuable tool to study signs of UMN involvement.

METHODS: We examined the dynamics of the wrist joint of 15 patients with ALS and 15 healthy controls using a Wristalyzer single-axis robotic manipulator and electromyography (EMG) recordings in the flexor and extensor muscles in the forearm. Multi-sinusoidal torque perturbations were applied, during which participants were asked to either relax, comply or resist. A neuromuscular model was used to study muscle viscoelasticity, e.g. stiffness (k) and viscosity (b), and reflexive properties, such as velocity, position and force feedback gains (kv, kp and kf, respectively) that dominated the responses. We further obtained clinical signs of LMN (muscle strength) and UMN (e.g. reflexes, spasticity) dysfunction, and evaluated their relation with the estimated neuromuscular model parameters.

RESULTS: Only force feedback gains (kf) were elevated in patients (p = 0.033) compared to controls. Higher kf, as well as the resulting reflexive torque (Tref), were both associated with more severe UMN dysfunction in the examined arm (p = 0.040 and p < 0.001). Patients with UMN symptoms in the examined arm had increased kf and Tref compared to controls (both p = 0.037). Neither of these measures was related to muscle strength, but muscle stiffness (k) was lower in weaker patients (p = 0.012). All these findings were obtained from the relaxed test. No differences were observed during the instructions comply and resist.

CONCLUSIONS: This findings are proof-of-concept that instrumented assessment using robotic manipulation is a feasible technique in ALS, which may provide quantitative, operator-independent measures relating to UMN symptoms. Elevated force feedback gains, driving larger reflexive muscle torques, appear to be particularly indicative of clinically established levels of UMN dysfunction in the examined arm.}, } @article {pmid39472842, year = {2024}, author = {Guazzo, A and Atzeni, M and Idi, E and Trescato, I and Tavazzi, E and Longato, E and Manera, U and Chió, A and Gromicho, M and Alves, I and de Carvalho, M and Vettoretti, M and Di Camillo, B}, title = {Predicting clinical events characterizing the progression of amyotrophic lateral sclerosis via machine learning approaches using routine visits data: a feasibility study.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {Suppl 4}, pages = {318}, pmid = {39472842}, issn = {1472-6947}, support = {GA01017598//HORIZON EUROPE Health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Feasibility Studies ; *Disease Progression ; *Machine Learning ; Male ; Middle Aged ; Female ; Aged ; Prognosis ; Noninvasive Ventilation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in death within a short time span (3-5 years). One of the major challenges in treating ALS is its highly heterogeneous disease progression and the lack of effective prognostic tools to forecast it. The main aim of this study was, then, to test the feasibility of predicting relevant clinical outcomes that characterize the progression of ALS with a two-year prediction horizon via artificial intelligence techniques using routine visits data.

METHODS: Three classification problems were considered: predicting death (binary problem), predicting death or percutaneous endoscopic gastrostomy (PEG) (multiclass problem), and predicting death or non-invasive ventilation (NIV) (multiclass problem). Two supervised learning models, a logistic regression (LR) and a deep learning multilayer perceptron (MLP), were trained ensuring technical robustness and reproducibility. Moreover, to provide insights into model explainability and result interpretability, model coefficients for LR and Shapley values for both LR and MLP were considered to characterize the relationship between each variable and the outcome.

RESULTS: On the one hand, predicting death was successful as both models yielded F1 scores and accuracy well above 0.7. The model explainability analysis performed for this outcome allowed for the understanding of how different methodological approaches consider the input variables when performing the prediction. On the other hand, predicting death alongside PEG or NIV proved to be much more challenging (F1 scores and accuracy in the 0.4-0.6 interval).

CONCLUSIONS: In conclusion, predicting death due to ALS proved to be feasible. However, predicting PEG or NIV in a multiclass fashion proved to be unfeasible with these data, regardless of the complexity of the methodological approach. The observed results suggest a potential ceiling on the amount of information extractable from the database, e.g., due to the intrinsic difficulty of the prediction tasks at hand, or to the absence of crucial predictors that are, however, not currently collected during routine practice.}, } @article {pmid39472796, year = {2024}, author = {Zheng, K and Chen, M and Xu, X and Li, P and Yin, C and Wang, J and Liu, B}, title = {Chemokine CXCL13-CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases.}, journal = {Cellular & molecular biology letters}, volume = {29}, number = {1}, pages = {134}, pmid = {39472796}, issn = {1689-1392}, support = {82474625//National Natural Science Foundation of China/ ; 82305368//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Chemokine CXCL13/metabolism/genetics ; *Chronic Pain/metabolism/immunology ; *Receptors, CXCR5/metabolism ; *Signal Transduction ; *Nervous System Diseases/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; }, abstract = {Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C-X-C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13-CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13-CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13-CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13-CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases.}, } @article {pmid39471924, year = {2024}, author = {Xu, Y and Xu, T and Huang, C and Liu, L and Kwame, AW and Zhu, Y and Ren, J}, title = {Preventive intervention with Agaricus blazei murill polysaccharide exerts anti-tumor immune effect on intraperitoneal metastasis colorectal cancer.}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 3}, pages = {136810}, doi = {10.1016/j.ijbiomac.2024.136810}, pmid = {39471924}, issn = {1879-0003}, mesh = {Animals ; *Agaricus/chemistry ; *Colorectal Neoplasms/pathology/immunology/prevention & control/drug therapy ; Mice ; Cell Line, Tumor ; Tumor Microenvironment/drug effects ; Peritoneal Neoplasms/secondary/drug therapy/prevention & control/immunology ; Fungal Polysaccharides/pharmacology/chemistry ; CD8-Positive T-Lymphocytes/drug effects/immunology ; Polysaccharides/pharmacology/chemistry ; Antineoplastic Agents/pharmacology ; }, abstract = {Agaricus blazei murill (ABM) mainly exerts its antitumor effect via modulation of the immune system. However, the immunomodulatory role of the ABM polysaccharide (ABMP) in mice with subcutaneously and intraperitoneally implanted MC38 tumor remains to be explored. This study aimed to define the progression effect of inhibiting tumor of ABMP in subcutaneous and intraperitoneal models and its effect on tumor microenvironment (TME) metabolism. In vitro experiments showed that ABMP could significantly promote the activity of CD8+ T immune cells in the co-culture system and promoted their colorectal cancer killing function (p < 0.05). In vivo animal exploration further showed that ABMP could inhibit the growth of intraperitoneal but not subcutaneous tumors. MCR-ALS analysis revealed a significant reduction in the signal of lipid-related spectral components in the TME of peritoneal tumors after ABMP intervention. In addition, preventive intervention with ABMP increased ω-3 polyunsaturated fatty acids content in intraperitoneal TME, revealing that ABMP shifted the metabolic landscape of the TME to promote T cell function and achieved immune regulation. These results suggest that the inhibitory effect of ABMP on colon cancer may be tumor stage-dependent, and that remodeling of fatty acid composition may be an important determinant of its action at any given stage.}, } @article {pmid39471842, year = {2024}, author = {Ferro, F and Wolf, CR and Henstridge, C and Inesta-Vaquera, F}, title = {Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240073}, pmid = {39471842}, issn = {2046-2441}, support = {//MND Scotland/ ; //ARUK/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; Animals ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; Humans ; *Mice, Transgenic ; *Genes, Reporter ; Oxidative Stress/drug effects ; NF-E2-Related Factor 2/metabolism/genetics ; Drug Development ; DNA Damage ; Biomarkers ; }, abstract = {The development of therapies to combat neurodegenerative diseases is widely recognized as a research priority. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS, before moderate clinical signs are observed. Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters' expression. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.}, } @article {pmid39471269, year = {2024}, author = {Stenson, K and Chew, S and Dong, S and Heithoff, K and Wang, MJ and Rosenfeld, J}, title = {Health care resource utilization and costs across stages of amyotrophic lateral sclerosis in the United States.}, journal = {Journal of managed care & specialty pharmacy}, volume = {30}, number = {11}, pages = {1239-1247}, pmid = {39471269}, issn = {2376-1032}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Humans ; United States ; Male ; Female ; Middle Aged ; Aged ; *Patient Acceptance of Health Care/statistics & numerical data ; *Health Care Costs/statistics & numerical data ; Adult ; Health Resources/economics/statistics & numerical data ; Severity of Illness Index ; Retrospective Studies ; Disease Progression ; Cost of Illness ; Databases, Factual ; }, abstract = {BACKGROUND: People living with ALS (plwALS) experience motor control loss, speech/swallowing difficulties, respiratory insufficiency, and early death. Advancing disease stage is typically associated with a greater burden on the health care system, and delays in diagnosis can result in substantial health care resource utilization (HCRU).

OBJECTIVE: To estimate HCRU and cost burden of plwALS across disease stages from a US payer perspective we assessed HCRU and costs in early-, mid-, and late-stage ALS.

METHODS: Using insurance claims data from the IBM MarketScan Databases between January 2013 and December 2019, we identified plwALS as having at least 2 claims at least 27 days apart with an ALS International Classification of Diseases, Ninth or Tenth Revision diagnosis code (335.20/G12.21) or at least 1 ALS diagnosis code and prescription filled for riluzole/edaravone. Eligible plwALS were aged at least 18 years and had at least 12 months of enrollment data before and at least 6 months after the index date (date diagnosis criteria met). plwALS were grouped into disease stages using an ALS severity-based staging algorithm developed using ALS symptom and staging survey data from 142 neurologists reporting on 880 plwALS. The starting date of each severity stage was defined as the first date of an ALS symptom within the early-, mid-, and late-stage categories, respectively. The ending date for a severity stage was defined as the day before the first date of an ALS symptom from a more severe category. plwALS could transition to more severe stages, with reverse transition of severity excluded. Mixed regression modeling was used to assess differences in HCRU and costs per person-year between severity stages, adjusted for age and sex.

RESULTS: 2,273 plwALS were included in the total ALS study sample, with 1,215 early-stage, 1,511 midstage, and 1,186 late-stage plwALS. 90% of early-stage plwALS had ALS symptoms before diagnosis, and 27% of late-stage plwALS had a late-stage symptom before diagnosis. In the evaluation period, later-stage ALS groups had more overall hospital admissions (early = 0.15, middle = 0.23, and late = 0.74; P < 0.01), outpatient visits/service (early = 26.81, middle = 32.78, and late = 48.54; P < 0.01), emergency department visits (early = 0.46, middle = 0.69, and late = 1.03; P < 0.01), and total prescription count (early = 9.23, middle = 11.37, and late = 12.72; P < 0.01) over 12 months. Annualized costs increased as ALS progressed (early = $31,411, middle = $51,481, and late = $121,903; P < 0.01), which was primarily driven by higher frequency of and cost per hospital admission.

CONCLUSIONS: HCRU and costs increased with ALS progression, with diagnosis frequently occurring even after experiencing late-stage symptoms. These findings highlight the potential value of delaying progression into a more resource-intensive stage by diagnosing and adequately treating plwALS earlier in the disease course.}, } @article {pmid39470866, year = {2024}, author = {Liu, Y and Fu, R and Jia, H and Yang, K and Ren, F and Zhou, MS}, title = {GHRH and its analogues in central nervous system diseases.}, journal = {Reviews in endocrine & metabolic disorders}, volume = {}, number = {}, pages = {}, pmid = {39470866}, issn = {1573-2606}, support = {82270434//National Natural Science Foundation of China/ ; }, abstract = {Growth hormone-releasing hormone (GHRH) is primarily produced by the hypothalamus and stimulates the release of growth hormone (GH) in the anterior pituitary gland, which subsequently regulates the production of hepatic insulin-like growth factor-1 (IGF-1). GH and IGF-1 have potent effects on promoting cell proliferation, inhibiting cell apoptosis, as well as regulating cell metabolism. In central nerve system (CNS), GHRH/GH/IGF-1 promote brain development and growth, stimulate neuronal proliferation, and regulate neurotransmitter release, thereby participating in the regulation of various CNS physiological activities. In addition to hypothalamus-pituitary gland, GHRH and GHRH receptor (GHRH-R) are also expressed in other brain cells or tissues, such as endogenous neural stem cells (NSCs) and tumor cells. Alternations in GHRH/GH/IGF-1 axis are associated with various CNS diseases, for example, Alzheimer's disease, amyotrophic lateral sclerosis and emotional disorders manifest GHRH, GH or IGF-1 deficiency, and GH or IGF-1 supplementation exerts beneficial therapeutic effects on these diseases. CNS tumors, such as glioma, can express GHRH and GHRH-R, and activating this signaling pathway promotes tumor cell growth. The synthesized GHRH antagonists have shown to inhibit glioma cell growth and may hold promising as an adjuvant therapy for treating glioma. In addition, we have shown that GHRH agonist MR-409 can improve neurological sequelae after ischemic stroke by activating extrapituitary GHRH-R signaling and promoting endogenous NSCs-derived neuronal regeneration. This article reviews the involvement of GHRH/GH/IGF-1 in CNS diseases, and potential roles of GHRH agonists and antagonists in treating CNS diseases.}, } @article {pmid39470847, year = {2024}, author = {Jellinger, KA}, title = {Mild cognitive impairment in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {39470847}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.}, } @article {pmid39470585, year = {2024}, author = {Lin, W and Wu, X and Ou, G}, title = {Causal association of circulating inflammatory proteins on neurodegenerative diseases: Insights from a mendelian randomization study.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {20}, pages = {e70176}, pmid = {39470585}, issn = {1582-4934}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/blood ; *Genome-Wide Association Study ; *Cytokines/blood/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics/blood ; Amyotrophic Lateral Sclerosis/genetics/blood ; Inflammation/genetics/blood ; Multiple Sclerosis/genetics/blood ; Parkinson Disease/genetics/blood ; }, abstract = {Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.}, } @article {pmid39470153, year = {2024}, author = {Xu, R}, title = {Overview of nomenclature and diagnosis of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2422572}, pmid = {39470153}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Humans ; *Terminology as Topic ; Electromyography/methods ; Motor Neurons/pathology ; }, abstract = {The nomenclature of amyotrophic lateral sclerosis (ALS) currently is blurred, indistinct and no accurate and haven't been properly updated since the first description, which is far from being suitable for the current implementation of clinical practise and scientific research of ALS, and urgently need an solution. Furthermore, the current diagnostic criteria need also further been improved, because the current clinical diagnosis of ALS majorly depends on the clinical manifestations yet. Up to now, no any objective clinical auxiliary examination can be helpful to diagnose ALS besides the electromyogram identifying the lower motor neuron damage, which isn't conducive to early diagnosis and prolongs the time of ALS confirmed diagnosis. In this mini review, we discussed the current doubt about the nomenclature and diagnostic criteria of ALS, and prospected in order to further improve and normalize the nomenclature and diagnosis of ALS.}, } @article {pmid39468607, year = {2024}, author = {Liu, C and Wu, Y and Wang, F and Sun, S and Wei, J and Tao, L}, title = {Cost-utility analysis for sublingual versus intravenous edaravone in the treatment of amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {400}, pmid = {39468607}, issn = {1750-1172}, mesh = {*Edaravone/therapeutic use/economics/administration & dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; *Cost-Benefit Analysis ; Administration, Sublingual ; Antipyrine/analogs & derivatives/therapeutic use/economics/administration & dosage ; Free Radical Scavengers/therapeutic use/economics/administration & dosage ; Administration, Intravenous ; Male ; }, abstract = {BACKGROUND: Edaravone has been widely used in amyotrophic lateral sclerosis (ALS) treatment, and a sublingual (SL) tablet has been developed to offer a more convenient alternative for injection. We present a cost-utility analysis to comprehensively evaluate the costs and health outcomes of oral and intravenous edaravone for the treatment of ALS in Chinese medical context.

METHODS: Cost-utility analysis of SL tablets of edaravone versus intravenous edaravone at home was performed by constructing a 20-year Markov model of ALS stage 1-4 and death. The data were extracted from the literature with model assumptions. Typical sensitivity analysis and scenario analysis for administering SL tablets at home versus intravenous tablets at the hospital were performed.

RESULTS: In the base case analysis, with SL tablets and intravenous injections both at home, the model estimated an additional cost of ¥12,670.04 and an additional 0.034 QALYs over 20 years (life time) of modeling analysis, and the ICER was ¥372,648.24 per QALY. However, in the scenario of intravenous administration at the hospital, SL tablet was demonstrated dominance to intravenous injection.

CONCLUSIONS: Using 3 times the GDP per capita of China in 2023 as the threshold, the SL tablet edaravone was not cost-effective in the context of home treatment for both formulationst, but was dominance to intravenous injection in hospital treatment. The results highlighted the importance of treatment context for health economic analysis.}, } @article {pmid39467933, year = {2024}, author = {Kang, M and Kim, BJ and Nguyen, B and Park, JS}, title = {Computed tomography-based radiological gynecomastia in SBMA as an independent differential diagnostic biomarker: a retrospective study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10072-024-07820-1}, pmid = {39467933}, issn = {1590-3478}, abstract = {BACKGROUND: Spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are motor neuron disorders that demonstrate overlapping clinical features, especially in the early stage. Therefore, the aim of this study was to investigate the utility of chest tomography (CT) imaging in distinguishing between SBMA and ALS.

METHODS: This was a retrospective study reviewing CT images from patients with SBMA and sporadic ALS and those in the control group. The CT images were assessed to measure the diameter and morphology of glandular tissue associated with gynecomastia. We compared CT-measured gynecomastia between the SBMA, ALS, and control groups. Additionally, correlation analyses were performed between the quantitative measurements of gynecomastia obtained from CT scans and various clinical/laboratory parameter in the SBMA group.

RESULTS: 15 chest CT images were collected from SBMA, 41 from ALS, and 29 from control group. No statistical differences were observed in BMI, functional scales, or age at the time of CT scans between the SBMA and ALS groups. Despite similar functional scales and age in both groups, the mean glandular tissue diameter of breast tissue observed in chest CT imaging differed significantly between SBMA, ALS, and controls: 32.22 ± 12.57 mm, 15.91 ± 4.81 mm, and 15.76 ± 7.26 mm, respectively. This disparity allowed for the differentiation of SBMA from ALS and controls with statistical significance. Clinical gynecomastia was 80%, while radiological gynecomastia was 93.3% in SBMA. A significantly higher prevalence of diffuse glandular morphology pattern in SBMA (50%) was observed, contrasting with the predominance of nodular morphology in ALS and controls (9.1% and 20%). Correlative analysis between glandular tissue diameter and other clinical/laboratory parameters within the SBMA group showed no specific finding.

CONCLUSION: CT-based radiological gynecomastia effectively differentiated SBMA from ALS. These findings support the usefulness of radiological gynecomastia as a potential differential diagnostic marker for SBMA, especially in the early stages.}, } @article {pmid39466798, year = {2024}, author = {Correa, T and Owen, SR}, title = {Invited Commentary: Santamaría-Gadea et al's "Non-Surgical Rhinoplasty After Rhinoplasty: Systematic Review of the Technique, Results, and Complications".}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/fpsam.2024.0267}, pmid = {39466798}, issn = {2689-3622}, } @article {pmid39465944, year = {2024}, author = {Chen, C and Rafael, KA and Cho, G and Lim, Y}, title = {Split-Luciferase Reassembly Assay to Measure Endoplasmic Reticulum-Mitochondria Contacts in Live Cells.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, doi = {10.3791/66862}, pmid = {39465944}, issn = {1940-087X}, mesh = {*Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Luciferases/metabolism/genetics ; Animals ; Mitochondria Associated Membranes ; }, abstract = {Endoplasmic reticulum (ER)-mitochondria contact sites play a critical role in cell health and homeostasis, such as the regulation of Ca[2+] and lipid homeostasis, mitochondrial dynamics, autophagosome and mitophagosome biogenesis, and apoptosis. Failure to maintain normal ER-mitochondrial coupling is implicated in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegia. It is of considerable significance to explore how the dysregulation of ER-mitochondrial contacts could lead to cell death and whether repairing these contacts to the normal level could ameliorate neurodegenerative conditions. Thus, improved assays that measure the level of these contacts could help to illuminate the pathogenic mechanisms of these diseases. Ultimately, establishing simple and reliable assays will facilitate the development of new therapeutic strategies. Here we describe a split-luciferase assay to quantitatively measure the level of ER-mitochondria contacts in live cells. This assay can be used to study the pathophysiological role of these contacts as well as to identify their modulators in high-throughput screening.}, } @article {pmid39465642, year = {2024}, author = {Erdaş, ÇB and Sümer, E}, title = {CNN-Based Neurodegenerative Disease Classification Using QR-Represented Gait Data.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70100}, pmid = {39465642}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/classification/diagnosis/physiopathology ; *Huntington Disease/diagnosis/physiopathology/classification ; *Parkinson Disease/classification/diagnosis/physiopathology ; *Neurodegenerative Diseases/classification/diagnosis/physiopathology ; Male ; Middle Aged ; Female ; Neural Networks, Computer ; Gait/physiology ; Aged ; Deep Learning ; Gait Analysis/methods ; Adult ; }, abstract = {PURPOSE: The primary aim of this study is to develop an effective and reliable diagnostic system for neurodegenerative diseases by utilizing gait data transformed into QR codes and classified using convolutional neural networks (CNNs). The objective of this method is to enhance the precision of diagnosing neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD), through the introduction of a novel approach to analyze gait patterns.

METHODS: The research evaluates the CNN-based classification approach using QR-represented gait data to address the diagnostic challenges associated with neurodegenerative diseases. The gait data of subjects were converted into QR codes, which were then classified using a CNN deep learning model. The dataset includes recordings from patients with Parkinson's disease (n = 15), Huntington's disease (n = 20), and amyotrophic lateral sclerosis (n = 13), and from 16 healthy controls.

RESULTS: The accuracy rates obtained through 10-fold cross-validation were as follows: 94.86% for NDD versus control, 95.81% for PD versus control, 93.56% for HD versus control, 97.65% for ALS versus control, and 84.65% for PD versus HD versus ALS versus control. These results demonstrate the potential of the proposed system in distinguishing between different neurodegenerative diseases and control groups.

CONCLUSION: The results indicate that the designed system may serve as a complementary tool for the diagnosis of neurodegenerative diseases, particularly in individuals who already present with varying degrees of motor impairment. Further validation and research are needed to establish its wider applicability.}, } @article {pmid39464638, year = {2024}, author = {Altuwaijri, F and Alrabiah, A and Alqarni, A and Habash, AK and Alghofili, M and Alotaibi, O and Altuwaijri, M}, title = {Comparison Between the Advanced Cardiac Life Support and Adult Advanced Life Support Protocols: A Simulation-Based Pilot Study.}, journal = {Emergency medicine international}, volume = {2024}, number = {}, pages = {6696879}, pmid = {39464638}, issn = {2090-2840}, abstract = {Introduction: Cardiac arrest is a public health concern associated with unfavorable disease outcomes. Cardiopulmonary resuscitation (CPR) of optimal quality is widely acknowledged as an indispensable technique in restoring spontaneous circulation. In order to perform advanced cardiac life support (ACLS), chest compression must be paused twice: once to assess the rhythm and again to administer the shock. Australian advanced life support (ALS) recommends that the defibrillator needs to be precharged in order to administer the shock during a solitary interval in chest compressions. While performing chest compressions, precharging defibrillators can decrease hands-off time without posing a risk of injury. Aim: To compare chest compression fraction (CCF)-which is the cumulative time spent providing chest compressions divided by the total time taken for the entire resuscitation-by calculating the hands-off time duration in cardiac arrest between the Australian Resuscitation Council (ARC) and American Heart Association (AHA) protocols for CPR. Methods: A simulation-based pilot study was designed using a Laerdal Resusci Anne mannequin and a LIFEPACK 20 defibrillator. The study included six participants recruited from King Khalid University Hospital in Riyadh, Saudi Arabia, where three participants were certified ACLS providers and there were certified ALS providers. Participants were divided into two groups, ALS and ACLS, each following one protocol. For each scenario, a random job was assigned to each participant, regardless of their role as assistant, team leader, or performer of CPR. Each case's shockable and nonshockable rhythms were hidden from the team leader and the chest compressor. Ten trials of CPR were performed, each for four cycles with a total time of 8 min. The simulation was video recorded for hands-off time counting. Comparison between CCF (seconds) per cycle between the two protocols was performed using an independent sample t-test. A p value of 0.05 was used to measure statistical significance. Results: Comparing CCF in shockable rhythms between ARC and AHA protocols, it was observed that the CCF of ALS-ARC was significantly higher than ACLS-AHA in all cycles; the first cycle: t = 3.782, p=0.004; the second cycle: t = 3.380, p=0.007; the third cycle: t = 3.803, p=0.003; and the fourth cycle: t = 4.341, p=0.001. Conclusion: Precharging a defibrillator before a rhythm check during chest compression, in anticipation of a potentially shockable rhythm, reduces the time required for defibrillation and limits interruptions in chest compression during CPR. This practice effectively enhances the CCF. Enhancing the continuity of chest compressions can potentially improve survival rates in ARC.}, } @article {pmid39464461, year = {2024}, author = {Karunakaran, V and Dadgar, S and Paidi, SK and Mordi, AF and Lowe, WA and Mim, UM and Ivers, JD and Rodriguez Troncoso, JI and McPeake, JA and Fernandes, A and Tripathi, SD and Barman, I and Rajaram, N}, title = {Investigating In Vivo Tumor Biomolecular Changes Following Radiation Therapy Using Raman Spectroscopy.}, journal = {ACS omega}, volume = {9}, number = {42}, pages = {43025-43033}, pmid = {39464461}, issn = {2470-1343}, support = {P20 GM139768/GM/NIGMS NIH HHS/United States ; }, abstract = {Treatment resistance is a major bottleneck in the success of cancer therapy. Early identification of the treatment response or lack thereof in patients can enable an earlier switch to alternative treatment strategies that can enhance response rates. Here, Raman spectroscopy was applied to monitor early tumor biomolecular changes in sensitive (UM-SCC-22B) and resistant (UM-SCC-47) head and neck tumor xenografts for the first time in in vivo murine tumor models in response to radiation therapy. We used a validated multivariate curve resolution-alternating least-squares (MCR-ALS) model to resolve complex multicomponent Raman spectra into individual pure spectra and their respective contributions. We observed a significant radiation-induced increase in the contributions of lipid-like species (p = 0.0291) in the radiation-sensitive UM-SCC-22B tumors at 48 h following radiation compared to the nonradiated baseline (prior to commencing treatment). We also observed an increase in the contribution of collagen-like species in the radiation-resistant UM-SCC-47 tumors at 24 h following radiation compared to the nonradiated baseline (p = 0.0125). In addition to the in vivo analysis, we performed ex vivo confocal Raman microscopic imaging of frozen sections derived from the same tumors. A comparison of all control and treated tumors revealed similar trends in the contributions of lipid-like and collagen-like species in both in vivo and ex vivo measurements; however, when evaluated as a function of time, longitudinal trends in the scores of collagen-like and lipid-like components were not consistent between the two data sets, likely due to sample numbers and differences in sampling depth at which information is obtained. Nevertheless, this study demonstrates the potential of fiber-based Raman spectroscopy for identifying early tumor microenvironmental changes in response to clinical doses of radiation therapy.}, } @article {pmid39464100, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464100}, issn = {2692-8205}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, } @article {pmid39463426, year = {2024}, author = {Yang, SF and Patel, PN}, title = {Commentary: Youssefi et al's 3D Smartphone Photography During Rhinoplasty Surgery.}, journal = {Facial plastic surgery & aesthetic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/fpsam.2024.0265}, pmid = {39463426}, issn = {2689-3622}, } @article {pmid39462586, year = {2024}, author = {Kurita, H and Hirasawa, N and Yabe, S and Okuda, A and Murakami, T and Ohuchi, K and Ogata, A and Yoshioka, H and Kakita, A and Hozumi, I and Inden, M}, title = {MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.}, journal = {Biological & pharmaceutical bulletin}, volume = {47}, number = {10}, pages = {1717-1725}, doi = {10.1248/bpb.b24-00418}, pmid = {39462586}, issn = {1347-5215}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Endoplasmic Reticulum Stress/drug effects/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Zinc/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; HEK293 Cells ; Transfection ; Tunicamycin/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS. Previously, we first reported miR-5572 as a microRNA (miRNA) among those identified in the spinal cords of patients with sporadic ALS. However, since its function in ALS remained unknown, this study further examined the role of miR-5572 in low-zinc status and ALS model cells which transfected with causative gene, Cu/Zn superoxide dismutase 1 (SOD1) G85R mutant vector. The miR-5572 level was increased by low-zinc condition accompanied by increase of endoplasmic reticulum (ER) stress. In addition, increase of miR-5572 enhanced the cellular toxicity induced by low-zinc treatment. The expression of miR-5572 was also increased, which was accompanied by an increase of ER stress markers associated with SOD1 aggregation formation. Cell death and ER stress makers levels induced by tunicamycin treatment were further increased in miR-5572 mimic-transfected cells. This study showed that miR-5572 exacerbated ER stress toxicity associated with low-zinc status and mutant SOD1 aggregates in ALS.}, } @article {pmid39462509, year = {2024}, author = {Dauer, LT and Mumma, MT and Lima, JC and Cohen, SS and Andresen, D and Bahadori, AA and Bellamy, M and Bierman, DA and Blattnig, S and French, B and Giunta, E and Held, K and Hertel, N and Keohane, L and Leggett, R and Lipworth, L and Miller, KB and Norman, RB and Samuels, C and Thomas, KS and Tolmachev, SY and Walsh, L and Boice, JD}, title = {A Million Person Study Innovation: Evaluating Cognitive Impairment and other Morbidity Outcomes from Chronic Radiation Exposure Through Linkages with the Centers for Medicaid and Medicare Services Assessment and Claims Data.}, journal = {Radiation research}, volume = {202}, number = {6}, pages = {847-861}, doi = {10.1667/RADE-23-00186.1}, pmid = {39462509}, issn = {1938-5404}, mesh = {Humans ; United States/epidemiology ; *Radiation Exposure/adverse effects ; Centers for Medicare and Medicaid Services, U.S. ; Male ; Medicare ; Female ; Cognition Disorders/epidemiology/etiology ; }, abstract = {The study of One Million U.S. Radiation Workers and Veterans, the Million Person Study (MPS), examines the health consequences, both cancer and non-cancer, of exposure to ionizing radiation received gradually over time. Recently the MPS has focused on mortality patterns from neurological and behavioral conditions, e.g., Parkinson's disease, Alzheimer's disease, dementia, and motor neuron disease such as amyotrophic lateral sclerosis. A fuller picture of radiation-related late effects comes from studying both mortality and the occurrence (incidence) of conditions not leading to death. Accordingly, the MPS is identifying neurocognitive diagnoses from fee-for-service insurance claims from the Centers for Medicare and Medicaid Services (CMS), among Medicare beneficiaries beginning in 1999 (the earliest date claims data are available). Linkages to date have identified ∼540,000 workers with available health information. Such linkages provide individual information on important co-factor and confounding variables such as smoking, alcohol consumption, blood pressure, obesity, diabetes and many other health and demographic characteristics. The total person-level set of time-dependent variables, outcomes, organ-specific dose measures, co-factors, and demographics will be massive and much too large to be evaluated with standard software. Thus, development of specialized open-source software designed for large datasets (Colossus) is nearly complete. The wealth of information available from CMS claims data, coupled with individual dose reconstructions, will thus greatly enhance the quality and precision of health evaluations for this new field of low-dose radiation and neurocognitive effects.}, } @article {pmid39461864, year = {2024}, author = {Imamura, K and Izumi, Y and Egawa, N and Ayaki, T and Nagai, M and Nishiyama, K and Watanabe, Y and Murakami, T and Hanajima, R and Kataoka, H and Kiriyama, T and Nanaura, H and Sugie, K and Hirayama, T and Kano, O and Nakamori, M and Maruyama, H and Haji, S and Fujita, K and Atsuta, N and Tatebe, H and Tokuda, T and Takahashi, N and Morinaga, A and Tabuchi, R and Oe, M and Kobayashi, M and Lobello, K and Morita, S and Sobue, G and Takahashi, R and Inoue, H}, title = {Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e082142}, pmid = {39461864}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Aniline Compounds/therapeutic use ; *Drug Repositioning ; *Nitriles/therapeutic use ; *Quinolines/therapeutic use ; Male ; Middle Aged ; Induced Pluripotent Stem Cells ; Female ; Adult ; Aged ; Clinical Trials, Phase II as Topic ; Multicenter Studies as Topic ; Japan ; Protein Kinase Inhibitors/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.

METHODS AND ANALYSIS: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.

ETHICS AND DISSEMINATION: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.

TRIAL REGISTRATION NUMBER: jRCT2051220002; Pre-results, NCT04744532; Pre-results.}, } @article {pmid39461630, year = {2024}, author = {Kouhi, ZH and Seyedalipour, B and Hosseinkhani, S and Chaichi, MJ}, title = {Bisdemethoxycurcumin, a novel potent polyphenolic compound, effectively inhibits the formation of amyloid aggregates in ALS-associated hSOD1 mutant (L38R).}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 2}, pages = {136701}, doi = {10.1016/j.ijbiomac.2024.136701}, pmid = {39461630}, issn = {1879-0003}, mesh = {*Diarylheptanoids/chemistry/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; *Protein Aggregates/drug effects ; *Amyloid/metabolism/chemistry ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Mutation ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; Curcumin/pharmacology/analogs & derivatives/chemistry ; Polyphenols/pharmacology/chemistry ; Protein Aggregation, Pathological/genetics/drug therapy ; Hemolysis/drug effects ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Protein misfolding is a biological process that leads to protein aggregation. Anomalous misfolding and aggregation of human superoxide dismutase (hSOD1) into amyloid aggregates is a characteristic feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative illness. Thus, focusing on the L38R mutant may be a wise decision to comprehend the SOD1 disease process in ALS. We suggest that Bisdemethoxycurcumin (BDMC) may be a strong anti-amyloidogenic polyphenol against L38R mutant aggregation. Protein stability, hydrophobicity, and flexibility were altered when BDMC was bound to the L38R mutant, as shown by molecular dynamic (MD) simulations and molecular docking. FTIR data shows α-Helix dominance in BDMC-containing samples, with reduced β-sheet and disordered peaks, indicating the decrease of aggregate species. ThT aggregation kinetics curves show BDMC reduces L38R mutant aggregation dose-dependently, with higher BDMC concentrations yielding greater reductions. TEM images showed various quantities of amorphous aggregates, but notably, 60 μM BDMC markedly reduced aggregate density, underscoring BDMC's inhibitory effect. Hemolysis tests revealed aggregate species in BDMC-treated samples were less toxic than in L38R mutant samples alone at the same concentrations and exposure times. Overall, BDMC has substantial potential to develop highly effective inhibitors that mitigate the risk of fatal ALS.}, } @article {pmid39461320, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {The reliability and validity of in-person and remote behavioural screening tools for people with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123282}, doi = {10.1016/j.jns.2024.123282}, pmid = {39461320}, issn = {1878-5883}, support = {GOLDSTEIN/OCT17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Aged ; *Psychometrics/methods/standards ; Surveys and Questionnaires/standards ; Neuropsychological Tests/standards ; Adult ; }, abstract = {OBJECTIVE: This study aimed to assess the psychometric properties of and relationships between total scores on different screening tools assessing behavioural change for people with amyotrophic lateral sclerosis (ALS), and whether administering the screens as online questionnaires (rather than on paper, in-person) influences total scores.

METHODS: The behavioural component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASb); the behavioural component of the ALS Cognitive Behavioural Screen (ALS-CBSb), the ALS-Frontotemporal Dementia Questionnaire (ALS-FTD-Q), the Beaumont Behavioural Inventory (BBI), and the Motor Neuron Disease Behavioural Instrument (MiND-B) were administered to 35 informants on paper. Online questionnaire versions of the behavioural screens were administered to 49 informants. Forward stepwise linear regressions were conducted to assess whether scores on behavioural screens were predicted by scores on the other behavioural screens and to assess whether total scores were predicted by the mode of administration (paper or online) of the screens.

RESULTS: Behavioural screening tools, except the ECASb, had good internal consistency but mixed item-total correlations. All regression models assessing whether behavioural screen scores predict other behavioural screen scores were significant. The BBI performed best and the ECASb performed worst in terms of their predictive relationships with other screening tools. The administration mode of the questionnaires did not significantly affect total scores.

CONCLUSIONS: The psychometric properties of the scales varied. The scales predicted each other's scores, supporting convergent validity. Online and paper versions performed similarly, and demographics did not predict scores.}, } @article {pmid39460670, year = {2024}, author = {Gondim, FAA and Fernandes, JMA}, title = {ALS due to c.1189 + 1G > T (splice donor) TBK1 mutation.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1}, doi = {10.1080/21678421.2024.2421754}, pmid = {39460670}, issn = {2167-9223}, } @article {pmid39459584, year = {2024}, author = {Silva, F and Silva, J and Salgueira, S and Mendes, A and Matos, E and Conde, B}, title = {Sleep Disturbances in Amyotrophic Lateral Sclerosis and Prognostic Impact-A Retrospective Study.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459584}, issn = {2075-1729}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with sleep disturbance, namely insomnia and sleep-disordered breathing. This study aims to evaluate the overall sleep characteristics of ALS patients, their association with lung function tests, and possible predictive survival factors. We conducted a retrospective observation study among ALS patients monitored during a pulmonology consultation. Type one polysomnography (PSG) and lung function tests were performed once the patients presented with sleep-related symptoms, and the relationship between their parameters was assessed, as well as a survival analysis. We included 35 patients, with an overall diminished sleep efficiency, a partially conserved forced vital capacity (FVC), and low maximal inspiratory pressure (MIP). A positive correlation between FVC and REM sleep percentage was observed. A survival analysis showed that a normal rapid eye movement (REM) sleep percentage and respiratory disturbance index (RDI) ≥ 15/h were independent predictors of survival. We observed a trend for higher sleep quality in patients with conserved lung function. A better sleep quality was associated with a higher survival. Obstructive events (reduced or absence of airflow associated with continued or increased inspiratory effort) did not seem to impact survival.}, } @article {pmid39459534, year = {2024}, author = {Nakhal, MM and Yassin, LK and Alyaqoubi, R and Saeed, S and Alderei, A and Alhammadi, A and Alshehhi, M and Almehairbi, A and Al Houqani, S and BaniYas, S and Qanadilo, H and Ali, BR and Shehab, S and Statsenko, Y and Meribout, S and Sadek, B and Akour, A and Hamad, MIK}, title = {The Microbiota-Gut-Brain Axis and Neurological Disorders: A Comprehensive Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459534}, issn = {2075-1729}, support = {12M159//UAEU/ ; G00004325//UAEU/ ; 12M142//UAEU/ ; }, abstract = {Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota-gut-brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut-brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer's disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer's neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson-Konovalov disease (WD), multisystem atrophy (MSA), Huntington's chorea (HC), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut-brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases.}, } @article {pmid39459490, year = {2024}, author = {Banciu, C and Chiriac, S and Pojoga, C and Marian, L and Fabian, A and Gogulescu, A and Simu, M and Parvanescu, R and Mioc, A and Racoviceanu, R and Munteanu, A}, title = {An Uncommon Overlap Syndrome Between Ankylosing Spondylitis and Amyotrophic Lateral Sclerosis-Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {10}, pages = {}, pmid = {39459490}, issn = {1648-9144}, support = {//"Victor Babes" University of Medicine and Pharmacy Timisoara/ ; }, mesh = {Humans ; *Spondylitis, Ankylosing/complications/drug therapy ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Middle Aged ; Etanercept/therapeutic use ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Syndrome ; }, abstract = {This case report describes an uncommon overlap syndrome between ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS). Initially, the patient was diagnosed with AS, for which he received various specific treatments, including TNF-α inhibitors. After five years of treatment with TNF-α inhibitor etanercept, the patient was referred for a full neurological assessment after he reported balance disturbances, postural instability, muscle weakness, and other neurological symptoms that indicated the presence of a neurological disorder. After a thorough investigation, the patient was diagnosed with ALS. This case report aims to contribute to the limited literature by providing a detailed case study regarding the crosstalk between AS and ALS while also exploring the potential underlying mechanisms and the possible link between TNF-α inhibitors therapy and ALS.}, } @article {pmid39459030, year = {2024}, author = {Al-Khayri, JM and Ravindran, M and Banadka, A and Vandana, CD and Priya, K and Nagella, P and Kukkemane, K}, title = {Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39459030}, issn = {1424-8247}, support = {GRANT0000//Deanship of Scientific Research, King Faisal University/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.}, } @article {pmid39458929, year = {2024}, author = {Giannakou, M and Akrani, I and Tsoka, A and Myrianthopoulos, V and Mikros, E and Vorgias, C and Hatzinikolaou, DG}, title = {Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39458929}, issn = {1424-8247}, support = {MIS-5000432//state scholarship foundation (GR)/ ; }, abstract = {BACKGROUND: Cu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.

METHODS: The approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC[®]) in the context of drug repurposing. Using differential scanning fluorimetry (DSF), these compounds were tested for their impact on SOD1(A4V) thermal stability.

RESULTS AND CONCLUSIONS: Dimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand Tm by 6 °C, eleven inducing a higher second Tm, suggesting a stabilization effect, and fourteen reducing Tm from 10 up to 26 °C, suggesting possible interactions or non-specific binding.}, } @article {pmid39458862, year = {2024}, author = {Palacıoğlu, G}, title = {Chitosan, Methyl Jasmonate, and Silicon Induce Resistance to Angular Leaf Spot in Common Bean, Caused by Pseudocercospora griseola, with Expression of Defense-Related Genes and Enzyme Activities.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {20}, pages = {}, pmid = {39458862}, issn = {2223-7747}, abstract = {This study assessed the efficacy of chitosan, methyl jasmonate, and silicon in the reduction of disease severity and the induction of defense responses in common bean plants against angular leaf spot caused by Pseudocercospora griseola. The expression level of several pathogenesis-related (PR) proteins, PR1, PR2 (β-1,3-glucanase), and PR3 (chitinase), and defense-related enzymes, phenylalanine ammonia-lyase, peroxidase, and lipoxygenase, was analyzed at different time points in common bean plants after different treatments. Elicitor treatments significantly reduced disease severity 21 days after inoculation, with silicon at a 2 mM concentration proving most effective with 38.93% disease control, followed by 1 mM MeJA and 2% chitosan, respectively. Treatments with chitosan, methyl jasmonate, and silicon, regardless of pathogen infection, significantly elevated PR1, PR2, and PR3 gene expressions at 48 h after inoculation (hpi). PAL and POD activities were similarly increased following elicitor treatments and pathogen infection, especially at 48 hpi. Chemical elicitors applied post-inoculation induced PR proteins, PAL, and POD enzyme activities at 48 hpi, while LOX activity exhibited a variable fluctuation with treatments. These findings suggested that chemical elicitors, especially silicon, were effective in reducing ALS disease severity in common beans, with improved resistance associated with the expression of pathogen-responsive genes. This study is the first to analyze the expression profiles of defense-related genes in common beans treated with chemical elicitors prior to P. griseola infection.}, } @article {pmid39457680, year = {2024}, author = {McGrath, MS and Zhang, R and Bracci, PM and Azhir, A and Forrest, BD}, title = {Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457680}, issn = {2227-9059}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.

METHODS: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.

CONCLUSIONS: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.}, } @article {pmid39457678, year = {2024}, author = {Forrest, BD and Goyal, NA and Fleming, TR and Bracci, PM and Brett, NR and Khan, Z and Robinson, M and Azhir, A and McGrath, M}, title = {The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457678}, issn = {2227-9059}, support = {01//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months' treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis.

METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities.

RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years.

CONCLUSIONS: The findings from this study suggest that a 6 months' treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.}, } @article {pmid39457513, year = {2024}, author = {Montiel-Troya, M and Mohamed-Mohamed, H and Pardo-Moreno, T and González-Díaz, A and Ruger-Navarrete, A and de la Mata Fernández, M and Tovar-Gálvez, MI and Ramos-Rodríguez, JJ and García-Morales, V}, title = {Advancements in Pharmacological Interventions and Novel Therapeutic Approaches for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457513}, issn = {2227-9059}, support = {PID2019-110960GB-I00//Ministry of Science and Innovation, Spain./ ; }, abstract = {(1) Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the patient suffers from an affection of both upper and lower motor neurons at the spinal and brainstem level, causing a progressive paralysis that leads to the patient's demise. Gender is also considered a predisposing risk factor for developing the disease. A brief review of the pathophysiological mechanisms of the disease is also described in this work. Despite the fact that a cure for ALS is currently unknown, there exists a variety of pharmacological and non-pharmacological therapies that can help reduce the progression of the disease over a certain period of time and alleviate symptoms. (2) We aim to analyze these pharmacological and non-pharmacological therapies through a systematic review. A comprehensive, multidisciplinary approach to treatment is necessary. (3) Drugs such as riluzole, edaravone, and sodium phenylbutyrate, among others, have been investigated. Additionally, it is important to stay updated on research on new drugs, such as masitinib, from which very good results have been obtained. (4) Therapies aimed at psychological support, speech and language, and physical therapy for the patient are also available, which increase the quality of life of the patients.}, } @article {pmid39457505, year = {2024}, author = {Seta, Y and Kimura, K and Masahiro, G and Tatsumori, K and Murakami, Y}, title = {SHED-CM: The Safety and Efficacy of Conditioned Media from Human Exfoliated Deciduous Teeth Stem Cells in Amyotrophic Lateral Sclerosis Treatment: A Retrospective Cohort Analysis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457505}, issn = {2227-9059}, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive and irreversible neurodegenerative disease with limited treatment options. Advances in regenerative medicine have opened up new treatment options. The primary and exploratory objectives of this retrospective cohort study were to evaluate the safety and efficacy of stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM).

METHODS: Safety assessments included adverse events, vital signs, and laboratory test changes before and after administration, and efficacy was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength, and forced vital capacity in 24 patients with ALS treated at a single facility between 1 January 2022, and 30 November 2023.

RESULTS: While ALSFRS-R scores typically decline over time, the progression rate in this cohort was slower, suggesting a potential delay in disease progression. Alternatively, improvements in muscle strength and mobility were observed in some patients. Although adverse events were reported in only 3% of cases (no serious allergic reactions), the treatment-induced changes in vital signs and laboratory results were not clinically significant.

CONCLUSIONS: The SHED-CM treatment is a safe and potentially effective therapeutic option for patients with ALS. Further research is needed to optimize the SHED-CM treatment; however, this study lays the groundwork for future exploration of regenerative therapies for ALS.}, } @article {pmid39457470, year = {2024}, author = {Trabacca, A and Ferrante, C and Oliva, MC and Fanizza, I and Gallo, I and De Rinaldis, M}, title = {Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457470}, issn = {2073-4425}, support = {2024//The Italian Health Ministry - Ricerca Corrente/ ; }, mesh = {Humans ; *Motor Neuron Disease/genetics/pathology ; Child ; Mutation ; Muscular Atrophy, Spinal/genetics/pathology/diagnosis ; Exome Sequencing ; }, abstract = {BACKGROUND: Inherited pediatric motor neuron diseases (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of motor neurons in the brain and the spinal cord. These diseases can manifest as early as infancy and originate from inherited pathogenic mutations in known genes. Key clinical features of MNDs include muscle weakness, hypotonia, and atrophy due to the degeneration of lower motor neurons or spasticity, hypertonia, and hyperreflexia caused by upper motor neuron dysfunction. The course of the disease varies among individuals and is influenced by the specific subtype.

METHODS: We performed a non-systematic, narrative clinical review, employing a systematic methodology for the literature search and article selection to delineate the features of hereditary pediatric motor neuron diseases.

RESULTS: The growing availability of advanced molecular testing, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has expanded the range of identified genetic factors. These advancements provide insights into the genetic complexity and underlying mechanisms of these disorders. As more MND-related genes are discovered, the accumulating genetic data will help prioritize promising candidate genes for future research. In some cases, targeted treatments based on specific genetic mechanisms have already emerged, underscoring the critical role of early and timely diagnosis in improving patient outcomes. Common MNDs include amyotrophic lateral sclerosis, spinal muscular atrophy, and bulbar spinal muscular atrophy.

CONCLUSION: This narrative clinical review covers the clinical presentation, genetics, molecular features, and pathophysiology of inherited pediatric MNDs.}, } @article {pmid39457468, year = {2024}, author = {Boura, I and Giannopoulou, IA and Pavlaki, V and Xiromerisiou, G and Mitsias, P and Spanaki, C}, title = {FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457468}, issn = {2073-4425}, mesh = {Humans ; *Parkinsonian Disorders/genetics/pathology/diagnostic imaging ; *Charcot-Marie-Tooth Disease/genetics/pathology ; *Flavoproteins/genetics ; Female ; Male ; Mutation, Missense ; Middle Aged ; Mutation ; Adult ; Phosphoric Monoester Hydrolases ; }, abstract = {Background/Objectives: The genetic underpinnings of Parkinson's disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Varón syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.}, } @article {pmid39457466, year = {2024}, author = {Moriyama, H and Yokota, T}, title = {Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457466}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Mutation ; Animals ; Oligonucleotides/therapeutic use/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.}, } @article {pmid39456682, year = {2024}, author = {Alshehri, RS and Abuzinadah, AR and Alrawaili, MS and Alotaibi, MK and Alsufyani, HA and Alshanketi, RM and AlShareef, AA}, title = {A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach.}, journal = {International journal of molecular sciences}, volume = {25}, number = {20}, pages = {}, pmid = {39456682}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/physiopathology/diagnosis ; Humans ; *Biomarkers/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers.}, } @article {pmid39456494, year = {2024}, author = {De Stefano, S and Tiberi, M and Salvatori, I and De Bardi, M and Gimenez, J and Pirshayan, M and Greco, V and Borsellino, G and Ferri, A and Valle, C and Mercuri, NB and Chiurchiù, V and Spalloni, A and Longone, P}, title = {Hydrogen Sulfide Modulates Astrocytic Toxicity in Mouse Spinal Cord Cultures: Implications for Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {39456494}, issn = {2076-3921}, abstract = {Hydrogen sulfide (H2S), a known inhibitor of the electron transport chain, is endogenously produced in the periphery as well as in the central nervous system, where is mainly generated by glial cells. It affects, as a cellular signaling molecule, many different biochemical processes. In the central nervous system, depending on its concentration, it can be protective or damaging to neurons. In the study, we have demonstrated, in a primary mouse spinal cord cultures, that it is particularly harmful to motor neurons, is produced by glial cells, and is stimulated by inflammation. However, its role on glial cells, especially astrocytes, is still under-investigated. The present study was designed to evaluate the impact of H2S on astrocytes and their phenotypic heterogeneity, together with the functionality and homeostasis of mitochondria in primary spinal cord cultures. We found that H2S modulates astrocytes' morphological changes and their phenotypic transformation, exerts toxic properties by decreasing ATP production and the mitochondrial respiration rate, disturbs mitochondrial depolarization, and alters the energetic metabolism. These results further support the hypothesis that H2S is a toxic mediator, mainly released by astrocytes, possibly acting as an autocrine factor toward astrocytes, and probably involved in the non-cell autonomous mechanisms leading to motor neuron death.}, } @article {pmid39456257, year = {2024}, author = {Perni, M and Mannini, B}, title = {Targeting Protein Aggregation in ALS.}, journal = {Biomolecules}, volume = {14}, number = {10}, pages = {}, pmid = {39456257}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Animals ; }, abstract = {Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery.}, } @article {pmid39456026, year = {2024}, author = {Albagli, EA and Calliari, A and Gendron, TF and Zhang, YJ}, title = {HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {79}, pmid = {39456026}, issn = {1750-1326}, support = {P01NS084974/NS/NINDS NIH HHS/United States ; U19AG063911/AG/NIA NIH HHS/United States ; R21NS127331/NS/NINDS NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; R01NS121125/NS/NINDS NIH HHS/United States ; R01NS117461/NS/NINDS NIH HHS/United States ; R01AG085307/AG/NIA NIH HHS/United States ; Target ALS//Target ALS/ ; U19 AG063911/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; }, } @article {pmid39455963, year = {2024}, author = {Alexander, E and Leong, KW}, title = {Discovery of nanobodies: a comprehensive review of their applications and potential over the past five years.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {661}, pmid = {39455963}, issn = {1477-3155}, mesh = {*Single-Domain Antibodies/chemistry ; Humans ; Animals ; *SARS-CoV-2/immunology ; COVID-19/virology/immunology ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field.}, } @article {pmid39455931, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {185}, pmid = {39455931}, issn = {1528-3658}, support = {1181645//Agencia Nacional de Investigación y Desarrollo/ ; DI-06-24/REG//UNAB/ ; 1221745//Agencia Nacional de Investigación y Desarrollo/ ; 21151265//Agencia Nacional de Investigación y Desarrollo/ ; R01-638 EY014420//National Institute of Mental Health and Neurosciences/ ; R01-EY014074//National Institute of Mental Health and Neurosciences/ ; R03 EY014420/EY/NEI NIH HHS/United States ; 1151293//Agencia Nacional de Investigación y Desarrollo/ ; 13220203 explorador//Agencia Nacional de Investigación y Desarrollo/ ; NCN2023_32//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Humans ; *Mice, Transgenic ; *Axonal Transport ; Cell Death ; Disease Models, Animal ; Mutation ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1[G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid39454934, year = {2025}, author = {Takeda, T and Her, YR and Kim, JK and Jha, NN and Monani, UR}, title = {A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1[G86R] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115024}, pmid = {39454934}, issn = {1090-2430}, support = {R01 NS104218/NS/NINDS NIH HHS/United States ; R01 NS123292/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; Mutation ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8[G470R] in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.}, } @article {pmid39451992, year = {2024}, author = {Ozdinler, PH}, title = {Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?.}, journal = {Brain sciences}, volume = {14}, number = {10}, pages = {}, pmid = {39451992}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation.}, } @article {pmid39451800, year = {2024}, author = {Drăgoi, MV and Nisipeanu, I and Frimu, A and Tălîngă, AM and Hadăr, A and Dobrescu, TG and Suciu, CP and Manea, AR}, title = {Real-Time Home Automation System Using BCI Technology.}, journal = {Biomimetics (Basel, Switzerland)}, volume = {9}, number = {10}, pages = {}, pmid = {39451800}, issn = {2313-7673}, abstract = {A Brain-Computer Interface (BCI) processes and converts brain signals to provide commands to output devices to carry out certain tasks. The main purpose of BCIs is to replace or restore the missing or damaged functions of disabled people, including in neuromuscular disorders like Amyotrophic Lateral Sclerosis (ALS), cerebral palsy, stroke, or spinal cord injury. Hence, a BCI does not use neuromuscular output pathways; it bypasses traditional neuromuscular pathways by directly interpreting brain signals to command devices. Scientists have used several techniques like electroencephalography (EEG) and intracortical and electrocorticographic (ECoG) techniques to collect brain signals that are used to control robotic arms, prosthetics, wheelchairs, and several other devices. A non-invasive method of EEG is used for collecting and monitoring the signals of the brain. Implementing EEG-based BCI technology in home automation systems may facilitate a wide range of tasks for people with disabilities. It is important to assist and empower individuals with paralysis to engage with existing home automation systems and gadgets in this particular situation. This paper proposes a home security system to control a door and a light using an EEG-based BCI. The system prototype consists of the EMOTIV Insight™ headset, Raspberry Pi 4, a servo motor to open/close the door, and an LED. The system can be very helpful for disabled people, including arm amputees who cannot close or open doors or use a remote control to turn on or turn off lights. The system includes an application made in Flutter to receive notifications on a smartphone related to the status of the door and the LEDs. The disabled person can control the door as well as the LED using his/her brain signals detected by the EMOTIV Insight™ headset.}, } @article {pmid39451396, year = {2024}, author = {Yang, CH and Huang, JL and Tsai, LK and Taniar, D and Pai, TW}, title = {An Effective DNA Methylation Biomarker Screening Mechanism for Amyotrophic Lateral Sclerosis (ALS) Based on Comorbidities and Gene Function Analysis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {39451396}, issn = {2306-5354}, support = {MOST 111-2221-E-027-113-414 MY2//National Science and Technology Council (Taiwan)/ ; NSTC113-2221-E-027-109//National Science and Technology Council (Taiwan)/ ; MOST104-2321-B-019-009//National Science and Technology Council (Taiwan)/ ; }, abstract = {This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3, CACNA1H, and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved.}, } @article {pmid39451238, year = {2024}, author = {Crescioli, C and Paronetto, MP}, title = {The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.}, journal = {Cells}, volume = {13}, number = {20}, pages = {}, pmid = {39451238}, issn = {2073-4409}, mesh = {Humans ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.}, } @article {pmid39449756, year = {2024}, author = {Filipi, T and Tureckova, J and Vanatko, O and Chmelova, M and Kubiskova, M and Sirotova, N and Matejkova, S and Vargova, L and Anderova, M}, title = {ALS-like pathology diminishes swelling of spinal astrocytes in the SOD1 animal model.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1472374}, pmid = {39449756}, issn = {1662-5102}, abstract = {Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.}, } @article {pmid39449457, year = {2024}, author = {Rosa, D and Ingrande, L and Marcomini, I and Poliani, A and Villa, G and Sodano, M and Manara, DF}, title = {Perceived Pain in People Living with Amyotrophic Lateral Sclerosis-A Scoping Review.}, journal = {Nursing reports (Pavia, Italy)}, volume = {14}, number = {4}, pages = {3023-3039}, pmid = {39449457}, issn = {2039-4403}, abstract = {(1) Background: Pain is a common symptom in patients with Amyotrophic Lateral Sclerosis (ALS). There are no evidence-based pharmacological treatments for pain in ALS; recommendations are based on guidelines for chronic non-oncological pain and clinical experience. The aim is to map the literature on how people with ALS experience pain, and how this affects their daily activities and social relationships. (2) Methods: This scoping review included studies concerning patients with spinal/bulbar ALS aged ≥ 18 years who experience pain, focusing on perception, characteristics, treatment, and impact on quality of life. Temporal and linguistic criteria were applied when searching the MEDLINE, CINAHL, and SCOPUS databases. (3) Results: The management of pain in these patients is complex and involves the use of anti-inflammatory drugs, analgesics, and opioids. Pain is associated with other conditions such as depression and anxiety, which contribute to a deterioration in the quality of life. Moreover, pain may also negatively influence patient compliance with prescribed treatment regimens and the quality of care they perceive themselves to be receiving. (4) Conclusions: It is of the most importance to identify effective ways to assess and treat this issue, with health care professionals taking an active role in this process.}, } @article {pmid39449162, year = {2024}, author = {Zhu, Y and Zhang, Y and Li, M and Bai, J and Wang, H and Pang, X and Du, R and Wang, J and Huang, X}, title = {Prognostic Value of Systemic Inflammation, Nutritional Status and Sarcopenia in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {15}, number = {6}, pages = {2743-2755}, pmid = {39449162}, issn = {2190-6009}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/mortality/blood ; Female ; Male ; *Nutritional Status ; *Sarcopenia/etiology/blood ; Middle Aged ; Prognosis ; *Inflammation/blood ; Aged ; Biomarkers/blood ; Proportional Hazards Models ; ROC Curve ; Kaplan-Meier Estimate ; Adult ; }, abstract = {BACKGROUND: Nutritional status, systemic inflammatory responses and muscle mass are associated with the prognosis of patients with amyotrophic lateral sclerosis (ALS). However, the optimal biomarker for predicting prognosis remains unclear. This study aimed to identify the optimal indicators of survival among the nutrition-based, inflammation-based and muscle mass-related markers for ALS patients.

METHODS: We enrolled ALS patients from January 2014 to December 2019. Experienced neurologists followed up with the participants until January 2022. This study included a total of 17 nutritional, systemic inflammatory or muscle mass-related indicators. Maximally selected rank statistics determined the cut-off points for these indicators. Kaplan-Meier estimation was used to assess survival. Uni- and multivariate Cox proportional hazards models were used to determine the effects of indicators on survival. Finally, time-dependent receiver operating characteristic (time-ROC) curves and the C-index were calculated to evaluate the predictive efficacy of different indicators.

RESULTS: A total of 506 patients with ALS were enrolled in this study, including 288 males (56.9%) and 218 females (43.1%), with a mean age of 54.2 ± 10.5 years. Among these ALS patients, 334 cases (68.0%) either died or underwent tracheotomy. In univariate Cox proportional hazards regression, 11 indicators were significantly associated with ALS survival (p < 0.05). And systemic immune inflammation (SII), platelet-to-lymphocyte ratio (PLR), modified geriatric nutritional risk index (mGNRI), creatinine and sarcopenia index (SI, (creatinine/cystatin C) × 100) were determined as independent predictors (p < 0.05) in multivariate Cox proportional hazards regression. A higher SI predicted longer survival (hazard ratio, 0.59; 95% confidence interval [CI], 0.46-0.76; p < 0.001). The results of time-ROC and C-index analyses indicated that SI had the best predictive efficacy for ALS survival, with a C-index of 0.65 (95% CI, 0.54-0.75) for 1-year, 0.61 (95% CI, 0.57-0.65) for 3-year and 0.59 (95% CI, 0.55-0.62) for 5-year survival. Across different subgroups, SI had the highest C-index in men and women, limb onset and aged < 60 year ALS patients, compared with other indicators. However, cystatin C was the best indicator for predicting the survival of ALS patients with bulbar onset, whereas the prognostic nutritional index (PNI) was the best for those aged ≥60 years.

CONCLUSIONS: The serum SI demonstrates superior prognostic ability compared to other inflammation-based, nutrition-based and muscle mass-related indicators for patients with ALS. Given its simplicity and availability, it is well suited for clinical use in evaluating the prognosis of ALS patients.}, } @article {pmid39448670, year = {2024}, author = {Stankiewicz-Kosyl, M and Wińska-Krysiak, M and Wrochna, M and Haliniarz, M and Marcinkowska, K}, title = {Regional diversity of the ALS gene and hormesis due to tribenuron-methyl in Centaurea cyanus L.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25197}, pmid = {39448670}, issn = {2045-2322}, support = {BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Hormesis ; *Herbicides/pharmacology ; *Centaurea/genetics ; Arylsulfonates/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Poland ; Plant Proteins/genetics ; Genetic Variation ; }, abstract = {Centaurea cyanus L. is a common field weed in Eastern Europe but only in Poland biotypes of this species with resistance to acetolactate synthase (ALS) inhibitors have been confirmed. This phenomenon is constantly developing and spreading to consecutive regions of Poland. This study aimed to assess the response of selected Polish C. cyanus populations to tribenuron-methyl and to analyse the genetic variability of the ALS gene of C. cyanus populations resistant to ALS inhibitors. Between 2017 and 2021, 13 seed samples were collected from eastern Poland and a dose-response study with tribenuron-methyl was performed. Eleven populations resistant to tribenuron-methyl were identified. All populations from this study as well as 6 additional resistant populations characterised in the previous dose-response studies were subjected to molecular analysis of the ALS gene. Target-site resistance due to mutations P197S, P197Q, P197T and P197A were identified in 8 populations from Warmia-Masuria and Podlaskie provinces. This is the first case of target-site resistance (TSR) in C. cyanus confirmed by sequencing of the ALS gene. Moreover in some resistant plants, ten changes in the amino acid ALS sequence were identified in comparison to those in the susceptible ones. In none of the populations were all mutations detected in the same individual. The highest frequency of mutations was detected in Warmia-Masuria province. Some C. cyanus populations resistant to ALS inhibitors showed hormesis effect concerning shoot fresh weight after tribenuron-methyl treatment. Stimulation due to half the recommended dose of tribenuron-methyl was the highest and the difference between untreated and treated plants was statistically significant in two populations from Warmia-Masuria and in one from Podlaskie province.}, } @article {pmid39447539, year = {2024}, author = {Zhu, H}, title = {Interference of nuclear speckles: A nexus of RNA foci, dipeptide repeats, and mis-splicing in C9ORF72 ALS/FTD.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3375-3377}, doi = {10.1016/j.neuron.2024.10.001}, pmid = {39447539}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *RNA Splicing/genetics ; Dipeptides/metabolism ; DNA Repeat Expansion/genetics ; Proteins/genetics/metabolism ; RNA/genetics ; }, abstract = {In this issue of Neuron, Wu et al.[1] show that nuclear speckle proteins are sequestered by both nuclear RNA foci and cytoplasmic dipeptide repeat aggregates in C9ORF72-ALS/FTD. Consequently, dysregulation of splicing induces widespread splicing alterations and contributes to neurodegeneration.}, } @article {pmid39444183, year = {2024}, author = {Alici, H and Uversky, VN and Kang, DE and Woo, JA and Coskuner-Weber, O}, title = {Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037335036241007043530}, pmid = {39444183}, issn = {1875-5550}, abstract = {INTRODUCTION: The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-- Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10Q108P proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.

METHOD: This study presents the foundational characterization of the structural features of CHCHD10Q108P and compares them with those of the wild-type counterpart. We conducted multiple run molecular dynamics simulations and bioinformatics analyses.

RESULT: Our findings reveal distinct differences in structural properties, free energy surfaces, and the outputs of principal component analysis between these two proteins. These results contribute significantly to the comprehension of CHCHD10 and its Q108P variant in terms of pathology, biochemistry, and structural biology.

CONCLUSION: The reported structural properties hold promise for informing the development of more effective treatments for ALS.}, } @article {pmid39444004, year = {2024}, author = {Hoshino, T and Mukai, A and Yamashita, H and Misawa, H and Urushitani, M and Tashiro, Y and Matsuzawa, SI and Takahashi, R}, title = {NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {77}, pmid = {39444004}, issn = {1756-6606}, support = {16H01695//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Up-Regulation/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Proteasome Endopeptidase Complex/metabolism ; Mice ; *Ubiquitin/metabolism ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Cell Line, Tumor ; Motor Neurons/metabolism/pathology ; Nerve Degeneration/pathology ; Cell Death ; Humans ; }, abstract = {Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.}, } @article {pmid39443862, year = {2024}, author = {Paulin, J and Lahti, M and Riihimäki, H and Hänninen, J and Vesanen, T and Koivisto, M and Peltonen, LM}, title = {The rate and predictors of violence against EMS personnel.}, journal = {BMC emergency medicine}, volume = {24}, number = {1}, pages = {200}, pmid = {39443862}, issn = {1471-227X}, mesh = {Humans ; Male ; Retrospective Studies ; Female ; Finland ; Adult ; Middle Aged ; *Emergency Medical Technicians/statistics & numerical data ; Emergency Medical Services/statistics & numerical data ; Workplace Violence/statistics & numerical data ; Violence/statistics & numerical data ; Logistic Models ; Electronic Health Records ; }, abstract = {BACKGROUND: Violence against Emergency Medical Services (EMS) personnel vary between studies. Current studies are mainly based on self-reporting, thus other designs are needed to provide more perspective. The purpose of this study was to explore the rate and predictors of violent behavior targeted at EMS personnel by exploring the Electronic patient care records (ePCR) documentation by EMS personnel.

METHODS: This was a retrospective cohort study of EMS patients in Finland. The data were collected from three regions between 1st June and 30th November 2018. Text mining and manual evaluation were used to identify and explore predictors of violence targeted at EMS personnel from the ePCR narratives. Multivariable logistic regressions were used to determine factors that were independently associated with violent behavior. The results are presented with odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: The EMS personnel reported experiences of violence in a total of 297 identified missions (0.7%) of all EMS missions (n = 40,263). The violence was mostly verbal (62.3%) and the most common violence perpetrator was the patient (98.0%). The police were alarmed to many missions where violence was reported (40.7%). Sometimes violence occurred suddenly although the police were present. The multivariable logistic regression model indicates that violence occurred typically in urban areas (OR 1.699; 95% CI 1.283 to 2.248), at weekend nights (OR 1.357; 95% CI 1.043 to 1.765), by male (OR 1.501; 95% CI 1.160 to 1.942), and patients influenced by alcohol (OR 3.464; 95% CI 2.644 to 4.538). A NEWS2 score of 3 in any parameter (vs. score 0-4, OR 2.386; 95% CI: 1.788 to 3.185) and ALS unit type (vs. BLS, OR 1.373; 95% CI: 1.009 to 1.866) increased the likelihood as well.

CONCLUSIONS: The documentation in ePCRs show low rates of violence targeted at EMS personnel. However, violence is a multidimensional phenomenon connected to unfamiliar patients, rushed situations, and an uncontrolled environment. This means that the EMS personnels' safety cannot be ensured in all situations. Therefore, a balance between safety margins and treating patients needs to be considered.}, } @article {pmid39443410, year = {2024}, author = {Zhang, T and Rui, W and Sun, Y and Tian, Y and Li, Q and Zhang, Q and Zhao, Y and Liu, Z and Wang, T}, title = {Identification of nitric oxide-mediated necroptosis as the predominant death route in Parkinson's disease.}, journal = {Molecular biomedicine}, volume = {5}, number = {1}, pages = {44}, pmid = {39443410}, issn = {2662-8651}, mesh = {*Necroptosis ; *Parkinson Disease/pathology/metabolism/genetics ; *Nitric Oxide/metabolism ; Humans ; Animals ; Mice ; Neurons/metabolism/pathology ; Signal Transduction ; Male ; Brain/pathology/metabolism ; Alzheimer Disease/pathology/metabolism/genetics ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Membrane Potential, Mitochondrial ; }, abstract = {Parkinson's disease (PD) involves multiple forms of neuronal cell death, but the dominant pathway involved in disease progression remains unclear. This study employed RNA sequencing (RNA-seq) of brain tissue to explore gene expression patterns across different stages of PD. Using the Scaden deep learning algorithm, we predicted neurocyte subtypes and modelled dynamic interactions for five classic cell death pathways to identify the predominant routes of neuronal death during PD progression. Our cell type-specific analysis revealed an increasing shift towards necroptosis, which was strongly correlated with nitric oxide synthase (NOS) expression across most neuronal subtypes. In vitro experiments confirmed that nitric oxide (NO) is a key mediator of necroptosis, leading to nuclear shrinkage and decreased mitochondrial membrane potential via phosphorylation of the PIP1/PIP3/MLKL signalling cascade. Importantly, specific necroptosis inhibitors significantly mitigated neuronal damage in both in vitro and in vivo PD models. Further analysis revealed that NO-mediated necroptosis is prevalent in early-onset Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and across multiple brain regions but not in brain tumours. Our findings suggest that NO-mediated necroptosis is a critical pathway in PD and other neurodegenerative disorders, providing potential targets for therapeutic intervention.}, } @article {pmid39441150, year = {2024}, author = {Hamad, AA and Alkhawaldeh, IM and Abbas, A and Elaraby, A and Meshref, M}, title = {Incidence and risk factors of venous thromboembolism in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {La Tunisie medicale}, volume = {102}, number = {10}, pages = {610-515}, pmid = {39441150}, issn = {2724-7031}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/complications ; Humans ; *Venous Thromboembolism/epidemiology/etiology ; Incidence ; Risk Factors ; Male ; Female ; }, abstract = {AIMS: This systematic review and meta-analysis aimed to determine the annual incidence rate of venous thromboembolism (VTE) and identify risk factors of VTE in amyotrophic lateral sclerosis (ALS) patients.

METHODS: A comprehensive search of three databases was conducted up to April 8, 2024, to identify longitudinal studies reporting VTE incidence in ALS patients. The included studies were either prospective or retrospective, following up with ALS patients. Quality assessment was performed using the NIH tool for observational cohort studies. Meta-analysis was conducted using Open Meta Analyst, employing a random-effect model. Subgroup, Meta-regression, and sensitivity analyses were also carried out.

RESULTS: Our analysis included eight studies comprising a total of 26,758 ALS patients that met the inclusion criteria. The pooled annual incidence of VTE across all studies was found to be 22 cases per 1,000 person-year (95% CI = 18 to 27). Subgroup analysis revealed that the annual incidence of VTE in males was 19 cases per 1,000 person-year (95% CI = 15 to 22), while in females, it was 20 cases per 1,000 person-year (95% CI = 16 to 25). Leave-one-out analysis demonstrated that the incidence ranged from 21 to 28 cases per 1,000 person-year when excluding each study individually. Meta-regression analysis did not find a significant association between age and the risk of VTE (P = 0.079). Based on the included studies, risk factors of VTE in ALS patients included a history of VTE, non-invasive ventilation, immobility, and decreased functional status.

CONCLUSION: Patients with ALS face a higher risk of developing VTE compared to individuals of the same age. These findings underscore the importance of implementing preventive measures and closely monitoring VTE in ALS patients.}, } @article {pmid39441015, year = {2024}, author = {Liu, Y and Li, Y and Zhang, P}, title = {Stress granules and organelles: Coordinating cellular responses in health and disease.}, journal = {Protein & cell}, volume = {}, number = {}, pages = {}, doi = {10.1093/procel/pwae057}, pmid = {39441015}, issn = {1674-8018}, abstract = {Membrane-bound organelles and membraneless organelles (MLOs) coordinate various biological processes within eukaryotic cells. Among these, stress granules (SGs) are significant cytoplasmic MLOs that form in response to cellular stress, exhibiting liquid-like properties alongside stable substructures. SGs interact with diverse organelles, thereby influencing cellular pathways that are critical in both health and disease contexts. This review discusses the interplay between SGs and organelles and explores the methodologies employed to analyze interactions between SGs and other MLOs. Furthermore, it highlights the pivotal roles SGs play in regulating cellular responses and the pathogenesis of ALS. Gaining insights into these interactions is essential for deciphering the mechanisms underlying both physiological processes and pathological conditions.}, } @article {pmid39440770, year = {2024}, author = {Allowitz, K and Taylor, J and Harames, K and Yoo, J and Baloch, O and Ramana, KV}, title = {Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X342720241014164650}, pmid = {39440770}, issn = {1875-6190}, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4- hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.}, } @article {pmid39440303, year = {2024}, author = {Dafinca, R and Tosat-Bitrian, C and Carroll, E and Vahsen, BF and Gilbert-Jaramillo, J and Scaber, J and Feneberg, E and Johnson, E and Talbot, K}, title = {Dynactin-1 mediates rescue of impaired axonal transport due to reduced mitochondrial bioenergetics in amyotrophic lateral sclerosis motor neurons.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae350}, pmid = {39440303}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature of ALS is the cytoplasmic mislocalization and aggregation of TDP-43 in affected motor neurons, which is found in 97% of cases. Recent reports have shown that mitochondrial dysfunction plays a significant role in motor neuron degeneration in ALS, and TDP-43 modulates several mitochondrial transcripts. In this study, we used induced pluripotent stem cell-derived motor neurons from ALS patients with TDP-43 mutations and a transgenic TDP-43[M337V] mouse model to determine how TDP-43 mutations alter mitochondrial function and axonal transport. We detected significantly reduced mitochondrial respiration and ATP production in patient induced pluripotent stem cell-derived motor neurons, linked to an interaction between TDP-43[M337V] with ATPB and COX5A. A downstream reduction in speed of retrograde axonal transport in patient induced pluripotent stem cell-derived motor neurons was detected, which correlated with downregulation of the motor protein complex, DCTN1/dynein. Overexpression of DCTN1 in patient induced pluripotent stem cell-derived motor neurons significantly increased the percentage of retrograde travelling mitochondria and reduced the percentage of stationary mitochondria. This study shows that ALS induced pluripotent stem cell-derived motor neurons with mutations in TDP-43 have deficiencies in essential mitochondrial functions with downstream effects on retrograde axonal transport, which can be partially rescued by DCTN1 overexpression.}, } @article {pmid39439710, year = {2024}, author = {Kelser, BM and Teichner, EM and Subtirelu, RC and Hoss, KN}, title = {A review of proposed mechanisms for neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1370580}, pmid = {39439710}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.}, } @article {pmid39437787, year = {2024}, author = {Saez-Atienzar, S and Souza, CDS and Chia, R and Beal, SN and Lorenzini, I and Huang, R and Levy, J and Burciu, C and Ding, J and Gibbs, JR and Jones, A and Dewan, R and Pensato, V and Peverelli, S and Corrado, L and van Vugt, JJFA and van Rheenen, W and Tunca, C and Bayraktar, E and Xia, M and , and , and , and , and Iacoangeli, A and Shatunov, A and Tiloca, C and Ticozzi, N and Verde, F and Mazzini, L and Kenna, K and Al Khleifat, A and Opie-Martin, S and Raggi, F and Filosto, M and Piccinelli, SC and Padovani, A and Gagliardi, S and Inghilleri, M and Ferlini, A and Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Grassano, M and Mandrioli, J and Mora, G and Lunetta, C and Tanel, R and Trojsi, F and Cardinali, P and Gallone, S and Brunetti, M and Galimberti, D and Serpente, M and Fenoglio, C and Scarpini, E and Comi, GP and Corti, S and Del Bo, R and Ceroni, M and Pinter, GL and Taroni, F and Bella, ED and Bersano, E and Curtis, CJ and Lee, SH and Chung, R and Patel, H and Morrison, KE and Cooper-Knock, J and Shaw, PJ and Breen, G and Dobson, RJB and Dalgard, CL and , and Scholz, SW and Al-Chalabi, A and van den Berg, LH and McLaughlin, R and Hardiman, O and Cereda, C and Sorarù, G and D'Alfonso, S and Chandran, S and Pal, S and Ratti, A and Gellera, C and Johnson, K and Doucet-O'Hare, T and Pasternack, N and Wang, T and Nath, A and Siciliano, G and Silani, V and Başak, AN and Veldink, JH and Camu, W and Glass, JD and Landers, JE and Chiò, A and Sattler, R and Shaw, CE and Ferraiuolo, L and Fogh, I and Traynor, BJ}, title = {Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100679}, pmid = {39437787}, issn = {2666-979X}, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Drug Repositioning ; *Frontotemporal Dementia/genetics/drug therapy ; Genomics/methods ; Riluzole/therapeutic use ; Male ; Female ; Neuroprotective Agents/therapeutic use/pharmacology ; DNA Repeat Expansion/genetics ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.}, } @article {pmid39436867, year = {2024}, author = {Firozjae, AA and Shiran, MR and Rashidi, M}, title = {The neuropharmacological and clinical effects of lutein: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {}, number = {}, pages = {}, pmid = {39436867}, issn = {1868-1891}, abstract = {OBJECTIVES: Neurodegenerative diseases are defined by specific protein accumulation and anatomic vulnerability leading to neuronal loss. Some studies have shown that lutein may have an effect on neurodegenerative diseases. As most of the neurodegenerative diseases don't have certain cure and therapies focus on symptom control, Lutein may be a complementary treatment. Due to controversies in studies investigating lutein effect on neurodegenerative diseases, we decided to perform a systematic review on these studies.

METHODS: A systematic search was carried out in the available databases. We used all MeSH terms and relevant keywords. Studies that reported relationship between lutein and any neurodegenerative disease were included.

RESULTS: We found 278 studies. After removing duplicates, screening by titles and abstracts and excluding irrelevant papers, 17 articles were included in this study. Fourteen studies investigated Alzheimer's disease, 2 studies Parkinson's disease and 1 study Amyotrophic lateral sclerosis. 1/17 study found that high serum levels of lutein at baseline were associated with a lower risk of AD mortality and lutein effect on lipid profile have been investigated in 2/17 studies. Also, 1/17 study has been shown that high intake of lutein may reduce the risk of ALS progression.

CONCLUSIONS: 4/17 studies confirm that lutein can improve cognitive function. 8/17 studies demonstrate a reduction in the progression of AD, and 2/17 studies indicate an improvement in lipid profiles. However, some studies did not find any significant associations. Additionally, there is a limited number of studies investigating the effects of lutein on other neurodegenerative diseases.}, } @article {pmid39436522, year = {2025}, author = {Ma, J and Wen, Q and Pang, X and Huang, S and Zhang, J and Wang, J and Chang, X and Guo, J and Zhang, W}, title = {Correction to: Fasciculation score: a sensitive biomarker in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {525-526}, doi = {10.1007/s10072-024-07807-y}, pmid = {39436522}, issn = {1590-3478}, } @article {pmid39435791, year = {2024}, author = {Brylev, LV and Bryukhov, VV and Druzhinina, ES and Kovalchuk, MO}, title = {[Lower motor neuron disease with MRI «snake eyes» pattern].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {9}, pages = {141-144}, doi = {10.17116/jnevro2024124091141}, pmid = {39435791}, issn = {1997-7298}, mesh = {Humans ; *Magnetic Resonance Imaging ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Motor Neurons/pathology ; *Pyramidal Tracts/diagnostic imaging ; }, abstract = {Motor neuron disease with isolated or predominant lesion of the lower motor neuron at one level of the pyramidal tract is a rare diagnostic finding. In the article, we analyze the case of a patient with asymmetric lesion of the inferior motor neuron at the cervical level: clinical manifestations, results of additional studies and dynamic observation of the patient. Special attention is paid to the MRI picture of changes in the pyramidal tracts in the cervical region, which have been called the «snake eyes» in the literature, and the impact of this finding on the diagnosis and prognosis of the disease.}, } @article {pmid39435635, year = {2025}, author = {Yang, X and Gao, X and Jiang, X and Yue, K and Luo, P}, title = {Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3076-3094}, doi = {10.4103/NRR.NRR-D-24-00462}, pmid = {39435635}, issn = {1673-5374}, abstract = {Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.}, } @article {pmid39434139, year = {2024}, author = {Agah, E and Mojtabavi, H and Behkar, A and Heidari, A and Ajdari, A and Shaka, Z and Mousavi, SV and Firoozeh, N and Tafakhori, A and Rezaei, N}, title = {CSF and blood levels of Neurofilaments, T-Tau, P-Tau, and Abeta-42 in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {953}, pmid = {39434139}, issn = {1479-5876}, mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; Biomarkers/blood/cerebrospinal fluid ; Neurofilament Proteins/blood/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid/blood ; Phosphorylation ; Publication Bias ; *tau Proteins/cerebrospinal fluid/blood ; }, abstract = {Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25-1.68]; blood: 1.35 [1.09-1.60]) and NFH (CSF: 1.32 [1.13-1.50], blood: 0.90 [0.58-1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.}, } @article {pmid39434103, year = {2024}, author = {Sun, S and Chen, Y and Yun, Y and Zhao, B and Ren, Q and Sun, X and Meng, X and Yan, C and Lin, P and Liu, S}, title = {Elevated peripheral inflammation is associated with choroid plexus enlargement in independent sporadic amyotrophic lateral sclerosis cohorts.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {83}, pmid = {39434103}, issn = {2045-8118}, support = {qnts202306347//Taishan Young Scholar Program/ ; ZR2024MH178//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; *Choroid Plexus/diagnostic imaging/pathology ; Female ; Middle Aged ; *Inflammation/blood/diagnostic imaging ; *Magnetic Resonance Imaging ; Cohort Studies ; Aged ; Adult ; }, abstract = {BACKGROUND: Using neuroimaging techniques, growing evidence has suggested that the choroid plexus (CP) volume is enlarged in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, the CP has been suggested to play an important role in inflammation-induced CNS damage under disease conditions. However, to our knowledge, no study has investigated the relationships between peripheral inflammation and CP volume in sporadic ALS patients. Thus, in this study, we aimed to verify CP enlargement and explore its association with peripheral inflammation in vivo in independent ALS cohorts.

METHODS: Based on structural MRI data, CP volume was measured using Gaussian mixture models and further manually corrected in two independent cohorts of sporadic ALS patients and healthy controls (HCs). Serum inflammatory protein levels were measured using a novel high-sensitivity Olink proximity extension assay (PEA) technique. Xtreme gradient boosting (XGBoost) was used to explore the contribution of peripheral inflammatory factors to CP enlargement. Then, partial correlation analyses were performed.

RESULTS: CP volumes were significantly higher in ALS patients than in HCs in the independent cohorts. Compared with HCs, serum levels of CRP, IL-6, CXCL10, and 35 other inflammatory factors were significantly increased in ALS patients. Using the XGBoost approach, we established a model-based importance of features, and the top three predictors of CP volume in ALS patients were CRP, IL-6, and CXCL10 (with gains of 0.24, 0.18, and 0.15, respectively). Correlation analyses revealed that CRP, IL-6, and CXCL10 were significantly associated with CP volume in ALS patients (r = 0.462 ∼ 0.636, p < 0.001).

CONCLUSION: Our study is the first to reveal a consistent and replicable contribution of peripheral inflammation to CP enlargement in vivo in sporadic ALS patients. Given that CP enlargement has been recently detected in other brain diseases, these findings should consider extending to other disease conditions with a peripheral inflammatory component.}, } @article {pmid39433597, year = {2024}, author = {Candrea, DN and Shah, S and Luo, S and Angrick, M and Rabbani, Q and Coogan, C and Milsap, GW and Nathan, KC and Wester, BA and Anderson, WS and Rosenblatt, KR and Uchil, A and Clawson, L and Maragakis, NJ and Vansteensel, MJ and Tenore, FV and Ramsey, NF and Fifer, MS and Crone, NE}, title = {A click-based electrocorticographic brain-computer interface enables long-term high-performance switch scan spelling.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {207}, pmid = {39433597}, issn = {2730-664X}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) can restore communication for movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command click detectors provide a basic yet highly functional capability.

METHODS: We sought to test the performance and long-term stability of click decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis. We trained the participant's click detector using a small amount of training data (<44 min across 4 days) collected up to 21 days prior to BCI use, and then tested it over a period of 90 days without any retraining or updating.

RESULTS: Using a click detector to navigate a switch scanning speller interface, the study participant can maintain a median spelling rate of 10.2 characters per min. Though a transient reduction in signal power modulation can interrupt usage of a fixed model, a new click detector can achieve comparable performance despite being trained with even less data (<15 min, within 1 day).

CONCLUSIONS: These results demonstrate that a click detector can be trained with a small ECoG dataset while retaining robust performance for extended periods, providing functional text-based communication to BCI users.}, } @article {pmid39432543, year = {2024}, author = {Liu, X and Dong, L and Li, S and Li, Z and Wang, Y and Mao, Z and Deng, L}, title = {Improving AGB estimations by integrating tree height and crown radius from multisource remote sensing.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0311642}, pmid = {39432543}, issn = {1932-6203}, mesh = {*Biomass ; *Trees/growth & development ; *Remote Sensing Technology/methods ; *Forests ; }, abstract = {Precise estimation of forest above ground biomass (AGB) is essential for assessing its ecological functions and determining forest carbon stocks. It is difficult to directly obtain diameter at breast height (DBH) based on remote sensing imagery. Therefore, it is crucial to accurately estimate the AGB with features extracted directly from RS. This paper demonstrates the feasibility of estimating AGB from crown radius (R) and tree height (H) features extracted from multi-source RS data. Accurate information on tree height (H), crown radius (R), and diameter at breast height (DBH) can be obtained through point clouds generated by airborne laser scanning (ALS) and terrestrial laser scanning (TLS), respectively. Nine allometric growth equations were used to fit coniferous forests (Larix principis-rupprechtii) and broadleaf forests (Fraxinus chinensis and Sophora japonica). The fitting performance of models constructed using only "H" or "R" was compared with that of models constructed using both combined. The results showed that the quadratic polynomial model constructed with "H+R" fitted the AGB estimation better in each vegetation type, especially in the scenario of mixed tall and short coniferous forests, in which the R2 and RMSE were 0.9282 and 25.30 kg (rRMSE 17.31%), respectively. Therefore, using high-resolution data to extract crown radius and tree height can achieve high-precision, global-scale estimation of forest above ground biomass.}, } @article {pmid39432435, year = {2024}, author = {Anjaneyulu, J and Godbole, A}, title = {Small organism models for mode of action research on anti-ageing and nootropic herbs, foods, and formulations.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/1028415X.2024.2409128}, pmid = {39432435}, issn = {1476-8305}, abstract = {With global increase in ageing population along with increasing age-related neurodegenerative diseases (NDs), development of sustainable, safe and effective solutions for promoting healthy ageing and preventing diseases has become a priority. Traditional healthcare systems/medicines prescribe several herbs, foods and formulations to promote healthy ageing and prevent and/or treat age-related diseases. However, the scientific data elucidating their mechanism of action is very limited and deeper research using different models is warranted for timely and wider use. The clinical studies and research with higher model organisms, although useful, have several practical, technical, and financial limitations. Conversely, small organism models like Yeast, Roundworm, Fruit fly, and Zebrafish, which have genetic similarities to humans, can replicate the disease features and provide behavioural, cellular and molecular insights. The common features of ageing and NDs, like amyloid protein aggregations, oxidative stress, energy dysregulation, inflammation and neurodegeneration can be mimicked in the small organism models for Alzheimer's, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis. This review focuses on small organism model- based research unveiling interesting modes of action and synergistic effects of herbal extracts, foods, and formulations, which are indicated especially for healthy ageing and management of NDs. This will provide leads for the quick and sustainable development of scientifically evaluated solutions for clinically relevant, age-related conditions.}, } @article {pmid39431591, year = {2024}, author = {Sheers, NL and Hannan, LM and Rautela, L and Graco, M and Jones, J and Retica, S and Saravanan, K and Burgess, N and McGaw, R and Donovan, A and Clohessy, T and Chao, C and Charles, C and Howard, ME and Berlowitz, DJ}, title = {NIV@Home: a pilot randomized controlled trial of in-home noninvasive ventilation initiation compared to a single-day admission model.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2416668}, pmid = {39431591}, issn = {2167-9223}, abstract = {Objective: Noninvasive ventilation (NIV) is the primary treatment for respiratory insufficiency in neuromuscular disease. NIV implementation is usually conducted within hospitals; however, in-home implementation with intensive follow-up is an effective alternative. This pilot study aimed to assess model feasibility, acceptability, and NIV usage at 12-weeks after a single visit in-home implementation of NIV with remote monitoring follow-up (NIV@Home) compared to an in-hospital day admission NIV initiation plus planned polysomnography (Usual care). Methods: A single-blinded randomized controlled trial (www.anzctr.org.au ACTRN12620000682943) of adults with neuromuscular disease referred for NIV implementation. Participants were stratified by disease (MND or Other diagnoses) and bulbar symptoms before randomization to NIV@Home or Usual care, with follow-up at 12-weeks. The primary outcome was NIV usage. Secondary outcomes included feasibility, health-related quality of life, symptoms, carer burden, and NIV experience (semi-structured qualitative interviews). Results: Twenty-three participants (MND bulbar = 9, MND non-bulbar = 11, Other = 3) were randomized (NIV@Home = 9). No statistical differences were observed in the percentage of MND participants using NIV for >4 hours/day (NIV@Home = 33% vs. Usual care = 60%, p = 0.370), average use (NIV@Home = 2.4 [1.5-9.3] vs. 5.3 [1.8-7.0] hours/day, p = 0.568), or secondary outcomes. In-home NIV implementation was feasible and safe but took more therapist time (NIV@Home = 278 [270-305] vs. 172 [130-200] minutes, p < 0.001). Participants in the NIV@Home group reported substantial advantages to receiving care in home. Conclusion: In-home NIV implementation is feasible and acceptable to people with MND but requires more therapist time. Larger studies are required to determine whether there are clinically important differences between this model of NIV initiation and a traditional hospital-based model.}, } @article {pmid39431590, year = {2024}, author = {Correa-Arrieta, C and Castellar-Leones, S and Forero Diaz, JJ and Peña-Preciado, M and Ortiz-Corredor, F}, title = {Slowly progressing Amyotrophic lateral sclerosis associated with the F21L variant in the SOD1 gene: Demographic and clinical characteristics.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2416669}, pmid = {39431590}, issn = {2167-9223}, abstract = {INTRODUCTION/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which genetic variants can significantly influence clinical presentation and prognosis. This study aims to describe the demographic and clinical characteristics of ALS patients carrying the SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant, as treated at a national reference center in Colombia.

METHODS: A descriptive study was conducted on patients identified with the SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant, selected from the database of a neuromuscular disease center in Colombia. Demographic and clinical data were collected through medical records and patient interviews. Molecular analysis was performed using PCR and automated sequencing to confirm the presence of the variant.

RESULTS: Eleven patients with SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant were identified. The mean age at onset was 48.4 years, with a mean disease duration of 76.7 months. The majority (90.9%) exhibited a slowly progressive course, predominantly with spinal onset and no cognitive impairment. Bulbar symptoms developed in 72.2% of the patients, and 81.8% required noninvasive ventilation. A family history of ALS or other neurodegenerative disorders was present in 54.5% of the patients.

CONCLUSIONS: The SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant is associated with a slowly progressive ALS phenotype, characterized by predominant lower motor neuron involvement and delayed onset of bulbar and respiratory symptoms. This variant appears to be predominantly distributed in central Colombia. Early detection of this variant may enable timely interventions and personalized care plans. Further research is required to establish a definitive causal relationship between this variant and the observed clinical course.}, } @article {pmid39428513, year = {2024}, author = {Shibasaki, N and Konishi, K and Nishiyama, Y and Miyagawa, T and Numayama, T}, title = {[A case of amyotrophic lateral sclerosis managed by tracheostomy and invasive ventilation in which air leaks occurred at the cuff].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {11}, pages = {789-793}, doi = {10.5692/clinicalneurol.cn-001990}, pmid = {39428513}, issn = {1882-0654}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *Tracheostomy ; *Respiration, Artificial ; Tomography, X-Ray Computed ; Trachea/diagnostic imaging ; Air ; Pressure ; Treatment Outcome ; }, abstract = {The patient was a 64-year-old woman who had been diagnosed with amyotrophic lateral sclerosis 8 years ago, and had been under artificial ventilation with tracheotomy for 6 years. Computed tomography indicated a dilated tracheal diameter of 29.6 ‍mm at the cuff, and a high cuff pressure of 80 ‍cmH2O. An adjustable flange tracheostomy tube with an optional length setting was used to extend the effective length by 28 ‍mm. A previously evident air leak disappeared with the change in cuff level, and cuff pressure decreased to 25 ‍cmH2O. X-ray images indicated a reduction in the size of the previous cuff area. Tracheal dilatation due to improper management of cuff pressure is a contributing factor to air leakage at the cuff area, and using an adjustable flange tracheostomy tube in an effort to resolve such air leaks is a valid option.}, } @article {pmid39428436, year = {2024}, author = {Assialioui, A and Marco-Pascual, C and Torrente-Segarra, V and Domínguez, R and Santos, N and Peñafiel, J and Juanola, X and Povedano, M and Ferrer, I}, title = {Microvascular abnormalities in skin capillaries of individuals with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24648}, pmid = {39428436}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Middle Aged ; Male ; *Capillaries/pathology ; Female ; *Skin/blood supply/pathology ; Aged ; Microscopic Angioscopy ; Case-Control Studies ; Adult ; }, abstract = {This is the first study aimed to detect morphological abnormalities in vivo in the skin capillaries of amyotrophic lateral sclerosis patients (ALS). Videocapillaroscopy assessed subungueal capillaries in 28 ALS patients (cases) and 35 controls (p = 0.42). The mean age was 61.46 and 61.23 years, respectively (p > 0.99). No statistically significant differences were observed between the groups regarding dominant hand, arterial hypertension, dyslipidemia, diabetes mellitus, active smoker, and former smoker variables. 78.57% of cases had spinal onset and 21.43% bulbar. The median disease duration (time between the onset of symptoms and the date of videocapillarscopy) was 29.71 months. Dilated capillaries were detected in 17.8% of cases and 11.43% of controls (p = 0.49). The median of capillary diameter in cases was 10.15 µm and 8.72 µm in controls (p = 0.011). 35.71% of cases and 2.86% of controls had severe capillary tortuosities (p < 0.001). Ramified capillaries were observed in 46.43% of cases and 11.43% of controls (p < 0.002). Micro-hemorrhages were only observed in 10.71% of cases. No significant correlations were observed between disease duration and dilated capillaries, tortuosity, ramified capillaries, and micro-hemorrhages. The present in vivo study shows abnormalities in the skin capillaries of ALS patients that do not depend on disease duration.}, } @article {pmid39428248, year = {2024}, author = {Luo, N and Wang, J and Zhang, ZY and Zhao, XY and Huang, RR and Wu, QY}, title = {[Research progress on Pb-induced neurotoxicity through glial cells].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {58}, number = {10}, pages = {1610-1615}, doi = {10.3760/cma.j.cn112150-20240513-00382}, pmid = {39428248}, issn = {0253-9624}, support = {8217348282, 82173554, 82101593//National Natural Science Foundation of China/ ; }, mesh = {*Neuroglia/drug effects ; Humans ; *Lead/toxicity ; }, abstract = {Lead is one of the most important occupational hazards in China, and occupational exposure is the leading cause of lead poisoning. Lead can be absorbed by the body through air, food, drinking water and skin, and accumulate in multiple organs in the body, posing health risks to humans, especially to lead workers. Many previous studies have shown that lead can affect the function of glial cells such as microglia, astrocytes and oligodendrocytes, resulting in irreversible neurological damage. This article provides an overview of the neurotoxic mechanism induced by lead through glial cells, elucidates that lead can induce neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and reviews the relationship between lead and glial cells, in order to provide reference for further research on the neurotoxic mechanism of lead on glial cells.}, } @article {pmid39428001, year = {2025}, author = {Simoes, FA and Christoforidou, E and Cassel, R and Dupuis, L and Hafezparast, M}, title = {Severe dynein dysfunction in cholinergic neurons exacerbates ALS-like phenotypes in a new mouse model.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {1}, pages = {167540}, doi = {10.1016/j.bbadis.2024.167540}, pmid = {39428001}, issn = {1879-260X}, mesh = {Animals ; *Disease Models, Animal ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Phenotype ; *Cholinergic Neurons/metabolism/pathology ; Cytoplasmic Dyneins/metabolism/genetics ; Neuromuscular Junction/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; Mice, Knockout ; Male ; Dyneins/metabolism/genetics ; Point Mutation ; }, abstract = {Cytoplasmic dynein 1, a motor protein essential for retrograde axonal transport, is increasingly implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this study, we developed a novel mouse model that combines the Legs at odd angles (Loa, F580Y) point mutation in the dynein heavy chain with a cholinergic neuron-specific knockout of the dynein heavy chain. This model, for the first time, allows us to investigate the impact of Loa allele exclusivity in these neurons into adulthood. Our findings reveal that this selective increase in dynein dysfunction exacerbated the phenotypes observed in heterozygous Loa mice including pre-wean survival, reduced body weight and grip strength. Additionally, it induced ALS-like pathology in neuromuscular junctions (NMJs) not seen in heterozygous Loa mice. Notably, we also found a previously unobserved significant increase in neurons displaying TDP-43 puncta in both Loa mutants, suggesting early TDP-43 mislocalisation - a hallmark of ALS. The novel model also exhibited a concurrent rise in p62 puncta that did not co-localise with TDP-43, indicating broader impairments in autophagic clearance mechanisms. Overall, this new model underscores the fact that dynein impairment alone can induce ALS-like pathology and provides a valuable platform to further explore the role of dynein in ALS.}, } @article {pmid39427550, year = {2024}, author = {Pan, Y and Sun, X and Tian, Y and Yu, M and Luo, Y and Sun, X}, title = {L-NRB alleviates amyotrophic lateral sclerosis by regulating P11-Htr4 signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {180}, number = {}, pages = {117588}, doi = {10.1016/j.biopha.2024.117588}, pmid = {39427550}, issn = {1950-6007}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; *Signal Transduction/drug effects ; Mice ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Male ; Benzofurans/pharmacology/therapeutic use ; Disease Models, Animal ; Motor Neurons/drug effects/pathology/metabolism ; Apoptosis/drug effects ; Mice, Inbred C57BL ; }, abstract = {INTRODUCTION: L-NRB is a compound formed as a ring cleavage product of butylphthalide and borneol in a molar ratio 1:2. This study aimed to explore the therapeutic effect of L-NRB on amyotrophic lateral sclerosis (ALS) and its possible mechanism.

METHODS: SOD1-G93A mice were used as an ALS model. Behavioral tests, histopathological staining, Nissl staining, immunohistochemistry, enzyme-linked immunosorbent assays, and Western blotting were used to analyze the therapeutic effect. The underlying mechanism of L-NRB in treating ALS was investigated using transcriptomic analyses.

RESULTS: It was found that L-NRB alleviated motor dysfunction, pathological changes in the gastrocnemius muscle, and motor neuron injuries. The results indicated that L-NRB had a neuroprotective function associated with the inhibition of neuroinflammation. The anti-apoptotic effect of L-NRB was found to be related to the regulation of the P11-Htr4 signaling pathway.

CONCLUSION: In summary, the results demonstrated the therapeutic effect of L-NRB on ALS and suggest a promising new therapeutic candidate for ALS.}, } @article {pmid39426615, year = {2024}, author = {Mackness, BC and Morgan, BR and Deveau, LM and Kathuria, SV and Zitzewitz, JA and Massi, F}, title = {A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168823}, doi = {10.1016/j.jmb.2024.168823}, pmid = {39426615}, issn = {1089-8638}, mesh = {*Protein Folding ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Hydrophobic and Hydrophilic Interactions ; *Molecular Dynamics Simulation ; Protein Structure, Secondary ; Protein Stability ; RNA Recognition Motif/genetics ; Protein Conformation ; Models, Molecular ; }, abstract = {Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43 (TAR DNA-binding protein-43), using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.}, } @article {pmid39425598, year = {2024}, author = {Zhang, L and Zhou, X and Cha, S}, title = {Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression.}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1028}, doi = {10.1002/ana.27092}, pmid = {39425598}, issn = {1531-8249}, } @article {pmid39425590, year = {2024}, author = {Zhu, L and Li, Y and Yu, X and Chen, Y and Zhang, J and Pang, C and Xie, J and Gao, L and Du, L and Cao, W and Fan, D and Cui, C and Yu, H and Deng, B}, title = {Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27115}, pmid = {39425590}, issn = {1531-8249}, support = {12101460//National Natural Science Foundation of China/ ; 81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, abstract = {BACKGROUND: Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.

METHODS: cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.

RESULTS: In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.

INTERPRETATION: Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2024.}, } @article {pmid39424779, year = {2024}, author = {Wu, H and Wang, LC and Sow, BM and Leow, D and Zhu, J and Gallo, KM and Wilsbach, K and Gupta, R and Ostrow, LW and Yeo, CJJ and Sobota, RM and Li, R}, title = {TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9026}, pmid = {39424779}, issn = {2041-1723}, support = {A-0007081-00-00//Ministry of Education - Singapore (MOE)/ ; NRF-MSG-2023-0001//National Research Foundation Singapore (National Research Foundation-Prime Minister's office, Republic of Singapore)/ ; NRF-SIS "SingMass"//A*STAR | Singapore Institute of Manufacturing Technology (Singapore Institute of Manufacturing Technology - A STAR)/ ; }, mesh = {Humans ; *Golgi Apparatus/metabolism ; *Endoplasmic Reticulum/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Protein Transport ; Protein Aggregates ; Motor Neurons/metabolism ; HeLa Cells ; HEK293 Cells ; }, abstract = {Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.}, } @article {pmid39424648, year = {2024}, author = {Chartier, C and Godard, J and Durand, S and Humeau-Heurtier, A and Menetrier, E and Allain, P and Besnard, J}, title = {Combinations of physical and cognitive training for subcortical neurodegenerative diseases with physical, cognitive and behavioral symptoms: a systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5571-5589}, pmid = {39424648}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Behavioral Symptoms/therapy/etiology ; Cognitive Behavioral Therapy/methods ; Exercise Therapy/methods ; Cognitive Dysfunction/therapy/rehabilitation/etiology ; Cognitive Training ; }, abstract = {BACKGROUND: The onset of the symptoms of subcortical NDs is due to a unique part of the brain which strengthens the idea of reciprocal influence of physical activity and cognitive training in improving clinical symptoms. Consequently, protocols combining the two stimulations are becoming increasingly popular in NDs. Our threefold aim was to (A) describe the different combinations of physical and cognitive training used to alleviate the motor and cognitive symptoms of patients with subcortical neurodegenerative disorders, (B) compare the effects of these different combinations (sequential, dual tasking, synergical) on symptoms, and (C) recommend approaches for further studies.

METHODS: We conducted literature searches of PubMed, BASE and ACM, to carry out a systematic review of randomized controlled trials and controlled trials of combined physical and cognitive training among patients with Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, spinocerebellar ataxia, Friedreich's ataxia, and progressive supranuclear palsy. Physical, neuropsychological, behavioral outcomes were considered. The Cochrane risk-of-bias tool was used to verify the critical appraisal.

RESULTS: Twenty-one studies focused on Parkinson's disease with 940 participants were included. Despites promising benefits on cognitive and physical function, our results revealed discrepant findings for research on combined training.

DISCUSSION: Inconsistencies were linked to the choice of tests, the functions that were targeted, disease progression, and trainings. There was a dearth of follow-up data.

CONCLUSIONS: Differences between combined training are unclear, particularly regarding the role of cognitive load. Future studies should focus on comparing the feasibility, tolerability, and effectiveness of different combinations of motor-cognitive training.}, } @article {pmid39424561, year = {2024}, author = {Crow, YJ}, title = {CNS disease associated with enhanced type I interferon signalling.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1158-1168}, pmid = {39424561}, issn = {1474-4465}, support = {786142/ERC_/European Research Council/International ; MC_UU_00035/11/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Interferon Type I/metabolism/immunology ; *Signal Transduction ; Animals ; Central Nervous System Diseases/immunology/metabolism ; }, abstract = {The ability to mount an interferon-mediated innate immune response is essential in protection against neurotropic viruses, but antiviral type I interferons also have neurotoxic potential. The production of type I interferons can be triggered by self-derived nucleic acids, and the brain can be susceptible to inappropriate upregulation of type I interferon signalling. Homoeostatic dysregulation of type I interferons has been implicated in rare inborn errors of immunity (referred to as type I interferonopathies) and more common neurodegenerative disorders (eg, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Recent developments include new insights into the pathogenesis of these disorders that involve dysregulated type I interferon signalling, as well as advances in their diagnosis and management. The role of type I interferons in brain cellular health suggests the future therapeutic potential of approaches that target these interferons and their signalling.}, } @article {pmid39424560, year = {2024}, author = {Koch, JC and Leha, A and Bidner, H and Cordts, I and Dorst, J and Günther, R and Zeller, D and Braun, N and Metelmann, M and Corcia, P and De La Cruz, E and Weydt, P and Meyer, T and Großkreutz, J and Soriani, MH and Attarian, S and Weishaupt, JH and Weyen, U and Kuttler, J and Zurek, G and Rogers, ML and Feneberg, E and Deschauer, M and Neuwirth, C and Wuu, J and Ludolph, AC and Schmidt, J and Remane, Y and Camu, W and Friede, T and Benatar, M and Weber, M and Lingor, P and , }, title = {Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1133-1146}, doi = {10.1016/S1474-4422(24)00373-9}, pmid = {39424560}, issn = {1474-4465}, mesh = {Humans ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/therapeutic use/pharmacology/adverse effects ; Middle Aged ; Male ; Double-Blind Method ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Aged ; Adult ; *rho-Associated Kinases/antagonists & inhibitors ; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration & dosage ; Treatment Outcome ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.

FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.

INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.

FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".}, } @article {pmid39424548, year = {2024}, author = {Andrews, JA}, title = {A new era of drug discovery for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1070-1072}, doi = {10.1016/S1474-4422(24)00407-1}, pmid = {39424548}, issn = {1474-4465}, } @article {pmid39424348, year = {2024}, author = {Yoganathan, S and Kumar, M and Aaron, R and Rangan, SR and Umakant, BS and Thomas, M and Oommen, SP and Danda, S}, title = {Phenotype and Genotype of Children with ALS2 gene-Related Disorder.}, journal = {Neuropediatrics}, volume = {}, number = {}, pages = {}, doi = {10.1055/s-0044-1791256}, pmid = {39424348}, issn = {1439-1899}, abstract = {INTRODUCTION: The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor. The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract. The phenotypes resulting from variants in ALS2 gene are infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225), juvenile primary lateral sclerosis (JPLS, OMIM # 606353), and juvenile amyotrophic lateral sclerosis (JALS, OMIM # 205100). Our study objectives were to describe the clinical phenotype and genotype of children with an established diagnosis of ALS2 gene-related disorder.

METHODS:  The clinical details, laboratory data, and genotype findings of children with an established diagnosis of ALS2 gene-related disorder were collected from the hospital electronic database after obtaining institutional review board approval.

RESULTS:  One family with three affected siblings, a second family with a proband and an affected fetus, and a third family with two affected siblings with ALS2 gene variants were identified. IAHSP was diagnosed in all of our patients with variants in ALS2 gene. The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria. Nonsense variants were observed in four patients while frameshift variant was observed in one family. Novel variants in ALS2 gene were identified in two unrelated families.

CONCLUSION:  ALS2 mutation results in rare neurodegenerative disorders with the clinical spectrum encompassing IAHSP, JPLS, and JALS disorders. In view of allelic heterogeneity described in the literature, more research studies are needed for establishing genotype-phenotype correlation in patients with ALS2 gene-related disorder.}, } @article {pmid39423873, year = {2024}, author = {Thapa, R and Moglad, E and Afzal, M and Gupta, G and Bhat, AA and Hassan Almalki, W and Kazmi, I and Alzarea, SI and Pant, K and Singh, TG and Singh, SK and Ali, H}, title = {The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102545}, doi = {10.1016/j.arr.2024.102545}, pmid = {39423873}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Sirtuin 1/metabolism ; *Aging/metabolism/genetics ; Animals ; Oxidative Stress/physiology ; }, abstract = {Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications.}, } @article {pmid39422938, year = {2024}, author = {Pappolla, MA and Wu, P and Fang, X and Poeggeler, B and Sambamurti, K and Wisniewski, T and Perry, G}, title = {Stem Cell Interventions in Neurology: From Bench to Bedside.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {101}, number = {s1}, pages = {S395-S416}, doi = {10.3233/JAD-230897}, pmid = {39422938}, issn = {1875-8908}, mesh = {Humans ; Animals ; *Stem Cell Transplantation/methods/trends ; Nervous System Diseases/therapy ; Neurology/trends/methods ; Translational Research, Biomedical/trends ; Neural Stem Cells/transplantation ; }, abstract = {Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.}, } @article {pmid39420987, year = {2024}, author = {Sun, H and Tang, Q and Yan, X and Xie, W and Xu, Y and Zhang, W}, title = {Cathepsins and neurological diseases: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1454369}, pmid = {39420987}, issn = {1662-4548}, abstract = {BACKGROUND: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases.

METHODS: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis.

RESULTS: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p = 0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p = 0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p = 0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases.

CONCLUSION: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions.}, } @article {pmid39419765, year = {2024}, author = {Johns, AE and Taga, A and Charalampopoulou, A and Gross, SK and Rust, K and McCray, BA and Sullivan, JM and Maragakis, NJ}, title = {Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model.}, journal = {Stem cells translational medicine}, volume = {13}, number = {12}, pages = {1198-1212}, pmid = {39419765}, issn = {2157-6580}, mesh = {Humans ; *Motor Neurons/metabolism/drug effects ; *Receptors, Purinergic P2X7/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Purinergic P2X Receptor Antagonists/pharmacology ; Animals ; Adenosine Triphosphate/metabolism ; Neuroprotection/drug effects ; Mice ; Rats ; }, abstract = {ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.}, } @article {pmid39419433, year = {2025}, author = {Majumder, P and Hsu, TI and Hu, CJ and Huang, JK and Lee, YC and Hsieh, YC and Ahsan, A and Huang, CC}, title = {Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {114999}, doi = {10.1016/j.expneurol.2024.114999}, pmid = {39419433}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; Female ; *Disease Models, Animal ; Male ; *DNA-Binding Proteins/metabolism/genetics ; *Estrogen Replacement Therapy/methods ; *Curcumin/pharmacology/administration & dosage/therapeutic use ; Mice, Transgenic ; Aromatase/metabolism ; Estradiol/pharmacology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS.

METHODS: Prp-TDP-43[A315T] mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43[A315T] mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43[A315T] mice with or without SLCP were determined.

RESULTS: We found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43[A315T] mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43[A315T] mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes.

CONCLUSIONS: Our results showed that Prp-TDP-43[A315T] mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.}, } @article {pmid39419034, year = {2024}, author = {Wijegunawardana, D and Nayak, A and Vishal, SS and Venkatesh, N and Gopal, PP}, title = {Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.}, journal = {Developmental cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.devcel.2024.09.023}, pmid = {39419034}, issn = {1878-1551}, abstract = {Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43 kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons in vivo. We report that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within RNP condensates and disrupt both its motility along the axon and liquid-like properties. We provide evidence that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, our results support a model in which Ataxin-2 polyQ expansions disrupt stability, localization, and/or translation of critical axonal and cytoskeletal mRNAs, particularly important for motor neuron integrity.}, } @article {pmid39418491, year = {2024}, author = {Kumar, R and Ghai, S and Finelli, A and Klotz, L and Kinnaird, A and Mannas, M and Bhindi, B and Sanchez-Salas, R and Anidjar, M and Ahmad, A and Chin, J and Inman, B and Perlis, N}, title = {The use of focal therapy for the treatment of prostate cancer in Canada: Where are we, how did we get here, and where are we going?.}, journal = {Canadian Urological Association journal = Journal de l'Association des urologues du Canada}, volume = {}, number = {}, pages = {}, doi = {10.5489/cuaj.8888}, pmid = {39418491}, issn = {1911-6470}, abstract = {INTRODUCTION: Focal therapy is an emerging treatment for localized prostate cancer. The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada.

METHODS: Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrial.gov.

RESULTS: FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events (SAEs) were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation (IRE), or transurethral ultrasound ablation (TULSA).

CONCLUSIONS: Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and, aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.}, } @article {pmid39416141, year = {2024}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Li, D and Cheung, V and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416141}, issn = {2692-8205}, support = {R21 ES034919/ES/NIEHS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels without affecting the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference, highlighting the potential of allele-specific siRNA as a therapeutic approach for ALS4.}, } @article {pmid39416104, year = {2024}, author = {Gunner, G and Basu, H and Lu, Y and Bergstresser, M and Neel, D and Choi, SY and Chiu, IM}, title = {Gasdermin D is activated but does not drive neurodegeneration in SOD1 [G93A] model of ALS: Implications for targeting pyroptosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.10.617609}, pmid = {39416104}, issn = {2692-8205}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1 [G93A] mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1 [G93A] animals across two strain backgrounds, with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred B6.SOD1 [G93A] mice onto a GSDMD - deficient background. In comparing SOD1 [G93A] ; Gsdmd +/+ and SOD1 [G93A] ; Gsdmd -/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1 [G93A] mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.}, } @article {pmid39415649, year = {2024}, author = {Kim, Y and O, JH and Cho, H and Ye, S}, title = {Recognized cases of amyotrophic lateral sclerosis in automobile workers by the Korean Epidemiologic Investigation Evaluation Committee.}, journal = {Annals of occupational and environmental medicine}, volume = {36}, number = {}, pages = {e28}, pmid = {39415649}, issn = {2052-4374}, abstract = {BACKGROUND: Three automobile company workers (one from Factory D and two from Factory E) were diagnosed with amyotrophic lateral sclerosis. The Korean Epidemiologic Investigation and Evaluation Committee determined that there is considerable scientific evidence supporting the association between amyotrophic lateral sclerosis and combined exposure to heavy metals, organic solvents, and diesel exhaust at the manufacturing plant.

CASE PRESENTATION: Patient A, who primarily engaged in engine processing and completed vehicle inspection at Factory D, was exposed to considerable amounts of heavy metals and organic solvents during medium- and large-engine processing, welding, and painting for over 23 years. Additionally, the patient was likely exposed to diesel exhaust for 33 years from forklifts delivering engines in the workshop. Patients B and C, who were responsible for engine assembly, ignition testing, and engine shipment at Factory E since around 1990, were exposed to lead and benzene from gasoline during engine ignition tests in the engine department for 15 and 16 years, respectively. They also encountered welding fumes, heavy metals, and organic solvents during welding and painting tasks. In addition, Patients B and C were continuously exposed to diesel exhaust from logistics vehicles on standby during work hours for 25 and 30 years, respectively.

CONCLUSIONS: Although the specific level of lead exposure causing amyotrophic lateral sclerosis remains undetermined, numerous studies have consistently reported a relationship between lead exposure and disease development. Limited evidence suggests that exposure to organic solvents and diesel exhaust may increase the risk of amyotrophic lateral sclerosis. Therefore, the Epidemiological Investigation and Evaluation Committee concluded that the three patients' work-related exposure to heavy metals, organic solvents, and diesel exhaust is significantly supported by scientific evidence as a cause of their amyotrophic lateral sclerosis.}, } @article {pmid39415277, year = {2024}, author = {Abdelnaby, R and Shabib, AS and El Din Moawad, MH and Salem, T and Wagih Youssef Awad, M and Awad, PD and Maallem, I and Atwan, H and Rabie, SA and Mohamed, KA and Abdelmageed, H and Karkour, AM and Elsayed, M and Cartwright, MS}, title = {Nerve ultrasound in amyotrophic lateral sclerosis: systematic review and meta-analysis.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {47}, pmid = {39415277}, issn = {2524-3489}, abstract = {BACKGROUND/ AIM: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, causing progressive atrophy of muscles, hypertonia, and paralysis. This study aimed to evaluate the current evidence and effectiveness of ultrasound in investigating nerve cross-sectional area (CSA) of peripheral nerves, vagus and cervical roots in those with ALS compared with healthy controls and to pool the CSA measurements.

METHODS: A systematic search was conducted on Cochrane, Clarivate Web of Science, PubMed, Scopus, and Embase for the mesh terms nerve, ultrasonography, and amyotrophic lateral sclerosis. A quality assessment was performed using the New-Ottawa scale. In addition, a double-arm meta-analysis using Review Manager 5 software version 5.4 was performed.

RESULTS: From the seventeen studies included in this review, the overall mean difference showed that individuals with ALS had a significantly smaller CSA in comparison to healthy controls for median, ulnar, C6 root, and phrenic nerves. However, no significant difference in the CSA was found in radial, vagal, sural, and tibial nerves.

DISCUSSION: This study confirmed results of some of the included studies regards the anatomic sites, where nerve atrophy in ALS could be detected to potentially support the diagnosis of ALS. However, we recommend further large, prospective studies to assess the diagnostic value of these anatomical sites for the diagnosis of ALS.

CONCLUSIONS: Our findings confirmed specific anatomic sites to differentiate ALS patients from healthy controls through ultrasound. However, these findings cannot be used to confirm the ALS diagnosis, but rather assist in differentiating it from other diagnoses.

TRIAL REGISTRATION: Retrospectively registered on July 30th 2024 in PROSPERO (PROSPERO (york.ac.uk)) with ID574702.}, } @article {pmid39414899, year = {2024}, author = {Kawata, S and Seki, S and Nishiura, A and Kitaoka, Y and Iwamori, K and Fukada, SI and Kogo, M and Tanaka, S}, title = {Preservation of masseter muscle until the end stage in the SOD1G93A mouse model for ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24279}, pmid = {39414899}, issn = {2045-2322}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics ; *Masseter Muscle/pathology ; *Disease Models, Animal ; Mice ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Satellite Cells, Skeletal Muscle/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) progressively impairs motor neurons, leading to muscle weakness and loss of voluntary muscle control. This study compared the effects of SOD1 mutation on masticatory and limb muscles from disease onset to death in ALS model mice. Notably, limb muscles begin to atrophy soon after ALS-like phenotype appear, whereas masticatory muscles maintain their volume and function in later stages. Our analysis showed that, unlike limb muscles, masticatory muscles retain their normal structure and cell makeup throughout most of the disease course. We found an increase in the number of muscle satellite cells (SCs), which are essential for muscle repair, in masticatory muscles. In addition, we observed no reduction in the number of muscle nuclei and no muscle fibre-type switching in masticatory muscles. This indicates that masticatory muscles have a higher resistance to ALS-related damage than limb muscles, likely because of differences in cell composition and repair mechanisms. Understanding why masticatory muscles are less affected by ALS could lead to the development of new treatments. This study highlights the importance of studying different muscle groups in ALS to clarify disease aetiology and mechanisms.}, } @article {pmid39413009, year = {2024}, author = {Ralbovsky, NM and Zhang, Y and Williams, DM and McKelvey, CA and Smith, JP}, title = {Machine Learning and Hyperspectral Imaging for Analysis of Human Papillomaviruses (HPV) Vaccine Self-Healing Particles.}, journal = {Analytical chemistry}, volume = {96}, number = {43}, pages = {17118-17127}, doi = {10.1021/acs.analchem.4c02327}, pmid = {39413009}, issn = {1520-6882}, mesh = {*Papillomavirus Vaccines/immunology ; *Machine Learning ; Humans ; Vaccines, Virus-Like Particle ; Human Papillomavirus Viruses ; }, abstract = {Human papillomaviruses (HPV) are known to cause a variety of diseases, including cervical cancer and genital warts. HPV is a highly prevalent virus and is considered the most common sexually transmitted disease. Because of the risks associated with HPV, Gardasil, a quadrivalent recombinant vaccine, was developed by Merck & Co., Inc., Rahway, NJ, USA, and approved by the Food and Drug Administration (FDA) in 2006. The second generation of the vaccine, Gardasil9, was subsequently approved by the FDA in 2014, providing significant protection against HPV. The HPV vaccine may be given as 2 or 3 doses; however, vaccine administration as a single dose with a sustained release mechanism may potentially offer benefits to meet emerging health needs. To explore this, HPV vaccines were formulated within microporous self-healing particles (SHPs) to enable potential controlled release of HPV virus-like particle (VLP) antigen. Machine learning, in the form of multivariate curve resolution-alternating least-squares (MCR-ALS), with Raman hyperspectral imaging was used to determine the molecular identity and spatial distribution of all relevant species within this HPV vaccine formulation. The results indicate that machine learning with Raman hyperspectral imaging was able to spatially resolve HPV VLP antigens within SHP vaccines for the first time, providing crucial information necessary for vaccine development.}, } @article {pmid39412921, year = {2024}, author = {Bahador, M and Soltaninejad, S and Mobasheri, M}, title = {Correlation of new two-dimensional geometrical parameters to lung and heart dose-volume parameters in breast cancer radiation therapy.}, journal = {Journal of cancer research and therapeutics}, volume = {20}, number = {5}, pages = {1570-1577}, doi = {10.4103/jcrt.jcrt_2351_23}, pmid = {39412921}, issn = {1998-4138}, mesh = {Humans ; Female ; *Heart/radiation effects/diagnostic imaging ; *Radiotherapy Dosage ; *Radiotherapy Planning, Computer-Assisted/methods ; *Lung/radiation effects/diagnostic imaging/pathology ; *Breast Neoplasms/radiotherapy/pathology ; *Organs at Risk/radiation effects ; Tomography, X-Ray Computed/methods ; ROC Curve ; Middle Aged ; }, abstract = {OBJECTIVE: To develop new two-dimensional geometric parameters for pulmonary and cardiac dose estimation in left-sided breast cancer radiation therapy without dose-volume histogram (DVH).

METHODS: On the CT image of 90 patients with left breast cancer, treatment planning was performed using two opposed tangent fields with/without supraclavicular. The field-in-field technique and 6MV photons were used. From DVH dosimetric parameters of mean dose, Vx (x (Gy) =5, 10, 15, 20, 30, 40, 50) were calculated, and from heart and lung outlines on the beam's eye view, new geometric parameters of percent of lung area in tangent and supraclavicular fields (%area of the lung in the tangent (ALT), %ALS) and percent of heart in tangent field (%area of the heart in the tangent (AHT)) were measured. Correlation, regression, and diagnostic performance by receiver operating characteristic curve (ROC) were investigated for statistical analysis.

RESULTS: The Pearson coefficient between %ALT and Vx (x = 10, 15, 20, 30, 40) show strong correlation in patient treatment with only opposed tangents (>0.85) and weaker in treatment by opposed tangents with supraclavicular (0.56-0.88), the %ALS indicate weak correlation (<0.5) and %AHT show strong correlation (0.93-0.98). The regression analysis shows a positive relation between %ALT and mean dose (R2 = 0.8), V20Gy (R2 = 0.9) in the lung (tangent treatment), and between %AHT and mean dose (R2 = 0.9), V20Gy (R2 = 1.0) in the heart. The ROC analysis shows by %ALT <20.3 for treatment by just opposed fields, %ALT <22.1% for treatment tangents with supra, and %AHT <11.6%, practical lung and heart dose constraints are addressed.

CONCLUSION: The proposed geometric parameters could replace previous one-dimensional maximum and central distances for predicting doses to lung and heart.

ADVANCES IN KNOWLEDGE: This study presents simple geometric parameters that could estimate pulmonary and cardiac dose in left breast cancer treatment from a 2D radiograph.}, } @article {pmid39412565, year = {2024}, author = {Sangari, S and Lackmy-Vallee, A and Preuilh, A and Peyre, I and Pradat, PF and Marchand-Pauvert, V}, title = {Synaptic dynamics linked to widespread elevation of H-reflex before peripheral denervation in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {132}, number = {5}, pages = {1541-1560}, doi = {10.1152/jn.00144.2024}, pmid = {39412565}, issn = {1522-1598}, support = {VMarchand/2013//ARSLA/ ; DdT1 2015- 2; CTL/SS/2016-0029/no 16597//AFM-Telethon/ ; FTL AAP7/2015//Fondation Thierry Latran (Thierry Latran Foundation)/ ; }, mesh = {Humans ; *H-Reflex/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Evoked Potentials, Motor/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Aged ; Adult ; Excitatory Postsynaptic Potentials/physiology ; Riluzole/pharmacology ; Motor Neurons/physiology ; }, abstract = {Changes in Hoffmann reflex (H-reflex) exhibit heterogeneity among patients with amyotrophic lateral sclerosis (ALS), likely due to phenotype diversity. Current knowledge primarily focuses on soleus H-reflex, which may demonstrate an initial increase before subsequent decline throughout the disease course. The main objective was to investigate other muscles, to determine whether H-reflex changes could be associated with patient phenotype (onset site, functional disabilities). Additional experiments were performed to elucidate the neurophysiological mechanisms underlying H-reflex modifications. In age- and sex-matched groups of control subjects and patients, we compared H-reflex recruitment curves in soleus, quadriceps, and forearm flexors. Additionally, we examined H-reflex and motor evoked potential (MEP) recruitment curves in quadriceps. Last, to assess potential changes in monosynaptic excitatory postsynaptic potentials (EPSPs) of both peripheral and cortical origins, we analyzed peristimulus time histograms (PSTHs) and peristimulus frequencygrams (PSFs) of single motor units, along with H-reflex occurrence after paired-pulse stimuli. The ratio between maximal amplitudes of H-reflex and direct motor response increased in all muscles, irrespective of disease onset, and was found positively correlated with exaggerated osteotendinous reflexes and spasticity but depressed in patients on riluzole. This finding was accompanied by a reduction in MEP size and no changes in PSTH, PSF, and paired-pulse H-reflex probability. It is speculated that spinal interneurons may compensate for potential depression of monosynaptic EPSPs in ALS. From a clinical perspective, although the added value of H-reflex to osteotendinous reflex evaluation may be limited, it can serve as a valuable quantitative biomarker of pyramidal dysfunction in clinical trials.NEW & NOTEWORTHY Without significant evidence of peripheral denervation, H-reflex enhancement appears to be a widespread phenomenon, regardless of disease onset site. This increase is likely associated with a decrease in inhibitory control over presynaptic transmission of the synapse between muscle group Ia afferents and motoneurons. Although the link to exaggerated osteotendinous reflexes and spasticity implies a restricted role in identifying a pyramidal syndrome, its quantitative aspect positions the H-reflex as a valuable biomarker in clinical trials.}, } @article {pmid39412227, year = {2024}, author = {Mascías Cadavid, J and Radakovic, R and Radakovic, C and Moran Benito, Y and Marín Esteban, S and Rodríguez-Santos, F and Salas Campos, T}, title = {Spanish adaptation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2416665}, pmid = {39412227}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized functional decline, traditionally measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). The Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is an alternative comprehensive, detailed functional disability measure for people with ALS (pwALS), not yet translated to Spanish. The aim of this study was to translate and validate the Spanish ROADS. 53 Spanish speaking pwALS were recruited. They completed the ALSFRS-R and Spanish ROADS. Reliability (internal consistency, intra-class correlation) and validity (ALSFRS-R total and item-total correlations) were determined. The Spanish ROADS internal consistency reliability was excellent (Cronbach's standardized alpha = 0.94), the test-retest reliability intra-class correlation value was 0.93. There was a strong significant correlation between the Spanish ROADS and ALSFRS-R totals (rs(52) = .89, p < .001). Additionally, the ALSFRS-R subscales and ROADS items correlations showed domain-to-item specific expected significant correlations. The Spanish ROADS is a psychometrically robust, valid and reliable measure for quantifying functional disability for pwALS.}, } @article {pmid39411168, year = {2024}, author = {An, D and Han, J and Fang, P and Bu, Y and Ji, G and Liu, M and Deng, J and Song, X}, title = {Evidence for the potential role of m6A modification in regulating autophagy in models of amyotrophic lateral sclerosis.}, journal = {CytoJournal}, volume = {21}, number = {}, pages = {33}, pmid = {39411168}, issn = {0974-5963}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Research indicates that N6-methyladenosine (m6A) modification plays a crucial role in cellular autophagy during ALS development. This study investigates the role of autophagy in ALS, with a focus on the effect of messenger ribonucleic acid m6A methylation modification on disease progression.

MATERIAL AND METHODS: We compared m6A levels and regulatory molecule expressions in transgenic superoxide dismutase (SOD1)-G93A and non-transgenic mice, categorized into end-stage and control groups, using quantitative polymerase chain reaction and Western blotting. The NSC-34 cell line, which was modified to model ALS, enabled the investigation of apoptosis, autophagy, and autophagy disruption through terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assays, Western blotting, and fluorescent staining.

RESULTS: Our findings indicate significantly elevated m6A methylation levels in ALS mice (0.262 ± 0.005) compared with the controls (0.231 ± 0.003) and in the ALS model cells (0.242±0.005) relative to those belonging to the wild-type control group (0.183 ± 0.007). Furthermore, the proteins involved in m6A RNA modification differed between groups, which suggest impaired autophagy flux in the ALS models.

CONCLUSION: These results suggest that m6A methylation may accelerate ALS progression through the disruption of autophagic processes. Our study underscores the role of m6A methylation in the pathology of ALS and proposes the targeting of m6A methylation as a potential therapeutic strategy for disease treatment. Although this study primarily used transgenic SOD1-G93A mice and NSC-34 cell models to investigate ALS pathology, potential differences in disease mechanisms between animal models and humans must be considered. Although a correlation was detected between m6A methylation levels and autophagy disruption in ALS, the study primarily established an association rather than provided detailed mechanistic insights.}, } @article {pmid39410995, year = {2024}, author = {Zaninotto, AL and Makary, MM and Rowe, HP and Eshghi, M and Tseng, CJ and Chan, J and Zürcher, NR and Hooker, J and Lewis, A and Keegan, M and Gifford, RF and Green, JR and Babu, S}, title = {Speech motor impairment in ALS is associated with multiregional cortical thinning beyond primary motor cortex.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1451177}, pmid = {39410995}, issn = {1664-2295}, abstract = {INTRODUCTION: Cortical thinning is well-documented in individuals with amyotrophic lateral sclerosis (ALS), yet its association with speech deterioration remains understudied. This study characterizes anatomical changes in the brain within the context of speech impairment patterns in individuals with ALS, providing insight into the disease's multiregional spread and biology.

METHODS: To evaluate patterns of cortical thickness in speakers with ALS with and without functional speech changes compared to healthy controls (HCs) using whole-brain and region of interest (ROI) analyses. Forty individuals with ALS and 22 HCs underwent a T1-weighted 3-Tesla magnetic resonance imaging (MRI). Individuals with ALS were divided into two groups based on the preserved speech [ps-ALS] (n = 18) or deteriorated speech [ds-ALS] (n = 22) as measured by the ALSFRSF-R speech subscore (=4 or <4 points, respectively). Sixteen a priori-defined and automatically segmented cortical and subcortical brain ROIs were selected based on their previously documented roles in speech production. Two cortical thickness analyses were performed: (1) group-level whole-brain surface-based analyses and (2) group-level ROI analyses. A case study of 6 ALS individuals examined the cortical thickness, and their speech was characterized using quantitative and qualitative measures.

RESULTS: Based on the group-level whole-brain surface-based analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in the left primary motor and somatosensory cortices and the right inferior parietal lobe with its adjacent lateral occipital cortical regions. The ps-ALS group demonstrated no significant cortical thinning compared to HCs. Based on the group-level ROI analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in bilateral middle motor cortices, right posterior dorsal premotor cortex, and left anterior cingulate cortex. The case study analysis revealed that ALS speakers with speech features characteristic of spastic dysarthria exhibited cortical thinning, while those with speech features characteristic of flaccid dysarthria did not.

DISCUSSION: Individuals with ALS have anatomical changes involving multiregional neocortical areas beyond the primary motor cortex that may manifest as subjective (i.e., clinical judgment) and objective (i.e., speaking rate) changes in speech production. Further longitudinal work in ALS is needed to better understand the link between MRI cortical thickness changes and bulbar dysfunction.}, } @article {pmid39408720, year = {2024}, author = {Du, X and Dong, Q and Zhu, J and Li, L and Yu, X and Liu, R}, title = {Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, pmid = {39408720}, issn = {1422-0067}, support = {XDB39050600//Strategic Priority Research Program of Chinese Academy of Sciences/ ; 82150107//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Rutin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Disease Models, Animal ; *Mice, Transgenic ; *Spinal Cord/drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Protein Aggregation, Pathological/drug therapy/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin's multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.}, } @article {pmid39408173, year = {2024}, author = {Rolling, J and Fath, M and Zanfonato, T and Durpoix, A and Mengin, AC and Schröder, CM}, title = {EMDR-Teens-cPTSD: Efficacy of Eye Movement Desensitization and Reprocessing in Adolescents with Complex PTSD Secondary to Childhood Abuse: A Case Series.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {19}, pages = {}, pmid = {39408173}, issn = {2227-9032}, abstract = {Background: Mental healthcare for children and adolescents with a history of childhood abuse constitutes a major public health issue. Indeed, abuse exposes children to severe and complex post-traumatic stress disorder (cPTSD) but also to neurodevelopmental and psychological repercussions impacting the developmental trajectory. Trauma-focused care is essential to avoid the chronicization of symptoms and disorders. Objective: The aim of this prospective case series study was to investigate the efficacy of eye movement desensitization and reprocessing (EMDR) on complex post-traumatic symptoms and associated psychiatric disorders in adolescents with a history of abuse. Method: Twenty-two adolescents, aged 12 to 17, who had been abused during childhood were included. All adolescents met ICD-11 criteria for complex PTSD. Subjective measures of PTSD and associated psychiatric disorders were taken before (T0) and after 3 months of EMDR therapy (T1). Results: The average PTSD symptom score on the CPTS-RI significantly decreased from 40.2 to 34.4 after EMDR, indicating improvement in post-traumatic symptoms. A significant decrease in the average depression score (CDI from 18.2 at T0 to 10.6 at T1), anxiety score (R-CMAS from 21.3 at T0 to 13.3 at T1), emotional regulation score (ALS from 29 at T0 to 10.8 at T1), insomnia score (ISI from 18.5 at T0 to T1 of 9.2 at T1), and harmful use of alcohol and drugs score (ADOSPA from 2.3 at T0 to 0.3 at T1) was observed after EMDR therapy, as well as an increase in quality of life (CBCL 4-16 score from 57.9 at T0 to 77.4 at T1). Conclusions: The results of this study are encouraging and suggest that EMDR may be effective in the symptom management reducing post-traumatic symptoms and certain comorbid disorders frequently seen in adolescents who have experienced childhood abuse. Further research is needed on adolescent populations suffering from cPTSD (e.g., randomized controlled trials with control groups and other therapies or evaluating the action of the different phases of the study).}, } @article {pmid39407861, year = {2024}, author = {Proaño, B and Cuerda-Ballester, M and Daroqui-Pajares, N and Del Moral-López, N and Seguí-Sala, F and Martí-Serer, L and Calisaya Zambrana, CK and Benlloch, M and de la Rubia Ortí, JE}, title = {Clinical and Sociodemographic Factors Related to Amyotrophic Lateral Sclerosis in Spain: A Pilot Study.}, journal = {Journal of clinical medicine}, volume = {13}, number = {19}, pages = {}, pmid = {39407861}, issn = {2077-0383}, support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknow etiology. Male sex is a well stablished risk factor, but other factors such as early and adult life expositions show contradictory evidence. Aim: to explore the link of clinical, sociodemographic, and occupational factors with ALS patients in Spain and the impact of these factors in functionality. Methods: A cross-sectional study was conducted with ALS patients and healthy controls. Registered variables were smoking, arterial hypertension, diabetes mellitus type 2, previous cancer to reproductive organs or breast, occupational exposure, and early life exposures. Functionality in ALS patients was compared according to each exposure. Results: The ALS group consisted of 59 participants and the control group of 90 participants. ALS patients showed a significant association with previous cancer (p = 0.011), occupational exposure (p < 0.001), and older siblings (p = 0.029). ALS patients presented significant differences in BMI according to hypertension and older-sibling factors. Moreover, respiratory function was affected in patients with previous cancer (p = 0.031). Conclusions: Occupational exposure and previous cancer to reproductive organs or breast could be linked to ALS patients. In addition, hypertension and previous cancer could affect their BMI and respiratory function. Other factors such as longer smoking periods and exposition to older siblings could also characterize ALS patients.}, } @article {pmid39407580, year = {2024}, author = {Forleo, T and Giannossa, LC and De Juan Capdevila, A and Lagioia, G and Mangone, A}, title = {Hats Off to Modeling! Profiling Early Synthetic Dyes on Historic Woolen Samples with ATR-FTIR Spectroscopy and Multivariate Curve Resolution-Alternating Least Square Algorithm.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {19}, pages = {}, pmid = {39407580}, issn = {1420-3049}, abstract = {This research focuses on analyzing wool samples dyed with synthetic dyes from the early 20th century. A methodology to identify and distinguish wool fibers dyed with azo, triphenylmethane, and xanthene dyes, which are no longer in use, using the ATR-FTIR spectra, is presented. Firstly, the dataset was subjected to PCA, which revealed the similarities and differences among the samples, illustrating a distribution pattern based on dye classes. MCR-ALS was employed to extract the spectral profiles of the dyed fibers, thereby enhancing the efficacy of the analytical techniques and extracting the comprehensive information from a single instrument. The combination of ATR-FTIR spectroscopy with chemometric methods, such as PCA and MCR-ALS, has proven to be an effective strategy for identifying and differentiating wool fibers dyed with early azo, triphenylmethane, and xanthene dyes. This approach has demonstrated particular effectiveness in enabling rapid analysis without requiring sampling or pretreatment. Moreover, the analysis is supported by thorough bibliographic research on these no longer used colorants. In order to maximize the potential of non-destructive spectroscopic techniques, such as ATR-FTIR, the approach used has proven to be crucial. This study underscores how chemometric techniques expand the capabilities of spectroscopy, extracting extensive information from a single instrument and aligning with the goals of cultural heritage analysis.}, } @article {pmid39406675, year = {2025}, author = {Schilfarth, P and Réginault, T and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Changes in Non-invasive Ventilation Compliance in Patients With Amyotrophic Lateral Sclerosis: A Post-hoc Analysis.}, journal = {Archivos de bronconeumologia}, volume = {61}, number = {1}, pages = {47-49}, doi = {10.1016/j.arbres.2024.09.003}, pmid = {39406675}, issn = {1579-2129}, } @article {pmid39406341, year = {2024}, author = {López-Royo, T and Moreno-Martínez, L and Zaragoza, P and García-Redondo, A and Manzano, R and Osta, R}, title = {Differentially expressed lncRNAs in SOD1[G93A] mice skeletal muscle: H19, Myhas and Neat1 as potential biomarkers in amyotrophic lateral sclerosis.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240015}, pmid = {39406341}, issn = {2046-2441}, support = {//Gobierno de Aragón/ ; //Instituto de Salud Carlos III/ ; //European Union/ ; //Gobierno de España/ ; //Center for Biomedical Research/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Muscle, Skeletal/metabolism/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Biomarkers/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Gene Expression Regulation ; Gene Expression Profiling ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor function and muscle mass loss. Despite extensive research in the field, the underlying causes of ALS remain incompletely understood, contributing to the absence of specific diagnostic and prognostic biomarkers and effective therapies. This study investigates the expression of long-non-coding RNAs (lncRNAs) in skeletal muscle as a potential source of biomarkers and therapeutic targets for the disease. The expression profiles of 12 lncRNAs, selected from the literature, were evaluated across different disease stages in tissue and muscle biopsies from the SOD1[G93A] transgenic mouse model of ALS. Nine out of the 12 lncRNAs were differentially expressed, with Pvt1, H19 and Neat1 showing notable increases in the symptomatic stages of the disease, and suggesting their potential as candidate biomarkers to support diagnosis and key players in muscle pathophysiology in ALS. Furthermore, the progression of Myhas and H19 RNA levels across disease stages correlated with longevity in the SOD1[G93A] animal model, effectively discriminating between long- and short-term survival individuals, thereby highlighting their potential as prognostic indicators. These findings underscore the involvement of lncRNAs, especially H19 and Myhas, in ALS pathophysiology, offering novel insights for diagnostic, prognostic and therapeutic targets.}, } @article {pmid39406000, year = {2024}, author = {Zhang, L and Du, Y and Deng, Y and Bai, T and Wang, J and Wang, W and Ji, M}, title = {Mutations in target gene confers resistance to acetolactate synthase inhibitors in Echinochloa phyllopogon.}, journal = {Plant physiology and biochemistry : PPB}, volume = {216}, number = {}, pages = {109194}, doi = {10.1016/j.plaphy.2024.109194}, pmid = {39406000}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/antagonists & inhibitors/metabolism ; *Echinochloa/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Mutation ; *Plant Proteins/genetics/metabolism ; Plants, Genetically Modified ; Enzyme Inhibitors/pharmacology ; Arabidopsis/genetics/enzymology/drug effects ; Molecular Docking Simulation ; Sulfonamides ; Uridine/analogs & derivatives ; }, abstract = {Echinochloa phyllopogon is a noxious weed that can harm rice over prolonged periods. Recently, a penoxsulam-resistant variant of E. phyllopogon with a mutation in the acetolactate synthase (ALS) gene was collected in Northeastern China. In the present study, the molecular mechanism underlying herbicide resistance in mutant populations was evaluated. The GR50 and IC50 values of the herbicide-resistant mutant 1-11 were 27.0- and 21.4-fold higher than those of the susceptible population 2-31, respectively. In addition, pre-application of malathion reduced the GR50 value of the resistant population. Additionally, mutant populations developed cross-resistance to other ALS inhibitors. E. phyllopogon ALS sequencing showed a Trp-574-Leu mutation in ALS2 variant 1-11. Molecular docking showed that the Trp-574-Leu substitution reduced the number of hydrogen bonds and altered the interaction between penoxsulam and ALS2. Transgenic Arabidopsis plants harboring the ALS2 mutant gene also showed resistance to penoxsulam and other ALS inhibitors. Overall, our study demonstrated that the Trp-574-Leu mutation and P450-mediated metabolic resistance lead to the cross-resistance of E. phyllopogon to ALS inhibitors.}, } @article {pmid39405005, year = {2024}, author = {Cheng, JL and Cook, AL and Talbot, J and Perry, S}, title = {How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?.}, journal = {Neurotoxicity research}, volume = {42}, number = {5}, pages = {43}, pmid = {39405005}, issn = {1476-3524}, mesh = {*Induced Pluripotent Stem Cells/drug effects/physiology ; Humans ; *Neurons/drug effects/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Differentiation/drug effects/physiology ; }, abstract = {Excitotoxicity linked either to environmental causes (pesticide and cyanotoxin exposure), excitatory neurotransmitter imbalance, or to intrinsic neuronal hyperexcitability, is a pathological mechanism central to neurodegeneration in amyotrophic lateral sclerosis (ALS). Investigation of excitotoxic mechanisms using in vitro and in vivo animal models has been central to understanding ALS mechanisms of disease. In particular, advances in induced pluripotent stem cell (iPSC) technologies now provide human cell-based models that are readily amenable to environmental and network-based excitotoxic manipulations. The cell-type specific differentiation of iPSC, combined with approaches to modelling excitotoxicity that include editing of disease-associated gene variants, chemogenetics, and environmental risk-associated exposures make iPSC primed to examine gene-environment interactions and disease-associated excitotoxic mechanisms. Critical to this is knowledge of which neurotransmitter receptor subunits are expressed by iPSC-derived neuronal cultures being studied, how their activity responds to antagonists and agonists of these receptors, and how to interpret data derived from multi-parameter electrophysiological recordings. This review explores how iPSC-based studies have contributed to our understanding of ALS-linked excitotoxicity and highlights novel approaches to inducing excitotoxicity in iPSC-derived neurons to further our understanding of its pathological pathways.}, } @article {pmid39404920, year = {2024}, author = {Aiello, EN and Curti, B and Torre, S and De Luca, G and Maranzano, A and Colombo, E and Gendarini, C and Cocuzza, A and Messina, S and Doretti, A and Verde, F and Morelli, C and Silani, V and Ticozzi, N and Poletti, B}, title = {Clinical usefulness of the Verbal Fluency Index (VFI) in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39404920}, issn = {1590-3478}, support = {NA//Ministero della Salute/ ; }, abstract = {BACKGROUND: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.

METHODS: N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency - S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60"-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale - Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores.

RESULTS: The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score - regardless of whether they presented or not with a below-cutoff NoW - reported worse ECAS-Executive scores than NoW + VFI + ones.

CONCLUSIONS: The present reports support the use of the Italian VFI as a mean to validly assess ALS patients' executive status by limiting the effect of motor disabilities that might undermine their speech rate.}, } @article {pmid39404532, year = {2024}, author = {Tanioka, S and Wu, B and Ballmer, SW}, title = {Experimental demonstration of frequency- downconverted arm-length stabilization for a future upgraded gravitational wave detector.}, journal = {Optics letters}, volume = {49}, number = {20}, pages = {5763-5766}, doi = {10.1364/OL.534141}, pmid = {39404532}, issn = {1539-4794}, abstract = {Ground-based laser interferometric gravitational wave detectors (GWDs) consist of multiple optical cavity systems whose lengths need to be interferometrically controlled. An arm-length stabilization (ALS) system has played an important role in bringing these interferometers into an operational state and enhancing their duty cycle. The sensitivity of these detectors can be improved if the thermal noise of their test mass mirror coatings is reduced. Crystalline AlGaAs coatings are a promising candidate for this. However, the current ALS system with a frequency-doubled 532 nm light is no longer an option with AlGaAs coatings because the 532 nm light is absorbed by AlGaAs coatings due to the narrow bandgap of GaAs. Therefore, alternative locking schemes must be developed. In this Letter, we describe an experimental demonstration of a novel ALS scheme, to the best of our knowledge, which is compatible with AlGaAs coatings. This ALS scheme will enable the use of AlGaAs coatings in current and future terrestrial gravitational wave detectors.}, } @article {pmid39403566, year = {2024}, author = {Biswas, DD and Sethi, R and Woldeyohannes, Y and Scarrow, ER and El Haddad, L and Lee, J and ElMallah, MK}, title = {Respiratory pathology in the TDP-43 transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1430875}, pmid = {39403566}, issn = {1664-042X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in death within 2-5 years of diagnosis. Respiratory failure is the most common cause of death in ALS. Mutations in the transactive response DNA binding protein 43 (TDP-43) encoded by the TARDBP gene are associated with abnormal cellular aggregates in neurons of patients with both familial and sporadic ALS. The role of these abnormal aggregates on breathing is unclear. Since respiratory failure is a major cause of death in ALS, we sought to determine the role of TDP-43 mutations on the respiratory motor unit in the Prp-hTDP-43[A315T] mouse model - a model that expresses human TDP-43 containing the A315T mutation. We assessed breathing using whole-body plethysmography, and investigated neuropathology in hypoglossal and phrenic respiratory motor units. Postmortem studies included quantification of hypoglossal and putative phrenic motor neurons, activated microglia and astrocytes in respiratory control centers, and assessment of hypoglossal and phrenic nerves of TDP43[A315T] mice. The male TDP43[A315T] mice display an early onset of rapid progression of disease, and premature death (less than 15 weeks) compared to control mice and compared to female TDP43[A315T] mice who die between 20 and 35 weeks of age. The TDP43[A315T] mice have progressive and profound breathing deficits at baseline and during a respiratory challenge. Histologically, hypoglossal and putative phrenic motor neurons of TDP43[A315T] mice are decreased and have increased microglial and astrocyte activation, indicating pronounced neurodegeneration and neuroinflammation. Further, there is axonopathy and demyelination in the hypoglossal and phrenic nerve of TDP43[A315T] mice. Thus, the TDP-43[A315T] mice have significant respiratory pathology and neuropathology, which makes them a useful translatable model for the study of novel therapies on breathing in ALS.}, } @article {pmid39403300, year = {2024}, author = {Aminianfar, A and Fatemi, MH and Azimi, F}, title = {Comprehensive characterization of volatile compounds in Iranian black teas using chemometric analysis of GC-MS fingerprints.}, journal = {Food chemistry: X}, volume = {24}, number = {}, pages = {101859}, pmid = {39403300}, issn = {2590-1575}, abstract = {Black tea, a widely popular non-alcoholic beverage, is renowned for its unique aroma and has attracted significant attention due to its complex composition. However, the chemical profile of Iranian tea remains largely unexplored. In this research, black tea samples from key tea cultivation regions in four geographical areas in northern Iran were firstly analyzed using headspace solid-phase microextraction followed by gas chromatography-mass spectrometry (HS-SPME-GC-MS) to separate, identify, and quantify their volatile organic compounds. Subsequently, employing a robust investigative strategy, we utilized for the first time the well-known multivariate curve resolution-alternating least square (MCR-ALS) method as a deconvolution technique to analyze the complex GC-MS peak clusters of tea samples. This approach effectively addressed challenges such as severe baseline drifts, overlapping peaks, and background noise, enabling the identification of minor components responsible for the distinct flavors and tastes across various samples. The MCR-ALS technique significantly improved the resolution of spectral and elution profiles, enabling both qualitative and semi-quantitative analysis of tea constituents. Qualitative analysis involved comparing resolved peak profiles to theoretical spectra, along with retention indices, while semi-quantification was conducted using the overall volume integration (OVI) approach for volatile compounds, providing a more accurate correlation between peak areas and concentrations. The application of chemometric tools in GC-MS analysis increased the number of recognized components in four tea samples, expanding from 54 to 256 components, all with concentrations exceeding 0.1 %. Among them, 32 volatile compounds were present in every tea sample. Hydrocarbons (including alkenes, alkanes, cycloalkanes, monoterpenes and sesquiterpenes), esters and alcohols were the three major chemical classes, comprising 78 % of the total relative content of volatile compounds. Analyzing black teas from four distinct regions revealed variations not only in their volatile components but also in their relative proportions. This integrated approach provides a comprehensive understanding of the volatile chemical profiles in Iranian black teas, enhances knowledge about their unique characteristics across diverse geographical origin, and lays the groundwork for quality improvement.}, } @article {pmid39402245, year = {2024}, author = {Wood, H}, title = {Altered muscle cholesterol transport in ALS.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {11}, pages = {643}, doi = {10.1038/s41582-024-01029-8}, pmid = {39402245}, issn = {1759-4766}, } @article {pmid39402174, year = {2024}, author = {Jellinger, KA}, title = {The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {39402174}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, abstract = {Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.}, } @article {pmid39401554, year = {2025}, author = {Duarte, RRR and Nixon, DF and Powell, TR}, title = {Ancient viral DNA in the human genome linked to neurodegenerative diseases.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {765-770}, doi = {10.1016/j.bbi.2024.10.020}, pmid = {39401554}, issn = {1090-2139}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/virology ; *Endogenous Retroviruses/genetics ; *Genome, Human ; Genome-Wide Association Study ; DNA, Viral/genetics ; Amyotrophic Lateral Sclerosis/genetics/virology ; Multiple Sclerosis/genetics/virology ; Genetic Predisposition to Disease/genetics ; Brain/metabolism/virology ; Parkinson Disease/genetics/virology ; Male ; Female ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) are sequences in the human genome that originated from infections with ancient retroviruses during our evolution. Previous studies have linked HERVs to neurodegenerative diseases, but defining their role in aetiology has been challenging. Here, we used a retrotranscriptome-wide association study (rTWAS) approach to assess the relationships between genetic risk for neurodegenerative diseases and HERV expression in the brain, calculated with genomic precision.

METHODS: We analysed genetic association statistics pertaining to Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease, using HERV expression models calculated from 792 cortical samples. Robust risk factors were considered those that survived multiple testing correction in the primary analysis, which were also significant in conditional and joint analyses, and that had a posterior inclusion probability above 0.5 in fine-mapping analyses.

RESULTS: The primary analysis identified 12 HERV expression signatures associated with neurodegenerative disease susceptibility. We found one HERV expression signature robustly associated with amyotrophic lateral sclerosis on chromosome 12q14 (MER61_12q14.2) and one robustly associated with multiple sclerosis on chromosome 1p36 (ERVLE_1p36.32a). A co-expression analysis suggested that these HERVs are involved in homophilic cell adhesion via plasma membrane adhesion molecules.

CONCLUSIONS: We found HERV expression profiles robustly associated with amyotrophic lateral sclerosis and multiple sclerosis susceptibility, highlighting novel risk mechanisms underlying neurodegenerative disease, and offering potential new targets for therapeutic intervention.}, } @article {pmid39401249, year = {2024}, author = {Pérez de la Lastra Aranda, C and Tosat-Bitrián, C and Porras, G and Dafinca, R and Muñoz-Torrero, D and Talbot, K and Martín-Requero, Á and Martínez, A and Palomo, V}, title = {Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {21}, pages = {3945-3953}, doi = {10.1021/acschemneuro.4c00328}, pmid = {39401249}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy/pathology ; *Proteome/metabolism ; Precision Medicine/methods ; Motor Neurons/metabolism/drug effects ; Lymphocytes/metabolism/drug effects ; Protein Aggregates/drug effects/physiology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Drug Evaluation, Preclinical/methods ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.}, } @article {pmid39400557, year = {2024}, author = {Gelpi, E and Reinecke, R and Gaig, C and Iranzo, A and Sabater, L and Molina-Porcel, L and Aldecoa, I and Endmayr, V and Högl, B and Schmutzhard, E and Poewe, W and Pfausler, B and Popovic, M and Pretnar-Oblak, J and Leypoldt, F and Matschke, J and Glatzel, M and Erro, EM and Jerico, I and Caballero, MC and Zelaya, MV and Mariotto, S and Heidbreder, A and Kalev, O and Weis, S and Macher, S and Berger-Sieczkowski, E and Ferrari, J and Reisinger, C and Klupp, N and Tienari, P and Rautila, O and Niemelä, M and Yilmazer-Hanke, D and Guasp, M and Bloem, B and Van Gaalen, J and Kusters, B and Titulaer, M and Fransen, NL and Santamaria, J and Dawson, T and Holton, JL and Ling, H and Revesz, T and Myllykangas, L and Budka, H and Kovacs, GG and Lewerenz, J and Dalmau, J and Graus, F and Koneczny, I and Höftberger, R}, title = {Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {53}, pmid = {39400557}, issn = {1432-0533}, support = {SYNABS//Austrian Science Fund/ ; I6565-B//Austrian Science Fund/ ; T996-B30//Austrian Science Fund/ ; 01GM2208B//Bundesministerium für Bildung und Forschung/ ; 01GM2208A//Bundesministerium für Bildung und Forschung/ ; PI21/00165//Instituto de Salud Carlos III/ ; PI21/00165//Instituto de Salud Carlos III/ ; N° 825575//Horizon 2020 Framework Programme/ ; 341007//Tekniikan Akatemia/ ; TYH2022316//Helsingin Yliopisto/ ; }, mesh = {Humans ; *Tauopathies/pathology/immunology ; Middle Aged ; *Brain Stem/pathology/metabolism/immunology ; Male ; Female ; Aged ; Aged, 80 and over ; *tau Proteins/metabolism/immunology ; *Cell Adhesion Molecules, Neuronal/metabolism/immunology ; Adult ; Autoantibodies/immunology ; DNA-Binding Proteins/metabolism ; }, abstract = {Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.}, } @article {pmid39400020, year = {2024}, author = {Ali, A and A Emad, N and Sultana, N and Waheed, A and Aqil, M and Sultana, Y and Mujeeb, M}, title = {Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273319597240927044906}, pmid = {39400020}, issn = {1996-3181}, abstract = {Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.}, } @article {pmid39399380, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Automated pipeline for denoising, missing data processing, and feature extraction for signals acquired via wearable devices in multiple sclerosis and amyotrophic lateral sclerosis applications.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1402943}, pmid = {39399380}, issn = {2673-253X}, abstract = {INTRODUCTION: The incorporation of health-related sensors in wearable devices has increased their use as essential monitoring tools for a wide range of clinical applications. However, the signals obtained from these devices often present challenges such as artifacts, spikes, high-frequency noise, and data gaps, which impede their direct exploitation. Additionally, clinically relevant features are not always readily available. This problem is particularly critical within the H2020 BRAINTEASER project, funded by the European Community, which aims at developing models for the progression of Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) using data from wearable devices.

METHODS: The objective of this study is to present the automated pipeline developed to process signals and extract features from the Garmin Vivoactive 4 smartwatch, which has been chosen as the primary wearable device in the BRAINTEASER project. The proposed pipeline includes a signal processing step, which applies retiming, gap-filling, and denoising algorithms to enhance the quality of the data. The feature extraction step, on the other hand, utilizes clinical partners' knowledge and feedback to select the most relevant variables for analysis.

RESULTS: The performance and effectiveness of the proposed automated pipeline have been evaluated through pivotal beta testing sessions, which demonstrated the ability of the pipeline to improve the data quality and extract features from the data. Further clinical validation of the extracted features will be performed in the upcoming steps of the BRAINTEASER project.

DISCUSSION: Developed in Python, this pipeline can be used by researchers for automated signal processing and feature extraction from wearable devices. It can also be easily adapted or modified to suit the specific requirements of different scenarios.}, } @article {pmid39397192, year = {2024}, author = {Hamdi, N and Mueller, K and Hamza, A and Soliman, R and Onbool, E and Omran, K and Ocab, O and Freischmidt, A and Siebert, R and Ludolph, A and Fahmy, N}, title = {First insights into genotype and phenotype of familial amyotrophic lateral sclerosis in Egypt: early onset and high consanguinity.}, journal = {Frontiers of medicine}, volume = {18}, number = {6}, pages = {1115-1118}, pmid = {39397192}, issn = {2095-0225}, } @article {pmid39396990, year = {2024}, author = {Hazell, G and McCallion, E and Ahlskog, N and Sutton, ER and Okoh, M and Shaqoura, EIH and Hoolachan, JM and Scaife, T and Iqbal, S and Bhomra, A and Kordala, AJ and Scamps, F and Raoul, C and Wood, MJA and Bowerman, M}, title = {Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1[G93A] amyotrophic lateral sclerosis (ALS) mouse model.}, journal = {Skeletal muscle}, volume = {14}, number = {1}, pages = {23}, pmid = {39396990}, issn = {2044-5040}, support = {SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *TWEAK Receptor/metabolism/genetics ; *Muscle, Skeletal/metabolism/pathology ; Male ; Female ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Physical Conditioning, Animal ; Mice, Knockout ; Cytokine TWEAK/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1[G93A] ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1[G93A] ALS mice could lead to differential and potentially improved benefits.

METHODS: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1[G93A] ALS mice. To do so, Fn14 knockout mice (Fn14[-/-]) were crossed onto the SOD1[G93A] background to generate SOD1[G93A];Fn14[-/-] mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14[-/-], SOD1[G93A] and SOD1[G93A];Fn14[-/-]).

RESULTS: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1[G93A] mice. We then show that Fn14-depleted SOD1[G93A] mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size.

CONCLUSIONS: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.}, } @article {pmid39396709, year = {2024}, author = {Wu, J and Wu, J and Chen, T and Cai, J and Ren, R}, title = {Protein aggregation and its affecting mechanisms in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105880}, doi = {10.1016/j.neuint.2024.105880}, pmid = {39396709}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Protein Aggregation, Pathological/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; Protein Aggregates/physiology ; tau Proteins/metabolism ; }, abstract = {Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.}, } @article {pmid39396264, year = {2024}, author = {Bermudo Fuenmayor, S and Serrano Castro, PJ and Quiroga Subirana, P and López Palmero, S and Requena Mullor, MM and Parrón Carreño, T}, title = {Design and validation of a questionnaire for monitoring neurological dysphagia and respiratory deterioration in patients with amyotrophic lateral sclerosis (DEREDELA).}, journal = {Neurologia}, volume = {39}, number = {8}, pages = {666-674}, doi = {10.1016/j.nrleng.2024.09.003}, pmid = {39396264}, issn = {2173-5808}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Humans ; *Deglutition Disorders/diagnosis/etiology ; Surveys and Questionnaires ; Male ; Female ; Reproducibility of Results ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of unknown origin that affects the motor neurons. It has a rapid, fatal course.

METHOD: For this study, an initial questionnaire of eleven items was developed by experts in the field, who evaluated the suitability and relevance of the items.

RESULTS: The questionnaire was then applied to a pilot group of 22 patients diagnosed with ALS. Confirmatory factor analysis, based on estimating maximum likelihood, confirmed the three domains detected in the exploratory factor analysis. The reliability of the scale was tested using Cronbach's α (0.801) and the Kaiser-Meyer-Olkin test (0.770) confirmed the construct validity.

CONCLUSIONS: The DEREDELA questionnaire is valid, in terms of its content, for monitoring the neurological dysphagia and respiratory deterioration suffered by patients diagnosed with ALS.}, } @article {pmid39395841, year = {2024}, author = {Tran, M and Rhee, J and Hu, W and Magin, P and Shulruf, B}, title = {General practice trainee, supervisor and educator perspectives on the transitions in postgraduate training: a scoping review.}, journal = {Family medicine and community health}, volume = {12}, number = {4}, pages = {}, pmid = {39395841}, issn = {2009-8774}, mesh = {Humans ; *General Practice/education ; Education, Medical, Graduate ; General Practitioners/education ; Students, Medical/psychology ; }, abstract = {UNLABELLED: Transitions are a period and a process, through which there is a longitudinal adaptation in response to changing circumstances in clinical practice and responsibilities. While the experience of the transition in medical student learning and in hospital-based specialty training programmes are well described and researched, the experience of the transition in community-based postgraduate general practitioner (GP) training has not been described comprehensively.

OBJECTIVE: We aimed to identify, and categorise, the formative experiences of transitions in GP training and their impacts on personal and professional development.

DESIGN: We adopted Levac et al's scoping review methodology. Of 1543 retrieved records, 76 were selected for data extraction. Based on a combined model of the socioecological and multiple and multi-dimensional theories of transitions, data relating to the experiences of transitions were organised into contextual themes: being physical, psychosocial, organisational culture and chronological.

ELIGIBILITY CRITERIA: Empirical studies focused on general practice trainees or training, that discussed the transitions experienced in general practice training and that were published in English were included.

INFORMATION SOURCES: PubMed, MEDLINE and Web of Science databases were searched in January 2024 with no date limits for empirical studies on the transition experiences of GP into, and through, training.

RESULTS: Our findings describe context-dependent formative experiences which advance, or impede, learning and development. Time is a significant modulator of the factors contributing to more negative experiences, with some initially adverse experiences becoming more positive. Identification of the inflection point that represents a shift from initially adverse to more positive experiences of transitions may help moderate expectations for learning and performance at different stages of training.

CONCLUSION: Challenges in training can either advance development and contribute positively to professional identity formation and clinical competency, or detract from learning and potentially contribute to burnout and attrition from training programmes. These findings will assist future research in identifying predictive factors of positive and adverse experiences of transitions and may strengthen existing and nascent GP training programmes. The findings are transferable to other community-based specialty training programmes.}, } @article {pmid39395630, year = {2024}, author = {Yeewa, R and Sangphukieo, A and Jantaree, P and Wongkummool, W and Yamsri, T and Poompouang, S and Chaiyawat, P and Lo Piccolo, L and Jantrapirom, S}, title = {ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2[ALS] phenotypes in Drosophila melanogaster.}, journal = {Progress in neurobiology}, volume = {242}, number = {}, pages = {102674}, doi = {10.1016/j.pneurobio.2024.102674}, pmid = {39395630}, issn = {1873-5118}, mesh = {Animals ; *Drosophila melanogaster ; *Endoplasmic Reticulum Stress/drug effects/physiology ; *Drosophila Proteins/metabolism/genetics ; *Neurons/metabolism/drug effects ; Phenotype ; Autophagy-Related Proteins/metabolism/genetics ; Disease Models, Animal ; Animals, Genetically Modified ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2[ALS] pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2[ALS] model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2[ALS] and other ER stress-related conditions.}, } @article {pmid39395475, year = {2024}, author = {Kim, SY and Kim, M and Park, K and Hong, S}, title = {A systematic review on analytical methods of the neurotoxin β-N-methylamino-L-alanine (BMAA), and its causative microalgae and distribution in the environment.}, journal = {Chemosphere}, volume = {366}, number = {}, pages = {143487}, doi = {10.1016/j.chemosphere.2024.143487}, pmid = {39395475}, issn = {1879-1298}, mesh = {*Amino Acids, Diamino/analysis ; *Microalgae/metabolism ; *Cyanobacteria Toxins ; *Neurotoxins/analysis ; *Cyanobacteria/metabolism ; *Tandem Mass Spectrometry ; *Environmental Monitoring/methods ; Ecosystem ; Chromatography, Liquid ; Diatoms/metabolism ; Water Pollutants, Chemical/analysis/metabolism ; }, abstract = {β-N-Methylamino-L-alanine (BMAA), a neurotoxin produced by various microalgal groups, is associated with neurodegenerative diseases and is considered a major environmental factor potentially linked to sporadic amyotrophic lateral sclerosis. This study systematically reviews the analytical methods used to study BMAA in publications from 2019 to the present. It also investigates the causative microalgae of BMAA and its geographical distributions in aquatic ecosystems based on studies conducted since 2003. A comprehensive search using the Web of Science database revealed that hydrolysis for extraction (67%), followed by quantification using LC-MS/MS (LC: 84%; MS/MS: 88%), is the most commonly employed method in BMAA analysis. Among analytical methods, RPLC-MS/MS had the highest percentage (88%) of BMAA-positive results and included a high number of quality control (QC) assessments. Various genera of cyanobacteria and diatoms have been reported to produce BMAA. The widespread geographical distribution of BMAA across diverse ecosystems highlights significant environmental and public health concerns. Notably, BMAA accumulation and biomagnification are likely more potent in marine or brackish water ecosystems than in freshwater ecosystems, potentially amplifying its ecological impacts. Future research should prioritize advanced, sensitive methods, particularly LC-MS/MS with as many QC assessments as possible, and should expand investigations to identify novel microalgal producers and previously uncharted geographical areas, with a special focus on marine or brackish water ecosystems. This effort will enhance our understanding of the environmental distribution and impacts of BMAA.}, } @article {pmid39394860, year = {2024}, author = {Zhao, J and Kong, D and Zhang, G and Zhang, S and Wu, Y and Dai, C and Chen, Y and Yang, Y and Liu, Y and Wei, D}, title = {An Efficient CRISPR/Cas Cooperative Shearing Platform for Clinical Diagnostics Applications.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {52}, pages = {e202411705}, doi = {10.1002/anie.202411705}, pmid = {39394860}, issn = {1521-3773}, support = {22304031, 61890940//National Natural Science Foundation of China/ ; 2021YFC2301100//the National Key R&D Program of China/ ; XDB30000000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 23XD1420200//the Program of Shanghai Academic Research Leaders/ ; DP2020036//the Chong-qing Bayu Scholar Program/ ; 2023M730635//the China Postdoctoral Science Foundation/ ; T2425006//National Science Fund for Distinguished Young Scholars/ ; }, mesh = {*CRISPR-Cas Systems/genetics ; Humans ; Electrochemical Techniques ; Amyotrophic Lateral Sclerosis/diagnosis/genetics ; }, abstract = {The CRISPR/Cas system is a powerful genome editing tool and possesses widespread applications in molecular diagnostics, therapeutics and genetic engineering. But easy folding of the target sequences causes remarkable deterioration of the recognition and shear efficiency in the case of single Cas-CRISPR RNA (crRNA) duplex. Here, we develop a CRISPR/Cas cooperative shearing (CRISPR-CS) system. Compared with traditional CRISPR/Cas system, two CRISPR/Cas-crRNA duplexes simultaneously recognize different sites in the target sequence, increasing recognition possibility and shearing efficiency. Cooperative shearing cuts more methylene blue-ssDNA reporters on the electrode, enabling unamplified nucleic acid electrochemical assay in less than 5 minutes with a detection limit of 9.5×10[-20] M, 2 to 9 orders of magnitude lower than those of other electrochemical assays. The CRISPR-CS platform detects monkeypox, human papilloma virus and amyotrophic lateral sclerosis with an accuracy up to 98.1 %, demonstrating the potential application of the efficient cooperative shearing.}, } @article {pmid39393594, year = {2024}, author = {Coppieters, R and Bouzigues, A and Jiskoot, L and Montembeault, M and Tee, BL and , and Rohrer, JD and Bruffaerts, R}, title = {A systematic review of the quantitative markers of speech and language of the frontotemporal degeneration spectrum and their potential for cross-linguistic implementation.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105909}, doi = {10.1016/j.neubiorev.2024.105909}, pmid = {39393594}, issn = {1873-7528}, mesh = {Humans ; *Frontotemporal Dementia/physiopathology/diagnosis ; *Speech/physiology ; Linguistics ; Language ; Biomarkers ; }, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disease spectrum with an urgent need for reliable biomarkers for early diagnosis and monitoring. Speech and language changes occur in the early stages of FTD and offer a potential non-invasive, early, and accessible diagnostic tool. The use of speech and language markers in this disease spectrum is limited by the fact that most studies investigate English-speaking patients. This systematic review examines the literature on psychoacoustic and linguistic features of speech that occur across the FTD spectrum across as many different languages as possible. 76 papers were identified that investigate psychoacoustic and linguistic markers in discursive speech. 75 % of these papers studied English-speaking patients. The most generalizable features found across different languages, are speech rate, articulation rate, pause frequency, total pause duration, noun-verb ratio, and total number of nouns. While there are clear interlinguistic differences across patient groups, the results show promise for implementation of cross-linguistic markers of speech and language across the FTD spectrum particularly for psychoacoustic features.}, } @article {pmid39393030, year = {2024}, author = {Aamodt, WW and Sun, C and Dahodwala, N and Elser, H and Schneider, ALC and Farrar, JT and Coe, NB and Willis, AW}, title = {End-of-Life Health Care Service Use and Cost Among Medicare Decedents With Neurodegenerative Diseases.}, journal = {Neurology}, volume = {103}, number = {9}, pages = {e209925}, pmid = {39393030}, issn = {1526-632X}, mesh = {Humans ; United States ; Male ; Female ; *Medicare/economics/statistics & numerical data ; Aged ; Retrospective Studies ; *Terminal Care/economics/statistics & numerical data ; Aged, 80 and over ; *Neurodegenerative Diseases/economics/therapy/epidemiology ; Patient Acceptance of Health Care/statistics & numerical data ; Health Care Costs/statistics & numerical data ; Emergency Service, Hospital/statistics & numerical data/economics ; Parkinson Disease/economics/therapy/epidemiology ; Hospice Care/economics/statistics & numerical data ; Alzheimer Disease/economics/therapy/epidemiology ; Amyotrophic Lateral Sclerosis/economics/therapy/epidemiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Although neurodegenerative diseases are a leading cause of death, little is known about health care utilization and cost during the end-of-life (EoL) period or how it compares with that of other life-limiting conditions. We aimed to describe and compare resource utilization among US Medicare decedents with neurodegenerative diseases with decedents with cancer.

METHODS: We conducted a retrospective study of Medicare Part A and B beneficiaries with Alzheimer disease (AD), Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS) who died in 2018. Decedents diagnosed with malignant brain tumors or pancreatic cancer served as non-neurodegenerative comparators. Descriptive analyses examined demographic and clinical characteristics in the last year of life. The probabilities and associated costs of emergency department (ED), inpatient, skilled nursing facility (SNF), and hospice utilization during the last 12 and 6 months of life were also compared between persons with neurodegenerative diseases and cancer, adjusting for sociodemographic factors and comorbidity burden.

RESULTS: A total of 1,126,799 Medicare beneficiaries died in 2018, of which 357,926 had a qualifying diagnosis. Persons with neurodegenerative diseases were older and more frequently received Medicaid assistance than persons with brain or pancreatic cancer. In all groups, health care service utilization increased over the last year of life, and total costs were predominantly attributable to inpatient care. In the last 6 months of life, neurologist care was infrequent among patients with neurodegenerative disease (AD: 1.5%; PD: 8.6%; ALS: 32.0%). Persons with neurodegenerative diseases as compared to persons with malignant brain tumors also had greater odds of ED use (AD: adjusted odds ratio [aOR] 1.17, 95% CI 1.11-1.23; PD: aOR 1.18, 95% CI 1.11-1.25; ALS: aOR 1.11, 95% CI 1.01-1.23), lower odds of hospitalization (AD: aOR 0.64, 95% CI 0.60-0.68; PD: aOR 0.65, 95% CI 0.61-0.69; ALS: aOR 0.33, 95% CI 0.30-0.37), and lower odds of hospice enrollment (AD: aOR 0.33, 95% CI 0.31-0.36; PD: aOR 0.33, 95% CI 0.31-0.36; ALS: aOR 0.41, 95% CI 0.36-0.46). The findings were similar in pancreatic cancer.

DISCUSSION: Persons with neurodegenerative diseases in the United States are more likely to visit the ED and less likely to use inpatient and hospice services at EoL than persons with brain or pancreatic cancer. These group differences may stem from prognostic uncertainty and reflect inadequate EoL care practices, requiring further investigation to ensure more timely palliative care and hospice referrals.}, } @article {pmid39392186, year = {2025}, author = {Corcia, P and Piras, R and Lunetta, C}, title = {Why is the treatment and management of amyotrophic lateral sclerosis so difficult?.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {1}, pages = {1-3}, doi = {10.1080/14737175.2024.2415002}, pmid = {39392186}, issn = {1744-8360}, } @article {pmid39392096, year = {2024}, author = {}, title = {Correction to "Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis".}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6125-6126}, doi = {10.1111/ejn.16562}, pmid = {39392096}, issn = {1460-9568}, } @article {pmid39391721, year = {2024}, author = {Hodgson, RE and Rayment, JA and Huang, WP and Sanchez Avila, A and Ellis, BCS and Lin, YH and Soni, N and Hautbergue, GM and Shelkovnikova, TA}, title = {C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology.}, journal = {iScience}, volume = {27}, number = {10}, pages = {110937}, pmid = {39391721}, issn = {2589-0042}, support = {MR/W028522/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Proteinaceous inclusions formed by C9orf72-derived dipeptide-repeat (DPR) proteins are a histopathological hallmark in ∼50% of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) cases. However, DPR aggregation/inclusion formation could not be efficiently recapitulated in cell models for four out of five DPRs. In this study, using optogenetics, we achieved chemical-free poly-PR condensation/aggregation in cultured cells including human motor neurons, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-center appearance, resembling TDP-43 anisosomes, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without stress response activation. Cytoplasmic poly-PR aggregates forming under prolonged opto-stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Thus, poly-PR condensation accompanied by nuclear TDP-43 dysfunction may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates of disease-linked proteins may represent a common molecular species in neurodegenerative disease.}, } @article {pmid39391382, year = {2024}, author = {Osaro, E and Fajardo-Rojas, F and Cooper, GM and Gómez-Gualdrón, D and Colón, YJ}, title = {Active learning of alchemical adsorption simulations; towards a universal adsorption model.}, journal = {Chemical science}, volume = {15}, number = {42}, pages = {17671-17684}, pmid = {39391382}, issn = {2041-6520}, abstract = {Adsorption is a fundamental process studied in materials science and engineering because it plays a critical role in various applications, including gas storage and separation. Understanding and predicting gas adsorption within porous materials demands comprehensive computational simulations that are often resource intensive, limiting the identification of promising materials. Active learning (AL) methods offer an effective strategy to reduce the computational burden by selectively acquiring critical data for model training. Metal-organic frameworks (MOFs) exhibit immense potential across various adsorption applications due to their porous structure and their modular nature, leading to diverse pore sizes and chemistry that serve as an ideal platform to develop adsorption models. Here, we demonstrate the efficacy of AL in predicting gas adsorption within MOFs using "alchemical" molecules and their interactions as surrogates for real molecules. We first applied AL separately to each MOF, reducing the training dataset size by 57.5% while retaining predictive accuracy. Subsequently, we amalgamated the refined datasets across 1800 MOFs to train a multilayer perceptron (MLP) model, successfully predicting adsorption of real molecules. Furthermore, by integrating MOF features into the AL framework using principal component analysis (PCA), we navigated MOF space effectively, achieving high predictive accuracy with only a subset of MOFs. Our results highlight AL's efficiency in reducing dataset size, enhancing model performance, and offering insights into adsorption phenomenon in large datasets of MOFs. This study underscores AL's crucial role in advancing computational material science and developing more accurate and less data intensive models for gas adsorption in porous materials.}, } @article {pmid39390888, year = {2024}, author = {Boran, HE and Kılınç, H and Kurtkaya Koçak, Ö and Yanık, E and Kuruoğlu, HR and Cengiz, B}, title = {Somatosensory temporal discrimination analysis reveals impaired processing in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {6}, pages = {1257-1262}, doi = {10.1002/mus.28278}, pmid = {39390888}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Evoked Potentials, Somatosensory/physiology ; Aged ; *Somatosensory Cortex/physiopathology ; Adult ; Hand/physiopathology ; Sensory Thresholds/physiology ; }, abstract = {INTRODUCTION/AIMS: While amyotrophic lateral sclerosis (ALS) is primarily characterized as a motor system disorder, there is a growing body of evidence indicating sensory involvement. This study aimed to examine the hypothesis that somatosensory processing is impaired in ALS.

METHODS: Study participants were ALS patients followed at the Neuromuscular Outpatient Unit, as well as healthy volunteers, from March 2021 to July 2023. The Medical Research Council (MRC) sum score was calculated for nine muscle groups bilaterally. The clinical status of patients was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Penn Upper Motor Neuron core. Somatosensory temporal discrimination thresholds (STDTs) were recorded on the medial and lateral parts of both hands. Somatosensory cortex excitability was investigated with the paired somatosensory evoked potentials (SEP) paradigm in a subgroup.

RESULTS: Increased STD values were detected in ALS patients compared to controls in both medial (107.66 ± 35 ms vs. 82.7 ± 32.5 ms, p = .001) and lateral (106.5 ± 34.5 ms vs. 82.9 ± 31.3 ms, p = .002) hands. There were no significant differences in STDTs among ALS patients across four regions (medial and lateral parts of the right and left hands). Amplitude ratios obtained from the paired-pulse SEP paradigm were approximately 1 for all interstimulus intervals (ISIs). STDTs did not show any correlations with motor findings or scales.

DISCUSSION: Somatosensory processing appears to be compromised among ALS patients. The lack of correlation between impaired STDT and motor findings implies that it is a purely sensory deficit in ALS.}, } @article {pmid39390661, year = {2024}, author = {Howard, IM and Babu, S and Carter, C and Sakowski, SA and Kurent, JE and Cudkowicz, ME and Feldman, EL}, title = {Priorities and Recommendations to Make ALS a Livable Disease Emanating from the 2024 National Academies of Sciences, Engineering, and Medicine Report Living with ALS.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1035-1039}, pmid = {39390661}, issn = {1531-8249}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; OT2 NS136938/NS/NINDS NIH HHS/United States ; U01 NS077179/NS/NINDS NIH HHS/United States ; U01 NS136020/NS/NINDS NIH HHS/United States ; //Charles H. Abdalian, Jr. ALS Research Fund/ ; OT2 NS136939/NS/NINDS NIH HHS/United States ; //NeuroNetwork for Emerging Therapies/ ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01TS000344//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; //American Academy of Neurology/ ; //ALS One/ ; //ALS Association/ ; UF1 NS131791/NS/NINDS NIH HHS/United States ; R01TS000327//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; 1U01NS136021-01/NH/NIH HHS/United States ; 1U01NS136020-01/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; //Scott L. Pranger/ ; //The Sean M. Healey & AMG Center for ALS/ ; 1U01NS077179-01/NH/NIH HHS/United States ; //Muscular Dystrophy Association/ ; U01 NS136021/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; //The Neurological Clinical Research Institute/ ; UF1NS131791-01/NH/NIH HHS/United States ; 1OT2NS136938-1/NH/NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; //ALS Finding a Cure/ ; OT2NS136939/NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Humans ; United States ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless, fatal neurodegenerative disease. The progressive loss of voluntary muscle function, diagnostic delays, lack of effective treatments, and challenges accessing multidisciplinary care and resources have tremendous impact on quality of life. The congressionally directed ALS committee of the National Academies of Science, Engineering, and Medicine, in their 2024 report "Living with ALS," recommends critical actions for specific United States stakeholders to make ALS a livable disease over the next decade. This review summarizes the context and recommendations of the report. Advocacy efforts are critical to make these recommendations a reality for the ALS community. ANN NEUROL 2024;96:1035-1039.}, } @article {pmid39390590, year = {2024}, author = {Vanderhaeghe, S and Prerad, J and Tharkeshwar, AK and Goethals, E and Vints, K and Beckers, J and Scheveneels, W and Debroux, E and Princen, K and Van Damme, P and Fivaz, M and Griffioen, G and Van Den Bosch, L}, title = {A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {161}, pmid = {39390590}, issn = {2051-5960}, support = {HBC.2019.2575//VLAIO Baekeland mandate/ ; 030383//Flanders Innovation & Entrepreneurship (VLAIO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Valosin Containing Protein/genetics/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Mitochondrial Permeability Transition Pore/metabolism ; *Mutation ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/genetics ; Mitochondrial Membrane Transport Proteins/genetics/metabolism ; Calcium/metabolism ; }, abstract = {Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA[+] ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP[R191Q/wt] mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.}, } @article {pmid39390534, year = {2024}, author = {Xu, M and Li, B and Li, C and Chai, P and Qiu, Q and Zheng, Z and Chen, Q and Luo, D and Xu, X and Zhou, C}, title = {Is longer axial length protective of vision-threatening diabetic retinopathy across different ages? A multicenter cohort of 736 patients.}, journal = {International journal of retina and vitreous}, volume = {10}, number = {1}, pages = {74}, pmid = {39390534}, issn = {2056-9920}, support = {22QA1407500//Shanghai Science and Technology Development Foundation/ ; SHWSRS [2022-65]//Shanghai Rising Stars of Medical Talent Youth Development Program/ ; CTCCR-2021C01//Clinical Research Innovation Plan of Shanghai General Hospital/ ; 82471104//National Natural Science Foundation of China/ ; }, abstract = {PURPOSE: Vision-threatening diabetic retinopathy (VTDR) included severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR) and clinically significant diabetic macular edema (DME). To compare the axial length (AL) and assess its influence on VTDR across different ages.

METHODS: A retrospective cohort study. Medical chart review was performed in 736 consecutive patients with VTDR. The patients were divided into young (≤ 45 years) and elderly group (> 45 years) based on their age at the diagnosis of VTDR. After at least one year of standardized treatments, all eligible patients were followed up. The main outcome measures included the presence of tractional retinal detachment (TRD) involving foveal, final best-corrected visual acuity (BCVA), the development of neovascular glaucoma (NVG), and recurrent vitreous hemorrhage (VH) post-vitrectomy. ALs were compared between two age groups. The impact of AL on clinical outcomes was determined by logistic analyses after controlling for systemic parameters.

RESULTS: The study included 144 patients ≤ 45 years and 592 patients > 45 years. Young patients had significantly longer AL than elderly participants (23.9 mm vs 23.0 mm, p < 0.001). Over a median follow-up of 25.9 months, a larger proportion of young patients developed TRD (34.7% vs 16.2%, p < 0.001) and recurrent VH (18.6% vs 10.3%, p = 0.040) than elderly patients. In elderly group, longer AL is an independent protective factor in preventing TRD (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4-0.7; P < 0.001). However, this beneficial effect was not observed in young patients.

CONCLUSIONS: Young patients with VTDR exhibited significantly longer AL but more aggressive clinical signs with compromised prognosis. In elderly group, a longer AL independently reduced the risk of TRD, while this protective effect did not exist for young patients.}, } @article {pmid39389966, year = {2024}, author = {Kamemura, K and Kozono, R and Tando, M and Okumura, M and Koga, D and Kusumi, S and Tamai, K and Okumura, A and Sekine, S and Kamiyama, D and Chihara, T}, title = {Secretion of endoplasmic reticulum protein VAPB/ALS8 requires topological inversion.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8777}, pmid = {39389966}, issn = {2041-1723}, support = {P40 OD010949/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; 21K18236//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H02479//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, mesh = {*Endoplasmic Reticulum/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Vesicular Transport Proteins/metabolism/genetics ; Cell Membrane/metabolism ; Mutation ; Protein Domains ; Membrane Proteins/metabolism/genetics ; HEK293 Cells ; Matrix Metalloproteinase 1/metabolism/genetics ; Protein Transport ; }, abstract = {VAMP-associated protein (VAP) is a type IV integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 is transported to the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis.}, } @article {pmid39386562, year = {2024}, author = {Dargan, R and Mikheenko, A and Johnson, NL and Packer, B and Li, Z and Craig, EJ and Sarbanes, SL and Bereda, C and Mehta, PR and Keuss, M and Nalls, MA and Qi, YA and Weller, CA and Fratta, P and Ryan, VH}, title = {Altered mRNA transport and local translation in iNeurons with RNA binding protein knockdown.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386562}, issn = {2692-8205}, support = {ZIA AG000547/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Neurons rely on mRNA transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA binding proteins (RBPs), including those known to be associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP knockdown on mRNA transport and local translation in iPSC-derived neurons. We find thousands of transcripts enriched in neurites and that many of these transcripts are locally translated, possibly due to the shorter length of transcripts in neurites. Loss of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS)-associated RBPs TDP-43 and hnRNPA1 lead to distinct alterations in the neuritic proteome and transcriptome. TDP-43 knockdown (KD) leads to increased neuritic mRNA and translation. In contrast, hnRNPA1 leads to increased neuritic mRNA, but not translation, and more moderate effects on local mRNA profiles, possibly due to compensation by hnRNPA3. These results highlight the crucial role of FTD/ALS-associated RBPs in mRNA transport and local translation in neurons and the importance of these processes in neuron health and disease.}, } @article {pmid39386496, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Ng, DQ and Baulch, JE and Du, M and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.23.614590}, pmid = {39386496}, issn = {2692-8205}, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo . In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT+Veh with the RT+RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, } @article {pmid39386447, year = {2024}, author = {Rodemer, W and Ra, I and Jia, E and Gujral, J and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Porta, S and Jensen, FE and Talos, DM and Lee, VM}, title = {Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.24.612703}, pmid = {39386447}, issn = {2692-8205}, abstract = {UNLABELLED: Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43ΔNLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.

SIGNIFICANCE STATEMENT: Cytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.}, } @article {pmid39386324, year = {2024}, author = {Ross, CW and Loudermilk, EL and O'Brien, JJ and Snitker, G}, title = {Lidar-derived structural-complexity data across four experimental forests.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {110955}, pmid = {39386324}, issn = {2352-3409}, abstract = {Structural complexity refers to the three-dimensional arrangement and variability of both biotic and abiotic components of an ecosystem. Metrics that characterize structural complexity are often used to manage various aspects of ecosystem function, such as light transmittance, wildlife habitat, and biological diversity. Additionally, these metrics aid in evaluating resilience to disturbance events, including hurricanes, bark-beetle outbreaks, and wildfire. Recent advances in wildland fire modelling have facilitated the integration of forest structural complexity metrics into the QUIC-Fire model, enabling real-time prediction of fire spread and behaviour by simulating interactions between fire, weather, topography, and forest structure. While QUIC-Fire is designed to be highly adaptable, model performance depends on the availability and accuracy of local data inputs. Expanding the model's usability across different regions can be facilitated by the availability of more comprehensive and high-quality data. Thus, the primary goal behind the data products we developed was to establish a basis for collaborative research across various disciplines, particularly within the focal areas of the Southern Research Station, such as forestry, wildland fire, hydrology, soil science, and cultural resources at Bent Creek, Coweeta, Escambia, and Hitchiti Experimental Forests (EFs). Airborne laser scanning (ALS) was used to collect point-cloud data for each EF during the leaf-off season to minimize interference from foliage. Subsequent processing of the raw lidar data involved outlier detection and filtering, ground and non-ground classification, and the computation of a variety of metrics representing various aspects of topography and forest structure at both the pixel-level and the tree-level. Pixel-level topographic data products include: digital elevation model (DEM), slope, aspect, topographic position index (TPI), topographic roughness index (TRI), roughness, and flow direction. Forest structural-complexity metrics include canopy height, foliar height diversity (FHD), vertical distribution ratio (VDR), canopy rugosity, crown relief ratio (CRR), understory complexity index (UCI), vertical complexity index (VCI), canopy cover, mean vegetation height, and the standard deviation of vegetation height. Tree-level data products were computed from the point cloud using multiple algorithms to perform individual tree detection (ITD) and individual tree segmentation (ITS). The datasets have been harmonized and are openly accessible through the USDA Forest Service Research Data Archive.}, } @article {pmid39385824, year = {2024}, author = {Chen, L and Chen, J and Weng, W and Wu, M and Zhou, X and Yan, P}, title = {Bibliometric analysis of microRNAs and Parkinson's disease from 2014 to 2023.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1466186}, pmid = {39385824}, issn = {1664-2295}, abstract = {BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Recent research has emphasized a significant correlation between microRNAs (miRNAs) and PD. To identify key research areas, provide a comprehensive overview of current research in various fields, and propose potential directions for future studies, a bibliometric analysis was conducted on the involvement of miRNAs in Parkinson's disease from 2014 to 2023.

METHODS: Relevant literature records were collected from the Web of Science Core Collection on February 29, 2024. Subsequently, the data underwent analysis using the Bibliometrix R package and VOSviewer (version 1.6.19).

RESULTS: The annual scientific publications on miRNAs and Parkinson's disease demonstrated an increasing trend, with an annual growth rate of 12.67%. China, the United States, and India emerged as the top three most productive countries/regions. The University of Barcelona had the highest annual publications, followed by Central South University and the Helmholtz Association. The INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES held the top position in terms of H-index and total citations, reflecting its extensive influence and prolific publication output. Kim, J., Junn, E., Hébert, S.S., and Doxakis, E. were the most frequently co-cited authors in the field. Based on the analysis of keywords, the most frequently occurring terms included "alpha-synuclein," "neurodegenerative disease," "exosome," "neuroinflammation," "oxidative stress," "autophagy," and "amyotrophic lateral sclerosis," which have emerged as prominent research topics. Concurrently, there has been notable interest in topics such as "ceRNA," "lncRNAs," "mitochondrial dysfunction," and "circular RNA."

CONCLUSION: This study focused on identifying emerging trends and critical research topics in the bibliometric analysis of microRNAs related to Parkinson's disease. These findings highlight the diverse research landscape and evolving trend of miRNA-related research in PD. The field of miRNA research in Parkinson's disease is actively exploring the underlying mechanisms of miRNA function, identifying potential diagnostic markers, and developing innovative therapeutic strategies. The results of our study offer significant contributions to researchers' ability to track contemporary developments and guide the trajectory of future research in this domain.}, } @article {pmid39385724, year = {2024}, author = {van den Bos, MAJ and Menon, P and Pavey, N and Higashihara, M and Kiernan, MC and Vucic, S}, title = {Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae317}, pmid = {39385724}, issn = {1460-2156}, abstract = {Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABA-ergic dysfunction in ALS, through recording focussed cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single pulse and novel inhibitory paired-pulse paradigms, TMS-EEG studies were undertaken on 21 ALS patients and results compared to healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30ms (P30), 60 ms (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 ms (N44), 100 ms (N100) and 280ms (N280) after T,MS stimulus. The single pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABA-ergic dysfunction. When compared to controls, the N100 component was significantly reduced (P<0.05) while the P190 component increased (P<0.05) in ALS patients. Additionally, the N44 component correlated with muscle weakness (r=-0.501, P<0.05). These finding were supported by reduced paired pulse inhibition of TEP components in ALS patients (P60, P<0.01; N100, P<0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Further, the reduction in SICI, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r=-0.698, P<0.001). In conclusion, intensive and focussed interrogation of the motor cortex utilising novel TMS-EEG combined technologies has established localised dysfunction of GABA-ergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABA-ergic circuits correlated with greater clinical disability and disease duration implying pathophysiological significance.}, } @article {pmid39385461, year = {2024}, author = {Li, X and Wicks, P and Brown, A and Shivaprasad, A and Greene, M and Crayle, J and Barnes, B and Jhooty, S and Ratner, D and Olby, N and Glass, JD and Jackson, C and Cole, N and Armon, C and Mascias Cadavid, J and Pattee, G and Mcdermott, CJ and Chang, V and Maragakis, N and Bertorini, T and Bowser, R and Bedlack, R}, title = {ALSUntangled #76: Wahls protocol.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2024.2407407}, pmid = {39385461}, issn = {2167-9223}, abstract = {The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.}, } @article {pmid39385408, year = {2024}, author = {Shekhar, AC and Alexander, A and Simms, M and Jahan, M and Haugen, A and Lu, M and Ball, R and Clement, J}, title = {Ambulance Transports from NCAA Division 1 Football Games.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {3}, pages = {266-269}, pmid = {39385408}, issn = {1945-1938}, mesh = {Humans ; *Ambulances ; Male ; Cross-Sectional Studies ; *Football ; Female ; Young Adult ; Minnesota ; Adult ; Emergency Medical Services ; Universities ; Adolescent ; Crowding ; }, abstract = {INTRODUCTION: There is significant public health interest towards providing medical care at mass-gathering events. Furthermore, mass gatherings have the potential to have a detrimental impact on the availability of already-limited municipal Emergency Medical Services (EMS) resources. This study presents a cross-sectional descriptive analysis to report broad trends regarding patients who were transported from National Collegiate Athletic Association (NCAA) Division 1 collegiate football games at a major public university in order to better inform emergency preparedness and resource planning for mass gatherings.

METHODS: Patient care reports (PCRs) from ambulance transports originating from varsity collegiate football games at the University of Minnesota across six years were examined. Pertinent information was abstracted from each PCR.

RESULTS: Across the six years of data, there were a total of 73 patient transports originating from NCAA collegiate football games: 45.2% (n = 33) were male, and the median age was 22 years. Alcohol-related chief complaints were involved in 50.7% (n = 37) of transports. In total, 31.5% of patients had an initial Glasgow Coma Scale (GCS) of less than 15. The majority (65.8%; n = 48; 0.11 per 10,000 attendees) were transported by Basic Life Support (BLS) ambulances. The remaining patients (34.2%; n = 25; 0.06 per 10,000 attendees) were transported by Advanced Life Support (ALS) ambulances and were more likely to be older, have abnormal vital signs, and have a lower GCS.

CONCLUSIONS: This analysis of ambulance transports from NCAA Division 1 collegiate football games emphasizes the prevalence of alcohol-related chief complaints, but also underscores the likelihood of more life-threatening conditions at mass gatherings. These results and additional research will help inform emergency preparedness at mass-gathering events.}, } @article {pmid39382075, year = {2025}, author = {Liang, B and Khan, M and Storts, H and Zhang, EH and Zheng, X and Xing, X and Claybon, H and Wilson, J and Li, C and Jin, N and Fishel, R and Miles, WO and Wang, JJ}, title = {Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {1}, pages = {131-140}, pmid = {39382075}, issn = {1538-8514}, support = {R01 CA251753/CA/NCI NIH HHS/United States ; R01 CA208063/CA/NCI NIH HHS/United States ; R01CA215389//National Cancer Institute (NCI)/ ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA215389/CA/NCI NIH HHS/United States ; R01 CA067007/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Nucleotidyltransferases/metabolism ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; Mice ; *Membrane Proteins/metabolism ; Humans ; *Signal Transduction/drug effects ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors/metabolism ; *Riluzole/pharmacology/therapeutic use ; CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Cell Line, Tumor ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; }, abstract = {Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.}, } @article {pmid39381976, year = {2024}, author = {Grassano, M and Moglia, C and Palumbo, F and Koumantakis, E and Cugnasco, P and Callegaro, S and Canosa, A and Manera, U and Vasta, R and De Mattei, F and Matteoni, E and Fuda, G and Salamone, P and Marchese, G and Casale, F and De Marchi, F and Mazzini, L and Mora, G and Calvo, A and Chiò, A}, title = {Reply to "Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression".}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1029}, doi = {10.1002/ana.27095}, pmid = {39381976}, issn = {1531-8249}, support = {//ALS Association/ ; //American Brain Foundation/ ; //American Academy of Neurology/ ; }, } @article {pmid39381934, year = {2024}, author = {Calati, R and Tambuzzi, S and Gravagnuolo, R and Muscatiello, L and Magrin, ME and Crippa, F and Madeddu, F and Zoja, R and Gentile, G}, title = {Suicide in prison in the North of Italy (1993-2022): a case-control study examining differences between suicides inside and outside prison.}, journal = {International clinical psychopharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1097/YIC.0000000000000569}, pmid = {39381934}, issn = {1473-5857}, abstract = {Prisoners constitute a group at suicide risk, showing higher relative rates of suicides than the general population. However, there is limited knowledge about the characteristics of those who die by suicide in Italian prisons. Based on the total sample of suicides of the Institute of Forensic Medicine of Milan (1993-2022), suicides in prison (N = 120) were matched by age and gender with cases that occurred outside prison (N = 300) and compared with them. The considered variables were sociodemographic, clinical, and suicide-related. Univariate analyses and logistic regression model were performed. In univariate analyses, suicides in prison showed higher rates of ethnicity different from white Caucasian, lower rates of depression, higher rates of alcoholism, addiction, respiratory system diseases, hepatitis, and amyotrophic lateral sclerosis, lower use of any medication, and in particular psychotropic medications, and a higher percentage of violent suicide method versus nonviolent compared to suicides outside prison. In the logistic regression model, ethnicity, depression, and addiction were the only features differentiating suicides in prison from ones outside prison. Particular attention should be paid to inmates with non-white ethnicity and those with addiction. Ensuring adequate access to psychiatric care and implementing comprehensive suicide prevention strategies within Italian prisons is crucial.}, } @article {pmid39380150, year = {2024}, author = {Meshram, VD and Balaji, R and Saravanan, P and Subbamanda, Y and Deeksha, W and Bajpai, A and Joshi, H and Bhargava, A and Patel, BK}, title = {Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.}, journal = {Chemical biology & drug design}, volume = {104}, number = {4}, pages = {e14640}, doi = {10.1111/cbdd.14640}, pmid = {39380150}, issn = {1747-0285}, support = {//Science and Engineering Research Board ; Department of Science and Technology/ ; SRG/2022/002109;SERB/CRG/2021/006856//Science Engineering Research Board, Govt. of India/ ; IFA20-PH-256//Deprartment of Science and Technology, Ministry of Science and Technology, Govt. of India, Inspire faculty fellowship/ ; }, mesh = {*Catechin/analogs & derivatives/chemistry/pharmacology/metabolism ; *DNA-Binding Proteins/metabolism/chemistry/antagonists & inhibitors ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; *Protein Binding ; Binding Sites ; Thermodynamics ; Protein Aggregates/drug effects ; Protein Domains ; }, abstract = {Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected in vitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (Kd, 7.8 μM; ΔG, -6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.}, } @article {pmid39379597, year = {2024}, author = {Fontdevila, L and Povedano, M and Domínguez, R and Boada, J and Serrano, JC and Pamplona, R and Ayala, V and Portero-Otín, M}, title = {Examining the complex Interplay between gut microbiota abundance and short-chain fatty acid production in amyotrophic lateral sclerosis patients shortly after onset of disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23497}, pmid = {39379597}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; *Gastrointestinal Microbiome ; Male ; *Fatty Acids, Volatile/metabolism ; Female ; Middle Aged ; Aged ; Adult ; Case-Control Studies ; }, abstract = {This study aimed to assess differences in the enteral microbiome of relatively recent-onset amyotrophic lateral sclerosis (ALS) patients (< 6-15 months since symptom onset) compared to healthy individuals, focusing on short-chain fatty acids (SCFAs) as potential mediators of host metabolism. We included 28 volunteers (16 ALS, 12 controls) with informed consent. No significant effect of ALS on alpha diversity (measuring the variety and abundance of species within a single sample, and indicating the health and complexity of the microbiome) was observed, but ALS patients had higher abundances of Fusobacteria and Acidobacteria. ALS subtypes influenced specific species, with increased Fusobacteria and Tenericutes in spinal ALS compared to bulbar ALS. ALS patients showed increased Enterobacter, Clostridium, Veillonella, Dialister, Turicibacter, and Acidaminococcus species and decreased Prevotella, Lactobacillus, and Butyricimonas. Correlations between species varied between ALS patients and healthy individuals and among ALS subtypes. No significant differences in SCFA concentrations were found, but spinal ALS samples showed a trend towards decreased propionate content. Relationships between SCFAs and phyla colonization differed by disease status. This study suggests distinct enteral microbiome characteristics in ALS patients, though the implications are unclear. Further research is needed to determine if these differences are causative or consequential and to explore their potential as diagnostic or therapeutic targets. The study also underscores the heterogeneity of microbiome constraints in ALS and the need for more research into ALS and SCFA metabolism.}, } @article {pmid39378795, year = {2024}, author = {Lehto, A and Schumacher, J and Kasper, E and Teipel, S and Hermann, A and Prudlo, J}, title = {Loss of the ipsilateral silent period in amyotrophic lateral sclerosis is associated with reduced white matter integrity in the motor section of the corpus callosum.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123267}, doi = {10.1016/j.jns.2024.123267}, pmid = {39378795}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/psychology ; *Corpus Callosum/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *White Matter/diagnostic imaging/pathology ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Motor Cortex/diagnostic imaging/pathology/physiopathology ; Diffusion Tensor Imaging ; Functional Laterality/physiology ; Diffusion Magnetic Resonance Imaging/methods ; Adult ; Neural Inhibition/physiology ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: Interhemispheric neurons in the motor section of the corpus callosum have an inhibitory effect on neurons of the contralateral motor cortex. Three quarters of patients with amyotrophic laterals sclerosis (ALS) show impaired transcallosal inhibition. We aimed to investigate whether structural changes co-occur with this functional impairment and to explore its phenotypic correlates.

METHODS: The demographic, clinical, and neuropsychological data of 127 ALS patients were analysed. Transcallosal inhibition was assessed with an ipsilateral silent period (iSP) protocol using transcranial magnetic stimulation. Patients were categorised based on an iSP response or its loss, and the groups were characterised by demographic, clinical, and neuropsychological variables. Diffusion-weighted images from a subset of 63 patients were analysed using tractography, and white matter (WM) structural integrity metrics were compared across groups.

RESULTS: 54 % of patients displayed iSP loss. The average free-water-corrected fractional anisotropy values within the callosal tract between the primary motor cortices were lower for patients with iSP loss compared to patients with an iSP response. There were no group differences based on other diffusivity metrics. The groups did not differ regarding any of the demographic, clinical, or neuropsychological variables.

INTERPRETATION: We found reduced WM integrity in the motor section of the corpus callosum that differentiated ALS patients with iSP loss from patients with an iSP response, but with a small effect size. Nevertheless, the underlying pathological substrate and potential genetic drivers for these structural and functional changes in a subset of ALS patients remain to be satisfactorily investigated.}, } @article {pmid39378530, year = {2025}, author = {Meng, T and Wu, W and Wang, B and Li, C and Li, J and Liu, J and Wang, J and Qie, R}, title = {Treating chronic pulmonary heart disease with traditional Chinese medicine: Systematic evaluation and mechanistic insights into the resolving phlegm and activating blood approach.}, journal = {Heart & lung : the journal of critical care}, volume = {69}, number = {}, pages = {111-126}, doi = {10.1016/j.hrtlng.2024.09.017}, pmid = {39378530}, issn = {1527-3288}, mesh = {Humans ; Chronic Disease ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Pulmonary Heart Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Chronic Pulmonary Heart Disease (CPHD) significantly impacts global health, especially among middle-aged and older adults. In China, the Traditional Chinese Medicine (TCM) technique of Resolving Phlegm and Activating Blood (RPAB) is widely used to treat CPHD, although high-quality evidence supporting its efficacy remains limited.

OBJECTIVES: The purpose of this study was to rigorously assess the clinical efficacy of RPAB for CPHD and elucidate the mechanisms underlying its primary herbal components.

METHODS: Through a detailed search of literature in both Chinese and English and strict inclusion and exclusion criteria, 18 randomized controlled trials (RCTs) were selected for meta-analysis. We identified RPAB's core herbal combinations using association rule analysis. This method statistically analyzes the frequency and correlation of herbal medicine usage. We then analyzed the chemical components of these combinations and investigated their potential intervention mechanisms on CPHD through network pharmacology.

RESULTS: The combination of RPAB with Western medicine was superior to Western medicine alone in improving blood gas analysis and pulmonary function and reducing plasma viscosity in CPHD patients. The core herbal combination identified was Astragalus membranaceus (Fisch.) Bunge, Ligusticum chuanxiong Hort. ex S. H. Qiu & al., and Stellaria alsine Grimm (ALS). This combination targeted 588 therapeutic and 27 core targets. It influenced ten core compounds across 34 pathways, primarily through the chemokine signaling pathway and the JAK-STAT signaling pathway.

CONCLUSION: RPAB with Western medicine significantly improves CPHD treatment outcomes. The study highlights the therapeutic potential of the ALS combination, which operates through multiple pathways to remodel pulmonary arteries, decrease inflammation, and lessen oxidative stress. These insights support the clinical application of RPAB in CPHD treatment and open new avenues for research and therapeutic development.}, } @article {pmid39378421, year = {2024}, author = {Knox, L and Coates, E and Griffiths, A and Ali, Y and Hobson, E and McDermott, C}, title = {Development and Evaluation of the Telehealth in Motor Neuron Disease System: The TIME Study Protocol.}, journal = {JMIR research protocols}, volume = {13}, number = {}, pages = {e57685}, pmid = {39378421}, issn = {1929-0748}, mesh = {*Motor Neuron Disease/therapy ; Humans ; *Telemedicine ; Surveys and Questionnaires ; Caregivers/psychology ; }, abstract = {BACKGROUND: For more responsive care provision for motor neuron disease and caregivers, a digital system called Telehealth in MND-Care (TiM-C) was created. TiM-C sends regular symptom questionnaires to users; their responses are sent to health care professionals (HCPs). To enable people with motor neuron disease to participate in research studies more easily, a parallel platform was developed from TiM-C, called Telehealth in MND-Research (TiM-R). TiM-R can advertise studies, collect data, and make them available to MND researchers.

OBJECTIVE: This study has 4 work packages (WPs) to facilitate service approval, codevelop the TiM systems, and evaluate the service. Each WP aims to understand (1) what helps and hinders the approval of the TiM-C system as a National Health Service; (2) what aspects of MND care and research are currently unmet and can be addressed through the TiM-C and TiM-R systems; (3) how TiM-C influences MND care, from the perspective of people with motor neuron disease, their caregivers, and HCPs; and (4) the costs and benefits associated with TiM-C.

METHODS: WP1 will use semistructured interviews with 10-15 people involved in the approval of TiM-C to understand the barriers and facilitators to governance processes. WP2 will use individual and group interviews with 25-35 users (people with motor neuron disease, caregivers, HCPs, MND researchers, and industry) of TiM-C and TiM-R to understand the current unmet needs of these user groups and how TiM services can be developed to meet these needs. WP3 will use a process evaluation involving 5 elements; local context, engagement, user experiences, service impact, and mechanisms of action. A range of methods, including audits, analysis of routine data, questionnaires, interviews, and observations will be used with people with motor neuron disease, caregivers, and HCPs, both those using the system and those who declined the service when invited. WP4 will use data collected through the process evaluation and known costs to conduct a cost-consequence and budget impact analysis to explore the cost-benefit of the TiM-C service. Most data collected will be qualitative, with thematic and framework analysis used to develop themes from transcripts and observations. Descriptive statistics or t tests and chi-square tests will be used to describe and analyze quantitative data.

RESULTS: This study has received ethical approval and has begun recruitment in 1 site. Further, 13 specialist MND centers will adopt TiM-C and the TIME study, beginning in July 2024. The study will conclude in November 2026 and a final report will be produced 3 months after the completion date.

CONCLUSIONS: This study will facilitate the implementation and development of TiM-C and TiM-R and fully evaluate the TiM-C service, enabling informed decision-making among health care providers regarding continued involvement and contribute to the wider literature relating to how technology-enabled care services can affect clinical care.

DERR1-10.2196/57685.}, } @article {pmid39377567, year = {2024}, author = {Rani, P and Rajak, BK and Mahato, GK and Rathore, RS and Chandra, G and Singh, DV}, title = {Strategic lead compound design and development utilizing computer-aided drug discovery (CADD) to address herbicide-resistant Phalaris minor in wheat fields.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8455}, pmid = {39377567}, issn = {1526-4998}, support = {//Science and Engineering Research Board, India/ ; //Department of Biotechnology, Ministry of Science and Technology, India/ ; //Department of Science and Technology, Ministry of Science and Technology, India/ ; }, abstract = {Wheat (Triticum aestivum) is a vital cereal crop and a staple food source worldwide. However, wheat grain productivity has significantly declined as a consequence of infestations by Phalaris minor. Traditional weed control methods have proven inadequate owing to the physiological similarities between P. minor and wheat during early growth stages. Consequently, farmers have turned to herbicides, targeting acetyl-CoA carboxylase (ACCase), acetolactate synthase (ALS) and photosystem II (PSII). Isoproturon targeting PSII was introduced in mid-1970s, to manage P. minor infestations. Despite their effectiveness, the repetitive use of these herbicides has led to the development of herbicide-resistant P. minor biotypes, posing a significant challenge to wheat productivity. To address this issue, there is a pressing need for innovative weed management strategies and the discovery of novel herbicide molecules. The integration of computer-aided drug discovery (CADD) techniques has emerged as a promising approach in herbicide research, that facilitates the identification of herbicide targets and enables the screening of large chemical libraries for potential herbicide-like molecules. By employing techniques such as homology modelling, molecular docking, molecular dynamics simulation and pharmacophore modelling, CADD has become a rapid and cost-effective medium to accelerate the herbicide discovery process significantly. This approach not only reduces the dependency on traditional experimental methods, but also enhances the precision and efficacy of herbicide development. This article underscores the critical role of bioinformatics and CADD in developing next-generation herbicides, offering new hope for sustainable weed management and improved wheat cultivation practices. © 2024 Society of Chemical Industry.}, } @article {pmid39376539, year = {2024}, author = {Kouchmeshky, A and Whiting, A and McCaffery, P}, title = {Neuroprotective effects of ellorarxine in neuronal models of degeneration.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422294}, pmid = {39376539}, issn = {1662-4548}, abstract = {INTRODUCTION: Retinoic acid (RA) was first recognised to be important for the central nervous system (CNS) in its developmental regulatory role and, given this action, it has been proposed in the adult CNS to regulate plasticity and promote regeneration. These types of roles have included support of neurogenesis, induction of neurite outgrowth, and protection from neuronal death. These functions are predominantly mediated by the retinoic acid receptor (RAR) transcription factor, and hence agonists for the RARs have been tested in a variety of models of neurodegeneration. This present study employs several in vitro models less explored for the action of RAR agonists to reverse neurodegeneration.

METHODS: A series of assays are used in which neuronal cells are placed under the types of stress that have been linked to neurodegeneration, in particular amyotrophic lateral sclerosis (ALS), and the neuroprotective influence of a new potent agonist for RAR, ellorarxine, is tested out. In these assays, neuronal cells were subjected to excitotoxic stress induced by glutamate, proteostasis disruption caused by epoxomicin, and oxidative stress leading to stress granule formation triggered by sodium arsenite.

RESULTS: Ellorarxine effectively reversed neuronal death in excitotoxic and proteostasis disruption assays and mitigated stress granule formation induced by sodium arsenite. This study also highlights for the first time the novel observation of RAR modulation of stress granules, although it is unknown whether this change in stress granules will be neuroprotective or potentially regenerative. Furthermore, the distribution of RAR agonists following intraperitoneal injection was assessed in mice, revealing preferential accumulation in the central nervous system, particularly in the spinal cord, compared to the liver. Gene expression studies in the spinal cord demonstrated that ellorarxine induces transcriptional changes at a low dose (0.01 mg/kg).

DISCUSSION: These findings underscore the therapeutic potential of RAR agonists, such as ellorarxine, for ALS and potentially other neurodegenerative diseases.}, } @article {pmid39376212, year = {2024}, author = {Tomiyama, ALMR and Cartarozzi, LP and de Oliveira Coser, L and Chiarotto, GB and Oliveira, ALR}, title = {Corrigendum: Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1493884}, doi = {10.3389/fncel.2024.1493884}, pmid = {39376212}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2023.1211486.].}, } @article {pmid39375835, year = {2024}, author = {Altomare, D and Bracca, V and Premi, E and Micheli, A and Cotelli, MS and Gasparotti, R and Alberici, A and Borroni, B}, title = {Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.}, journal = {Psychiatry and clinical neurosciences}, volume = {78}, number = {12}, pages = {818-825}, pmid = {39375835}, issn = {1440-1819}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Frontotemporal Dementia/diagnostic imaging/physiopathology/pathology ; Longitudinal Studies ; Magnetic Resonance Imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; }, abstract = {AIM: Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes.

METHODS: This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory.

RESULTS: A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P < 0.05); was associated with younger age (odds ratio [OR] = 0.96 [95% CI: 0.94-0.99]), (P = 0.003) and positive family history for dementia (OR = 2.03 [95% CI: 1.18-3.49], P = 0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR = 1.08 [95% CI: 1.06-1.10], P < 0.001) and with the presence of several behavioral symptoms (P < 0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (β = +0.15, P = 0.011) or semantic variant of primary progressive aphasia (β = +0.34, P = 0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P < 0.05).

CONCLUSION: Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.}, } @article {pmid39375041, year = {2024}, author = {Shah, NM and Rossel, A and Abdulaziz, B and Sheridan, S and Madden-Scott, S and Radcliffe, G and D'Cruz, R and Suh, ES and Steier, J and Hart, N and Murphy, PB and Ramsay, M and Kaltsakas, G}, title = {Effect of nostril occlusion and mouth sealing in the measurement of sniff nasal inspiratory pressure.}, journal = {Thorax}, volume = {80}, number = {1}, pages = {42-44}, doi = {10.1136/thorax-2024-221910}, pmid = {39375041}, issn = {1468-3296}, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Respiratory Muscles/physiology/physiopathology ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Inhalation/physiology ; *Mouth ; Adult ; Nose ; Muscle Strength/physiology ; Respiratory Function Tests/methods ; }, abstract = {Sniff nasal inspiratory pressure (SNIP) is used to assess respiratory muscle strength in neuromuscular diseases like amyotrophic lateral sclerosis (ALS). The effect of contralateral nostril occlusion and mouth sealing on SNIP measurement are unclear. 81 participants were included (16 healthy, 39 patients with limb-onset ALS and 26 patients with bulbar-onset ALS). SNIP was obtained with combinations of mouth open/sealed and contralateral nostril open/occluded. Occluding the contralateral nostril (with mouth closed) increased SNIP by 12 cmH2O (95% CI 4, 20; p=0.003) in the healthy participants, by 9 cmH2O (95% CI 5, 12; p<0.001) in the limb-onset cohort and by 10 cmH2O (95% CI 5, 14; p<0.001) in the bulbar-onset cohort. Opening the mouth decreased SNIP by 19 cmH2O (95% CI 5, 34; p<0.009) in healthy participants, by 8 cmH2O (95% CI 4, 13; p<0.001) in the limb-onset cohort and by 13 cmH2O (95% CI 7, 19; p<0.001) in the bulbar-onset cohort. With contralateral nostril occlusion, 11% fewer individuals would have qualified for non-invasive ventilation. In conclusion, contralateral nostril occlusion increased SNIP compared with standard technique, likely reflecting true strength. Opening the mouth reduced SNIP, emphasising the need for good mouth sealing. Documenting SNIP technique is important for longitudinal assessments and clinical decision-making.}, } @article {pmid39374890, year = {2024}, author = {Zhang, J and Liu, L and Li, M and Liu, H and Gong, X and Tang, Y and Zhang, Y and Zhou, X and Lin, Z and Guo, H and Pan, L}, title = {Molecular Basis of the Recognition of the Active Rab8a by Optineurin.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168811}, doi = {10.1016/j.jmb.2024.168811}, pmid = {39374890}, issn = {1089-8638}, mesh = {*rab GTP-Binding Proteins/metabolism/chemistry/genetics ; *Cell Cycle Proteins/metabolism/chemistry/genetics ; *Membrane Transport Proteins/metabolism/chemistry/genetics ; Humans ; *Protein Binding ; *Transcription Factor TFIIIA/metabolism/genetics/chemistry ; Models, Molecular ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Crystallography, X-Ray ; GTPase-Activating Proteins/metabolism/chemistry/genetics ; Mutation ; Protein Conformation ; }, abstract = {Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitate the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism. Here, using biochemical and structural approaches, we systematically characterize the interaction between OPTN and Rab8a, revealing that OPTN selectively recognizes the GTP-bound active Rab8a through its leucine-zipper domain (LZD). The determined crystal structure of OPTN LZD in complex with the active Rab8a not only elucidates the detailed binding mechanism of OPTN with Rab8a but also uncovers a unique binding mode of Rab8a with its effectors. Furthermore, we demonstrate that the central coiled-coil domain of OPTN and the active Rab8a can simultaneously interact with the TBC domain of TBC1D17 to form a ternary complex. Finally, based on the OPTN LZD/Rab8a complex structure and relevant biochemical analyses, we also evaluate several known ALS-associated mutations found in the LZD of OPTN. Collectively, our findings provide mechanistic insights into the interaction of OPTN with Rab8a, expanding our understanding of the binding modes of Rab8a with its effectors and the potential etiology of diseases caused by OPTN mutations.}, } @article {pmid39374680, year = {2024}, author = {Tirassa, P and Rosso, P and Fico, E and Marenco, M and Mallone, F and Gharbiya, M and Lambiase, A and Severini, C}, title = {Perspective role of Substance P in Amyotrophic Lateral Sclerosis: From neuronal vulnerability to neuroprotection.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105914}, doi = {10.1016/j.neubiorev.2024.105914}, pmid = {39374680}, issn = {1873-7528}, mesh = {*Substance P/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Humans ; Animals ; Receptors, Neurokinin-1/metabolism ; Neuroprotection/physiology ; Motor Neurons/metabolism/physiology ; }, abstract = {The neuropeptide Substance P (SP) and its preferred Neurokinin1 Receptor (NK1R) are known to participate in the physiopathology of neurodegenerative diseases and mainly exert a neuroprotective role. In the present work, we have described the involvement of SP and NK1R in Amyotrophic Lateral Sclerosis (ALS). This was demonstrated by the detection of altered levels of SP in the brain, spinal cord and cerebrospinal fluid (CSF) of patients and preclinical models of ALS, and by its ability to inhibit excitotoxicity-induced neurodegeneration in ALS animal models. These data are supported by results indicating an excitatory effect of SP at the motor neuron (MN) level, which promotes locomotor activity. ALS patients are characterized by a differential susceptibility to MNs degeneration, since sphincters and extraocular muscles are classically spared. It is hypothesized that SP may play a role in the maintenance of the ocular system and the innervation of the pelvic floor by contributing directly or indirectly to the selective resistance of this subset of MNs.}, } @article {pmid39373990, year = {2024}, author = {Appel, SH and Thonhoff, JR}, title = {Barriers to Tofersen Therapy for Variant SOD1-Mediated ALS.}, journal = {JAMA neurology}, volume = {81}, number = {12}, pages = {1239-1240}, doi = {10.1001/jamaneurol.2024.3331}, pmid = {39373990}, issn = {2168-6157}, } @article {pmid39373307, year = {2024}, author = {Rajagopalan, V and Pioro, EP}, title = {Graph theory network analysis reveals widespread white matter damage in brains of patients with classic ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2024.2410281}, pmid = {39373307}, issn = {2167-9223}, abstract = {Objective: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients. Methods: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients. Results and Conclusions: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p < 0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an "axonopathy" in this ALS subtype.}, } @article {pmid39372031, year = {2024}, author = {Pillai, M and Jha, SK}, title = {Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.}, journal = {ACS omega}, volume = {9}, number = {39}, pages = {40286-40297}, pmid = {39372031}, issn = {2470-1343}, abstract = {Misfolding and aggregation of the protein remain some of the most common phenomena observed in neurodegeneration. While there exist multiple neurodegenerative disorders characterized by accumulation of distinct proteins, what remains particularly interesting is the ability of these proteins to undergo a conformational change to form aggregates. TDP-43 is one such nucleic acid binding protein whose misfolding is associated with many neurogenerative diseases including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). TDP-43 protein assumes several different conformations and oligomeric states under the diseased condition. In this review, we explore the intrinsic relationship between the conformational variability of TDP-43 protein, with a particular focus on the RRM domains, and its propensity to undergo aggregation. We further emphasize the probable mechanism behind the formation of these conformations and suggest a potential diagnostic and therapeutic strategy in the context of these conformational states of the protein.}, } @article {pmid39371851, year = {2024}, author = {Po, K and Olaivar, M}, title = {Juvenile Amyotrophic Lateral Sclerosis: A Case Report of a Rare and Aggressive Presentation in a 22-Year-Old Filipino Male.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68579}, pmid = {39371851}, issn = {2168-8184}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder primarily affecting adults, but juvenile-onset ALS is exceptionally rare. We report a rare case of a 22-year-old Filipino male patient who exhibited early-onset weakness, muscle atrophy, and tongue fasciculations, followed by rapidly progressive dysphagia and respiratory distress. Electromyography - Nerve Conduction Velocity (EMG-NCV) findings showed evidence for a chronic, active predominantly motor neuronal-axonal loss type of neuropathy involving the tongue and limb muscles bilaterally consistent with a motor neuron disease. The patient was treated with riluzole with no significant improvement in symptoms. Despite multidisciplinary interventions, the disease rapidly progressed, highlighting the challenges in managing juvenile ALS cases. This case report emphasizes the importance of considering ALS in the differential diagnosis of progressive motor dysfunction in younger patients and the complexities involved in their care.}, } @article {pmid39371161, year = {2024}, author = {Angrick, M and Luo, S and Rabbani, Q and Joshi, S and Candrea, DN and Milsap, GW and Gordon, CR and Rosenblatt, K and Clawson, L and Maragakis, N and Tenore, FV and Fifer, MS and Ramsey, NF and Crone, NE}, title = {Real-time detection of spoken speech from unlabeled ECoG signals: A pilot study with an ALS participant.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39371161}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: Brain-Computer Interfaces (BCIs) hold significant promise for restoring communication in individuals with partial or complete loss of the ability to speak due to paralysis from amyotrophic lateral sclerosis (ALS), brainstem stroke, and other neurological disorders. Many of the approaches to speech decoding reported in the BCI literature have required time-aligned target representations to allow successful training - a major challenge when translating such approaches to people who have already lost their voice.

APPROACH: In this pilot study, we made a first step toward scenarios in which no ground truth is available. We utilized a graph-based clustering approach to identify temporal segments of speech production from electrocorticographic (ECoG) signals alone. We then used the estimated speech segments to train a voice activity detection (VAD) model using only ECoG signals. We evaluated our approach using held-out open-loop recordings of a single dysarthric clinical trial participant living with ALS, and we compared the resulting performance to previous solutions trained with ground truth acoustic voice recordings.

MAIN RESULTS: Our approach achieves a median error rate of around 0.5 seconds with respect to the actual spoken speech. Embedded into a real-time BCI, our approach is capable of providing VAD results with a latency of only 10 ms.

SIGNIFICANCE: To the best of our knowledge, our results show for the first time that speech activity can be predicted purely from unlabeled ECoG signals, a crucial step toward individuals who cannot provide this information anymore due to their neurological condition, such as patients with locked-in syndrome.

CLINICAL TRIAL INFORMATION: ClinicalTrials.gov, registration number NCT03567213.}, } @article {pmid39370211, year = {2024}, author = {Kajitani, GS and Xavier, G and Villena-Rueda, BE and Karia, BTR and Santoro, ML}, title = {Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.}, journal = {Current topics in membranes}, volume = {94}, number = {}, pages = {299-336}, doi = {10.1016/bs.ctm.2024.06.002}, pmid = {39370211}, issn = {1063-5823}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Biomarkers/metabolism ; Mental Disorders/metabolism/drug therapy/therapy ; Animals ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.}, } @article {pmid39369804, year = {2024}, author = {Daniels, N and Bindoff, AD and Vickers, JC and King, AE and Collins, JM}, title = {Vulnerability of neurofilament-expressing neurons in frontotemporal dementia.}, journal = {Molecular and cellular neurosciences}, volume = {131}, number = {}, pages = {103974}, doi = {10.1016/j.mcn.2024.103974}, pmid = {39369804}, issn = {1095-9327}, mesh = {Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Aged ; *Neurons/metabolism/pathology ; *Neurofilament Proteins/metabolism ; Female ; Male ; Middle Aged ; *tau Proteins/metabolism/genetics ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.}, } @article {pmid39369616, year = {2024}, author = {Zhao, Y and Li, X and Wang, K and Iyer, G and Sakowski, SA and Zhao, L and Teener, S and Bakulski, KM and Dou, JF and Traynor, BJ and Karnovsky, A and Batterman, SA and Feldman, EL and Sartor, MA and Goutman, SA}, title = {Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {109}, number = {}, pages = {105383}, pmid = {39369616}, issn = {2352-3964}, support = {P30 ES017885/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/etiology/mortality ; Male ; Female ; *Epigenesis, Genetic ; *Occupational Exposure/adverse effects ; Middle Aged ; *DNA Methylation ; Aged ; Sex Factors ; Aging/genetics ; Case-Control Studies ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival.

METHODS: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes.

FINDINGS: Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p < 0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16-2.00, p = 0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11-2.17, p = 0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p < 0.0001) and metals (adj.p = 0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons.

INTERPRETATION: EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS.

FUNDING: NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.}, } @article {pmid39368746, year = {2024}, author = {Sharma, R and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105876}, doi = {10.1016/j.neuint.2024.105876}, pmid = {39368746}, issn = {1872-9754}, mesh = {Animals ; *Oleanolic Acid/pharmacology/therapeutic use ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Male ; *Methylmercury Compounds/toxicity ; *Glycogen Synthase Kinase 3 beta/metabolism ; *TOR Serine-Threonine Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Rats, Wistar ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Neuroprotection/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.}, } @article {pmid39368179, year = {2025}, author = {Brito, ALB and Cardoso, IF and Viegas, LP and Fausto, R}, title = {Semi-quantitative chemometric models for characterization of mixtures of sugars using infrared spectral data.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {326}, number = {}, pages = {125225}, doi = {10.1016/j.saa.2024.125225}, pmid = {39368179}, issn = {1873-3557}, mesh = {*Principal Component Analysis ; *Sugars/analysis/chemistry ; Chemometrics/methods ; Spectrophotometry, Infrared/methods ; Carbohydrates/chemistry/analysis ; }, abstract = {Sugars (saccharides) are sweet-tasting carbohydrates that are abundant in foods and play very important roles in living organisms, particularly as sources and stores of energy, and as structural elements in cellular membranes. They are desirable therapeutic targets, as they participate in multiple metabolic processes as fundamental elements. However, the physicochemical characterization of sugars is a challenging task, mostly due to the structural similarity shared by the large diversity of compounds of this family. The need for fast, accurate enough, and cost-effective analytical methods for these substances is of extreme relevance, in particular because of the recently increasing importance of carbohydrates in Medicine and food industry. With this in view, this work focused on the development of chemometric models for semi-quantitative analysis of samples of different types of sugars (glucose, galactose, mannitol, sorbose and fructose) using infrared spectra as data, as an example of application of a novel approach, where the Principal Component Analysis (PCA) score plots are used to estimate the composition (weight-%) of the mixtures of the sugars. In these plots, polygonal geometric shapes emerge in the vectorial space of the most significant principal components, that allow grouping different types of samples on the vertices, edges, faces and interior of the polygons according to the composition of the samples. This approach was applied successfully to mixtures of up to 5 sugars and shown to appropriately extract the compositional information from the hyper-redundant complex spectral data. Thought the method has been applied here to a specific problem, it shall be considered as a general procedure for the semi-quantitative analysis of other types of mixtures and applicable to other types of data reflecting their composition. In fact, the methodology appears as an efficient tool to solve three main general problems: (i) use hyper-redundant (in variables) data, as spectral information, directly and with minimum pre-treatment, to evaluate semi-quantitatively the composition of mixtures; (ii) do this for systems which produce data that can be considered rather similar; and (iii) do it for a number of substances present in the mixtures that might be greater than that usually considered in chemistry, which in general is limited to 3 components. In addition, this work also demonstrates that, similarly to the developed analysis based on the PCA score plots, the Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) chemometric method can also be used successfully for the qualitative (when used without any previous knowledge of the components present in the samples) or semi-quantitative (when the pure components spectral profiles are provided as references) analyses of mixtures of (at least) up to 5 distinct sugars.}, } @article {pmid39367779, year = {2024}, author = {Duran, S and Aydogdu, A}, title = {The effect of structured psychoeducation for caregivers of ALS patients on perceived stress, psychological resilience and self-compassion.}, journal = {Health education research}, volume = {}, number = {}, pages = {}, doi = {10.1093/her/cyae031}, pmid = {39367779}, issn = {1465-3648}, abstract = {Patients diagnosed with amyotrophic lateral sclerosis (ALS) become dependent on caregivers to meet their daily needs and perform personal care activities. For this reason, ALS is a disease that can challenge both the patient and the caregiver physically, mentally and socially. Supporting the caregiver indirectly affects the patient's quality of care and mental well-being. Therefore, this study aimed to determine the effect of a structured psychoeducation program on coping with stress, psychological resilience and self-compassion in caregivers of ALS patients. This quasi-experimental study with a pre-test-post-test control group was conducted with caregivers of 62 ALS patients in Türkiye. The study was conducted between July 2023 and February 2024. A psychoeducation program was applied to five different groups via zoom application for 6 weeks each. The survey form, Perceived Stress Scale, Brief Resilience Scale and Short Form of Self-Compassion Questionnaire were used as measurement tools. The chi-squared test and paired samples t-test were used to analyze the data. While there was no significant difference between the intervention group and the control group in the pre-test in terms of their mean scores on the coping with stress inventory, short psychological resilience scale and self-compassion scale, at the post-test, psychological resilience and self-compassion scores were significantly higher in the intervention group. This study revealed that psychoeducational programs that support caregivers are effective in increasing psychological resilience and self-compassion.}, } @article {pmid39367309, year = {2024}, author = {Makled, AF and Ali, SAM and Labeeb, AZ and Salman, SS and Shebl, DZM and Hegazy, SG and Sabal, MS}, title = {Characterization of Candida species isolated from clinical specimens: insights into virulence traits, antifungal resistance and molecular profiles.}, journal = {BMC microbiology}, volume = {24}, number = {1}, pages = {388}, pmid = {39367309}, issn = {1471-2180}, mesh = {Humans ; *Candida/genetics/pathogenicity/drug effects/isolation & purification/classification ; *Drug Resistance, Fungal/genetics ; *Antifungal Agents/pharmacology ; *Virulence Factors/genetics ; *Candidiasis/microbiology ; *Biofilms/growth & development ; *Microbial Sensitivity Tests ; Virulence/genetics ; Multiplex Polymerase Chain Reaction ; Male ; Female ; Adult ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Candida species have emerged as a significant cause of opportunistic infections. Alongside the expression of various virulence factors, the rise of antifungal resistance among Candida species presents a considerable clinical challenge.

AIM: This study aimed to identify different Candida species isolated from clinical specimens, evaluate their antifungal sensitivity patterns, identify key genes regulating virulence mechanisms using multiplex PCR and to assess any correlation between their virulence profiles and antifungal resistance patterns.

METHOD: A total of 100 Candida spp. was isolated from 630 different clinical specimens and identified to the species level. Their antifungal susceptibility was phenotypically evaluated in accordance with CLSI guidelines using the Vitek-2 Compact System. Virulence markers, including biofilm formation capacity, protease production, melanin production, coagulase production and hemolysin production, were also phenotypically detected. The genetic determinants for biofilm formation and extracellular hydrolytic enzymes were assessed using a multiplex PCR assay.

RESULTS: The prevalence of Candida spp. was 15.9%, with C. albicans (48%) and C. glabrata (16%) being the most common. C. albicans showed the highest virulence, with strong biofilm formation, and high proteinase and melanin production. Multiplex PCR revealed Hlp in 22.0%, Hwp in 80.0%, Als in 56.0%, and Sap genes in 56.0% of isolates. Virulence genes were more common in C. albicans than in non-albicans Candida (NAC). Resistance patterns significantly correlated with virulence profiles, with notable associations between flucytosine resistance and the presence of Hlp and Hwp genes.

CONCLUSION: The significant correlation between virulent markers such as germination, coagulase, hemolysin production and resistance patterns among different Candida isolates is crucial for predicting the severity and outcomes of Candida infections. This understanding aids in guiding tailored treatment strategies.}, } @article {pmid39367212, year = {2024}, author = {Cogan, G and Zaki, MS and Issa, M and Keren, B and Guillaud-Bataille, M and Renaldo, F and Isapof, A and Lallemant, P and Stevanin, G and Guillot-Noel, L and Courtin, T and Buratti, J and Freihuber, C and Gleeson, JG and Howarth, R and Durr, A and de Sainte Agathe, JM and Mignot, C}, title = {Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.}, journal = {Human genetics}, volume = {143}, number = {11}, pages = {1353-1362}, pmid = {39367212}, issn = {1432-1203}, mesh = {Humans ; Female ; Male ; *Paraparesis, Spastic/genetics ; *Pedigree ; Child ; Adolescent ; Adult ; Membrane Proteins/genetics ; Alleles ; Phenotype ; Mutation ; Child, Preschool ; Young Adult ; Intellectual Disability/genetics ; }, abstract = {Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement.}, } @article {pmid39367160, year = {2024}, author = {Metzger, M and Dukic, S and McMackin, R and Giglia, E and Mitchell, M and Bista, S and Costello, E and Peelo, C and Tadjine, Y and Sirenko, V and McManus, L and Buxo, T and Fasano, A and Chipika, R and Pinto-Grau, M and Schuster, C and Heverin, M and Coffey, A and Broderick, M and Iyer, PM and Mohr, K and Gavin, B and Pender, N and Bede, P and Muthuraman, M and Hardiman, O and Nasseroleslami, B}, title = {Distinct Longitudinal Changes in EEG Measures Reflecting Functional Network Disruption in ALS Cognitive Phenotypes.}, journal = {Brain topography}, volume = {38}, number = {1}, pages = {3}, pmid = {39367160}, issn = {1573-6792}, support = {multi-year grant 20-IIA-546//ALS Association/ ; IceBucket Award; MRCG2018-02 to B.N., McManus/Apr22/888-791 to L.M. and McMackin/Oct20/972-799 to R.M//Irish/UK Motor Neurone Disease Research Foundation/ ; GOIPD/2015/213 to B.N. and GOIPG/2017/1014 to R.M.//Irish Research Council/ ; 16/ ERCD/3854 and Royal Society/SFI URF\R1\221917 to L.M./SFI_/Science Foundation Ireland/Ireland ; Emerging Investigator Award HRB-EIA-2017-019//Health Research Board of Ireland/ ; HRA-POR-2013-246; MRCG-2018-02 and HRB ILP-POR-2022-046//Health Research Board of Ireland/ ; Project-ID 424778381-TRR 295//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; *Electroencephalography/methods ; Middle Aged ; Longitudinal Studies ; Aged ; Phenotype ; Brain/physiopathology ; Cognition/physiology ; Disease Progression ; Cognitive Dysfunction/physiopathology ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. We have shown previously that resting-state EEG captures dysfunction in motor and cognitive networks in ALS. However, the longitudinal development of these dysfunctional patterns, especially in networks linked with cognitive-behavioural functions, remains unclear. Longitudinal studies on non-motor changes in ALS are essential to further develop our understanding of disease progression, improve care and enhance the evaluation of new treatments. To address this gap, we examined 124 ALS individuals with 128-channel resting-state EEG recordings, categorised by cognitive impairment (ALSci, n = 25), behavioural impairment (ALSbi, n = 58), or non-impaired (ALSncbi, n = 53), with 12 participants meeting the criteria for both ALSci and ALSbi. Using linear mixed-effects models, we characterised the general and phenotype-specific longitudinal changes in brain network, and their association with cognitive performance, behaviour changes, fine motor symptoms, and survival. Our findings revealed a significant decline in [Formula: see text]-band spectral power over time in the temporal region along with increased [Formula: see text]-band power in the fronto-temporal region in the ALS group. ALSncbi participants showed widespread β-band synchrony decrease, while ALSci participants exhibited increased co-modulation correlated with verbal fluency decline. Longitudinal network-level changes were specific of ALS subgroups and correlated with motor, cognitive, and behavioural decline, as well as with survival. Spectral EEG measures can longitudinally track abnormal network patterns, serving as a candidate stratification tool for clinical trials and personalised treatments in ALS.}, } @article {pmid39366938, year = {2024}, author = {Hutchings, AJ and Hambrecht, B and Veh, A and Giridhar, NJ and Zare, A and Angerer, C and Ohnesorge, T and Schenke, M and Selvaraj, BT and Chandran, S and Sterneckert, J and Petri, S and Seeger, B and Briese, M and Stigloher, C and Bischler, T and Hermann, A and Damme, M and Sendtner, M and Lüningschrör, P}, title = {Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8622}, pmid = {39366938}, issn = {2041-1723}, support = {LU 2347/3-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; VORAN-2 16LW066//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; }, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Autophagy ; Disease Models, Animal ; Exocytosis ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Lysosomes/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; *Motor Neurons/metabolism ; Presynaptic Terminals/metabolism ; rab GTP-Binding Proteins/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1[G93A] following deletion of Plekhg5 in SOD1[G93A] mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.}, } @article {pmid39365785, year = {2024}, author = {Putri, KD and Guntoro, D and Ardie, SW and Hariyadi, }, title = {A new amino acid substitution in the MvALS1 gene of metsulfuron-methyl resistant biotypes Monochoria vaginalis (Burm. f.) C. Presl from West Java, Indonesia.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0308465}, pmid = {39365785}, issn = {1932-6203}, mesh = {Indonesia ; *Arylsulfonates/pharmacology ; *Amino Acid Substitution ; *Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics ; Mutation ; }, abstract = {The most bothersome weed in rice fields in the Indonesian province of West Java is Monochoria vaginalis (Burm. F.) C. Presl, an aquatic herbaceous plant. Metsulfuron-methyl has long been used in wetland rice in West Java with a high enough intensity. However, the case of Monochoria vaginalis resistance to metsulfuron-methyl herbicides in Indonesia has not been widely reported and investigated. The study aims to (1) classify the resistance level of M. vaginalis toward metsulfuron-methyl, (2) identify Target Site Resistance (TSR) mechanism mutations in the MvALS1 gene of the resistant biotype of M. vaginalis. The Whole Plant Pot Test method was utilized to assess the resistance level of Monochoria vaginalis. Following that, all samples were subjected to DNA sequencing using the PCR method to identify mutations in the MvALS1 gene from the resistant biotype. After then, this study used DUET, a server with an integrated computational methodology, to anticipate the effect of mutations on protein stability. The result showed that Monochoria vaginalis from Rawamerta, Karawang showed a moderate level of resistance to metsulfuron-methyl with a resistance ratio of 6.00, Patokbeusi, Subang showed a low level of resistance to metsulfuron-methyl with a resistance ratio of 3.89, compared to susceptible Monochoria vaginalis. Nucleotide base alignment in the MvALS1 gene revealed that base substitutions occurred in the Monochoria vaginalis biotype from Rawamerta and Patokbeusi, resulting in 5 amino acid substitutions: Ser-64-Ala, Asp-66-Glu, Asn-240-Asp, Glu-426-Asn, and Ser-469-Asn and Sukra: Ser-64-Ala, Asp-66-Glu, and Asn-240-Asp. The analysis showed that S64A, D66E, and N240D stabilize the protein, whereas E426N and S469N destabilize it. This study confirms for the first time that Ser-64-Ala, Asn-240-Asp, and Glu-426-Asn amino acid mutations were found in cases of M. vaginalis resistance to metsulfuron-methyl (ALS inhibitor).}, } @article {pmid39364420, year = {2024}, author = {Aiello, EN and Contarino, VE and Conte, G and Solca, F and Curti, B and Maranzano, A and Torre, S and Casale, S and Doretti, A and Colombo, E and Verde, F and Silani, V and Liu, C and Cinnante, C and Triulzi, FM and Morelli, C and Poletti, B and Ticozzi, N}, title = {QSM-detected iron accumulation in the cerebellar gray matter is selectively associated with executive dysfunction in non-demented ALS patients.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1426841}, pmid = {39364420}, issn = {1664-2295}, abstract = {BACKGROUND: This study aimed to assess whether quantitative susceptibility imaging (QSM)-based measures of iron accumulation in the cerebellum predict cognitive and behavioral features in non-demented amyotrophic lateral sclerosis (ALS) patients.

METHODS: A total of ALS patients underwent 3-T MRI and a clinical assessment using the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Regression models were applied to each subscale of the cognitive section of the ECAS and the ECAS-Carer Interview to examine the effect of QSM-based measures in white and gray matter (WM; GM) of the cerebellum, separately for right, left, and bilateral cerebellar regions of interest (ROIs). These effects were compared to those of cerebellar volumetrics in WM/GM, right and left hemispheres while controlling for demographics, disease status, and total intracranial volume.

RESULTS: Higher QSM measures of the cerebellar GM on the left, right, and bilateral sides significantly predicted (ps ≤ 0.003) a greater number of errors on the executive functioning (EF) subscale of the ECAS (ECAS-EF). Moreover, higher GM-related, QSM measures of the cerebellum were associated with an increased probability of a below-cut-off performance on the ECAS-EF (ps ≤ 0.024). No significant effects were observed for QSM measures of the cerebellar WM or for volumetric measures on the ECAS-EF. Other ECAS measures showed no significant effects. Bilateral QSM measures of the cerebellar GM also selectively predicted performance on backward digit span and social cognition tasks.

DISCUSSION: Iron accumulation within the cerebellar GM, particularly in the cerebellar cortices, may be associated with executive functioning deficits in non-demented ALS patients. Therefore, QSM-based measures could be useful for identifying the neural correlates of extra-motor cognitive deficits in ALS patients.}, } @article {pmid39364217, year = {2024}, author = {Samuel Olajide, T and Oyerinde, TO and Omotosho, OI and Okeowo, OM and Olajide, OJ and Ijomone, OM}, title = {Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.}, journal = {Neuroprotection}, volume = {2}, number = {3}, pages = {182-195}, pmid = {39364217}, issn = {2770-730X}, support = {K43 TW011920/TW/FIC NIH HHS/United States ; }, abstract = {The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.}, } @article {pmid39363643, year = {2024}, author = {Capelle, DP and Sabirin, W and Zulhairy-Liong, NA and Edgar, S and Goh, KJ and Ahmad-Annuar, A and Shahrizaila, N}, title = {Multistep modeling applied to a Malaysian ALS registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2024.2410280}, pmid = {39363643}, issn = {2167-9223}, abstract = {OBJECTIVE: To apply the multistep model of pathogenesis in amyotrophic lateral sclerosis (ALS) to data from a multiethnic Malaysian registry.

METHODS: Clinical data, including age at symptom onset, was collected from 289 patients who presented to our multidisciplinary clinic from 2016 until 2024. A least squares linear regression model was constructed from the logarithm of approximated incidence and the logarithm of age. Population incidence was approximated by adjusting the absolute numbers of patients in 5 year groups by the size of the general population in the respective age group.

RESULTS: A linear relationship between log of incidence versus log of age was observed, with a slope of 4.57 (95% CI, 3.3-5.8) and an r[2] value of 0.93, suggesting a 6-step process.

CONCLUSION: Progression toward symptom onset in Malaysian ALS patients appears consistent with a multistep model of disease as observed in other cohorts.}, } @article {pmid39363348, year = {2024}, author = {Chevalier, E and Audrain, M and Ratnam, M and Ollier, R and Fuchs, A and Piorkowska, K and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T and Afroz, T}, title = {Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {156}, pmid = {39363348}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; Mice ; *Disease Models, Animal ; *Frontotemporal Dementia/pathology/metabolism ; *Antibodies, Monoclonal/pharmacology ; Humans ; Mice, Transgenic ; }, abstract = {Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.}, } @article {pmid39362869, year = {2024}, author = {Ma, YY and Li, X and Yu, ZY and Luo, T and Tan, CR and Bai, YD and Xu, G and Sun, BD and Bu, XL and Liu, YH and Jin, WS and Gao, YQ and Zhou, XF and Liu, J and Wang, YJ}, title = {Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {415}, pmid = {39362869}, issn = {2158-3188}, support = {92249305//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Edaravone/pharmacology/administration & dosage ; *Cognitive Dysfunction/etiology/drug therapy/prevention & control ; Mice ; *Oxidative Stress/drug effects ; Male ; *Hypoxia/complications/drug therapy/metabolism ; *Altitude ; Antioxidants/pharmacology/administration & dosage ; Mice, Inbred C57BL ; Administration, Oral ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/administration & dosage/pharmacology ; Brain/drug effects/metabolism ; }, abstract = {Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.}, } @article {pmid39362568, year = {2024}, author = {Velasquez, E and Savchenko, E and Marmolejo-Martínez-Artesero, S and Challuau, D and Aebi, A and Pomeshchik, Y and Lamas, NJ and Vihinen, M and Rezeli, M and Schneider, B and Raoul, C and Roybon, L}, title = {TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106687}, doi = {10.1016/j.nbd.2024.106687}, pmid = {39362568}, issn = {1095-953X}, mesh = {*Astrocytes/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; Mice ; *Tumor Necrosis Factor-alpha/metabolism ; *Fibroblast Growth Factor 4/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1[G93A] mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.}, } @article {pmid39361871, year = {2025}, author = {Fernandes, JPM and Garcia, LP and Gouhie, FA and Pereira, RC and Santos, DFD}, title = {Association between motor neuron disease and HIV infection: A systematic review of case reports.}, journal = {International journal of STD & AIDS}, volume = {36}, number = {1}, pages = {24-35}, doi = {10.1177/09564624241288283}, pmid = {39361871}, issn = {1758-1052}, mesh = {Humans ; *HIV Infections/drug therapy/complications ; *Motor Neuron Disease/complications ; Adult ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Female ; Middle Aged ; Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a well-known group of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most common form. Since 1985, a possible association between MND/ALS and HIV infection has been described.

METHODS: We performed a systematic review of case reports and case series involving people living with HIV with MND/ALS through PubMed, Bireme, Embase, and Lilacs databases. The risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Case Reports.

RESULTS: We analyzed 36 articles presenting 88 cases. The mean age was 41.6 years. Antiretroviral therapy (ART) was used by 89.8% and riluzole by 16.9%. First signs and symptoms were similarly present on cervical/upper (25%) and lumbosacral/lower limbs (23.9%), mostly with fasciculations (69.8%) and hyperreflexia (58.8%). MND had a progressive course in 32.9% patients and a clinical improve in 54.6% following ART. The mean survival of the 32 patients who died was 12.3 months and the mean survival of the living patients was 62 months. Respiratory failure was the main cause of death (35.7%).

CONCLUSIONS: MND/ALS may present differently in the people living with HIV as a rapidly progressive disease in younger people but with the potential to improve weakness and survival through antiretroviral therapy.}, } @article {pmid39361759, year = {2024}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Barattucci, S and Harley, P and Mattedi, F and Mehta, PR and Pisliakova, M and Ryadnov, E and Keuss, MJ and Thompson, D and Digby, H and Knez, L and Simkin, RL and Diaz, JA and Zanovello, M and Brown, AL and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS and FTD precision medicine.}, journal = {Science (New York, N.Y.)}, volume = {386}, number = {6717}, pages = {61-69}, pmid = {39361759}, issn = {1095-9203}, support = {MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; CC0102/ARC_/Arthritis Research UK/United Kingdom ; 215593/WT_/Wellcome Trust/United Kingdom ; CC0102/CRUK_/Cancer Research UK/United Kingdom ; CC0102/MRC_/Medical Research Council/United Kingdom ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; CC0102/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Deep Learning ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/therapy ; Gene Editing ; HEK293 Cells ; *Precision Medicine ; RNA Splice Sites ; *RNA Splicing ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders.}, } @article {pmid39360635, year = {2024}, author = {Abbassi, Y and Cappelli, S and Spagnolo, E and Gennari, A and Visani, G and Barattucci, S and Paron, F and Stuani, C and Droppelmann, CA and Strong, MJ and Buratti, E}, title = {Axon guidance genes are regulated by TDP-43 and RGNEF through long-intron removal.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {19}, pages = {e70081}, doi = {10.1096/fj.202400743RR}, pmid = {39360635}, issn = {1530-6860}, support = {//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA)/ ; //Temetry Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; Introns ; Guanine Nucleotide Exchange Factors/metabolism/genetics ; Animals ; Axon Guidance/genetics ; Motor Neurons/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Gene Expression Regulation ; }, abstract = {Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA-binding protein. RGNEF is known to act as a destabilizing factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localize with inclusions of TDP-43, the major well-known RNA-binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterize their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA-binding factors that can be co-aggregated in neuronal cells. A deeper understanding of these complex scenarios may lead to a better understanding of pathogenic mechanisms occurring in patients, where more than one specific protein may be aggregating in their neurons.}, } @article {pmid39360554, year = {2024}, author = {Quigley, S and McNamara, B and Cronin, S}, title = {Alteration in ornithine metabolism due to mutation in ALDH18A1 masquerading as ALS in pregnancy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2024.2410982}, pmid = {39360554}, issn = {2167-9223}, abstract = {Clinical onset and exacerbation of autosomal dominant SPG9A hereditary spastic paraplegia, including reversible wasting, has been described during pregnancy. SPG9A is due to ALDH18A1 mutations resulting in proline and ornithine deficiency. We present the case of a 29 year old primagravida at 32 weeks who presented with six months of upper limb amyotrophic wasting on a background unrecognized progressive spasticity due to SPG9A. The wasting reversed significantly following delivery. Our report highlights the unusual clinical features including cataract and joint laxity which may suggest SPG9A, echoes the existing descriptions of pregnancy-related provocation of amyotrophy in this condition and documents the outcome of two subsequent pregnancies following dietary intervention.}, } @article {pmid39360074, year = {2024}, author = {Puri, SN and Raghuveer, R and Jachak, S and Tikhile, P}, title = {Exploring the Impact of Personalized Physical Therapy on a Patient With Motor Neuron Disorder: A Case Study.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68373}, pmid = {39360074}, issn = {2168-8184}, abstract = {This case study examines the effect of a tailor-made physiotherapy regimen on an 85-year-old male patient who was suffering from bulbar motor neuron disease (MND) and had a history of stroke and COVID-19. The physiotherapy plan was designed to strategically address the patient's respiratory issues, generalized weakness affecting limb muscles, and speech and swallowing difficulties. Frequent evaluations made it possible to adjust the treatment plan, emphasizing a holistic strategy to improve the patient's overall quality of life. Improvements in scores on multiple functional scales and manual muscle testing were shown by outcome measures and follow-up evaluations. This case emphasizes how important customized physiotherapy is for maximizing functional outcomes and enhancing the quality of life for patients dealing with the complicated conditions of bulbar MND.}, } @article {pmid39359088, year = {2025}, author = {Kim, K}, title = {Carboplatin restores neuronal toxicity in FUS-linked amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {8}, pages = {2319-2320}, doi = {10.4103/NRR.NRR-D-24-00489}, pmid = {39359088}, issn = {1673-5374}, } @article {pmid39353548, year = {2025}, author = {Bosco, DB and Kremen, V and Haruwaka, K and Zhao, S and Wang, L and Ebner, BA and Zheng, J and Xie, M and Dheer, A and Perry, JF and Barath, A and Nguyen, AT and Worrell, GA and Wu, LJ}, title = {Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {540-555}, doi = {10.1016/j.bbi.2024.09.034}, pmid = {39353548}, issn = {1090-2139}, mesh = {*Receptors, Immunologic/metabolism/genetics ; Animals ; *Status Epilepticus/metabolism/genetics ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Mice, Knockout ; Male ; *Phagocytosis/physiology/genetics ; Mice ; *Neurons/metabolism ; Humans ; Disease Models, Animal ; Kainic Acid ; Mice, Inbred C57BL ; Epilepsy, Temporal Lobe/metabolism/genetics ; Seizures/metabolism/genetics ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; }, abstract = {In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute status epilepticus and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology.}, } @article {pmid39355693, year = {2024}, author = {Leger, D and Bater, S and Paulin, MV and Linn, K and Taylor, S and Shelton, GD}, title = {Presumptive motor neuron degeneration in an adult cat.}, journal = {The Canadian veterinary journal = La revue veterinaire canadienne}, volume = {65}, number = {10}, pages = {1034-1040}, pmid = {39355693}, issn = {0008-5286}, mesh = {Cats ; Male ; Animals ; *Cat Diseases/pathology/diagnosis/drug therapy ; *Motor Neuron Disease/veterinary/pathology/diagnosis ; Prednisolone/therapeutic use ; Immunosuppressive Agents/therapeutic use ; Motor Neurons/pathology ; Muscular Atrophy/veterinary/pathology ; Muscle, Skeletal/pathology ; }, abstract = {An 8-year-old neutered male Bengal cat was referred because of a 1-year history of progressive and relapsing generalized muscle weakness and muscle atrophy. Before referral, the cat was treated with immunosuppressive doses of oral prednisolone, intermittently for 6 mo, and had responded well when the immunosuppressive dose was maintained. Generalized paresis, diffuse muscle atrophy, and diminished spinal reflexes were present in all limbs, consistent with a generalized lower motor neuron disease. Histopathologic evaluation of muscle biopsies confirmed a pattern of muscle fiber atrophy consistent with chronic and severe denervation. No specific abnormalities were identified in the nerve biopsy or within intramuscular nerve branches. A presumptive antemortem diagnosis of an adult-onset motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS) or spinal muscle atrophy was suspected. However, given the response to immunosuppressive doses of corticosteroids, an autoimmune process or other degenerative process could not be definitively excluded. Key clinical message: In this case, an adult cat had a chronic, progressive history of lower motor neuron weakness and absent spinal reflexes; biopsies revealed a neurogenic pattern of muscle fiber atrophy and histologically normal peripheral nerve and intramuscular nerve branches. Although reports of motor neuron disease are rare in the veterinary literature, this case report highlights the importance of muscle and nerve biopsies that lead to a presumptive diagnosis of motor neuron degeneration.}, } @article {pmid39355247, year = {2024}, author = {Yang, JL and Wu, JY and Liu, JJ and Zheng, GQ}, title = {Herbal medicines for SOD1[G93A] mice of amyotrophic lateral sclerosis: preclinical evidence and possible immunologic mechanism.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1433929}, pmid = {39355247}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology/genetics ; Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1/genetics ; Herbal Medicine ; }, abstract = {Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.}, } @article {pmid39352715, year = {2024}, author = {Sung, SF and Hu, YH and Chen, CY}, title = {Disambiguating Clinical Abbreviations by One-to-All Classification: Algorithm Development and Validation Study.}, journal = {JMIR medical informatics}, volume = {12}, number = {}, pages = {e56955}, pmid = {39352715}, issn = {2291-9694}, mesh = {*Natural Language Processing ; *Electronic Health Records ; Humans ; *Algorithms ; *Abbreviations as Topic ; }, abstract = {BACKGROUND: Electronic medical records store extensive patient data and serve as a comprehensive repository, including textual medical records like surgical and imaging reports. Their utility in clinical decision support systems is substantial, but the widespread use of ambiguous and unstandardized abbreviations in clinical documents poses challenges for natural language processing in clinical decision support systems. Efficient abbreviation disambiguation methods are needed for effective information extraction.

OBJECTIVE: This study aims to enhance the one-to-all (OTA) framework for clinical abbreviation expansion, which uses a single model to predict multiple abbreviation meanings. The objective is to improve OTA by developing context-candidate pairs and optimizing word embeddings in Bidirectional Encoder Representations From Transformers (BERT), evaluating the model's efficacy in expanding clinical abbreviations using real data.

METHODS: Three datasets were used: Medical Subject Headings Word Sense Disambiguation, University of Minnesota, and Chia-Yi Christian Hospital from Ditmanson Medical Foundation Chia-Yi Christian Hospital. Texts containing polysemous abbreviations were preprocessed and formatted for BERT. The study involved fine-tuning pretrained models, ClinicalBERT and BlueBERT, generating dataset pairs for training and testing based on Huang et al's method.

RESULTS: BlueBERT achieved macro- and microaccuracies of 95.41% and 95.16%, respectively, on the Medical Subject Headings Word Sense Disambiguation dataset. It improved macroaccuracy by 0.54%-1.53% compared to two baselines, long short-term memory and deepBioWSD with random embedding. On the University of Minnesota dataset, BlueBERT recorded macro- and microaccuracies of 98.40% and 98.22%, respectively. Against the baselines of Word2Vec + support vector machine and BioWordVec + support vector machine, BlueBERT demonstrated a macroaccuracy improvement of 2.61%-4.13%.

CONCLUSIONS: This research preliminarily validated the effectiveness of the OTA method for abbreviation disambiguation in medical texts, demonstrating the potential to enhance both clinical staff efficiency and research effectiveness.}, } @article {pmid39352708, year = {2024}, author = {Crose, JJ and Crose, A and Ransom, JT and Lightner, AL}, title = {Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {3-4}, pages = {111-117}, pmid = {39352708}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Extracellular Vesicles ; Male ; Middle Aged ; Female ; Pilot Projects ; Aged ; Mesenchymal Stem Cells ; Mesenchymal Stem Cell Transplantation/methods ; Infusions, Intravenous ; Adult ; Treatment Outcome ; }, abstract = {Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients.Methods: Ten ALS patients received two 10-ml intravenous infusions of the IP given 1 month apart and evaluated over 3 months.Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline.Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.}, } @article {pmid39351695, year = {2024}, author = {Wang, PS and Yang, XX and Wei, Q and Lv, YT and Wu, ZY and Li, HF}, title = {Clinical characterization and founder effect analysis in Chinese amyotrophic lateral sclerosis patients with SOD1 common variants.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2407522}, pmid = {39351695}, issn = {1365-2060}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics ; China/epidemiology ; East Asian People ; Exome Sequencing ; *Founder Effect ; Genetic Association Studies ; Haplotypes ; Mutation ; Phenotype ; *Superoxide Dismutase-1/genetics ; }, abstract = {OBJECTIVE: In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1. This study aimed to summarize the genotype-phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor.

METHODS: A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members.

RESULTS: A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2-5 years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1[V48A] fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder.

CONCLUSIONS: Our study expanded the understanding of the genotype-phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.}, } @article {pmid39351260, year = {2024}, author = {Gao, FQ and Zhu, JQ and Feng, XD}, title = {Innovative mesenchymal stem cell treatments for fatty liver disease.}, journal = {World journal of stem cells}, volume = {16}, number = {9}, pages = {846-853}, pmid = {39351260}, issn = {1948-0210}, abstract = {The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.}, } @article {pmid39350404, year = {2024}, author = {Mohan, M and Mannan, A and Kakkar, C and Singh, TG}, title = {Nrf2 and Ferroptosis: Exploring Translational Avenues for Therapeutic Approaches to Neurological Diseases.}, journal = {Current drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113894501320839240918110656}, pmid = {39350404}, issn = {1873-5592}, abstract = {Nrf2, a crucial protein involved in defense mechanisms, particularly oxidative stress, plays a significant role in neurological diseases (NDs) by reducing oxidative stress and inflammation. NDs, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, stroke, epilepsy, schizophrenia, depression, and autism, exhibit ferroptosis, iron-dependent regulated cell death resulting from lipid and iron-dependent reactive oxygen species (ROS) accumulation. Nrf2 has been shown to play a critical role in regulating ferroptosis in NDs. Age-related decline in Nrf2 expression and its target genes (HO-1, Nqo-1, and Trx) coincides with increased iron-mediated cell death, leading to ND onset. The modulation of iron-dependent cell death and ferroptosis by Nrf2 through various cellular and molecular mechanisms offers a potential therapeutic pathway for understanding the pathological processes underlying these NDs. This review emphasizes the mechanistic role of Nrf2 and ferroptosis in multiple NDs, providing valuable insights for future research and therapeutic approaches.}, } @article {pmid39349916, year = {2024}, author = {Soliman, R and Onbool, E and Omran, K and Fahmy, N}, title = {Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39349916}, issn = {1590-3478}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons. It is a growing and underestimated disease, prompting this epidemiological study to describe the characteristics of ALS in Egyptian patients.

METHODS: This is a prospective hospital based study. ALS patients were recruited consecutively from Neuromuscular Unit in Ain Shams university Hospital from December 2018 to June 2023. Demographic data and disease related parameters were recorded.

RESULTS: 203 ALS patients had a mean age of onset equal 39 years and an inter quartile range IQR of (28.00-51.00). 76% of the cases were spinal onset ALS. Median disease duration was 2 years with IQR of (1-4 years); male to female ratio was 2.5:1; 18% of patients were familial ALS (FALS), while 19% were Juvenile ALS (JALS). Median diagnostic delay was 12 ± (6-36) months. Median Amyotrophic Lateral Sclerosis Functional Rating Scale Revised scores (ALSFRS-R) at presentation was 34.5 IQR of (26.00-40.00). Also, the mean rate of disease progression ALSFRS-R decline [points/month] was 0.76 ± 0.51.

CONCLUSION: Our cohort was characterized by a younger age of onset, male predominance, more familial cases, within average Initial ALSFRS-R scores as well as diagnostic delay. Juvenile ALS patients were much more common in our population. These findings suggest an influential presence of genetic and epigenetic factors affecting the clinical phenotype of Egyptian ALS patients.}, } @article {pmid39349171, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Dupuy, C and Lefevre, A and Emond, P and Beltran, S and Gissot, V and Pisella, PJ and Blasco, H and Corcia, P}, title = {Metabolomics of basal tears in amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {The ocular surface}, volume = {34}, number = {}, pages = {363-369}, doi = {10.1016/j.jtos.2024.09.005}, pmid = {39349171}, issn = {1937-5913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis ; Male ; Female ; Prospective Studies ; Middle Aged ; *Metabolomics/methods ; Cross-Sectional Studies ; Aged ; *Tears/metabolism ; Case-Control Studies ; Biomarkers/metabolism ; Chromatography, High Pressure Liquid ; Adult ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) clinical variability, along with the lack of conclusive diagnostic instruments, result in average diagnosis delays of 9 months. This study aimed to assess whether metabolomic profiling of basal tears in ALS patients could act as a biological marker for diagnosing ALS, predicting prognosis, and discriminating between endophenotypes.

METHODS: A single-center prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. Two microliters of basal tears were collected using microcapillary glass tubes and analyzed with ultra-high performance liquid chromatography coupled with mass spectrometry. Both univariate and multivariate analyses were performed.

RESULTS: Twenty-five patients with ALS and 30 controls were included. No significant differences in metabolite levels were found between ALS and control groups (p > 0.05). The basal tear metabolome significantly discriminated bulbar and spinal forms of ALS based on 6 metabolites, among which 5 were decreased (aniline, trigonelline, caffeine, theophylline and methyl beta-D-galactoside) in the bulbar form and 1 was decreased in the spinal form (dodecanedioic acid).

CONCLUSION: This study represents the first prospective analysis of basal tear metabolomics in individuals with ALS. Despite the inability to distinguish between ALS patients and controls based on metabolic signatures, these findings could contribute to understanding the phenotypic diversity of ALS. Notably, distinct metabolic profiles were identified that differentiate between the bulbar and spinal forms of the disease.}, } @article {pmid39349054, year = {2024}, author = {Simpson, JT and Nordham, KD and Tatum, D and Haut, ER and Ali, A and Maher, Z and Goldberg, AJ and Tatebe, LC and Chang, G and Taghavi, S and Raza, S and Toraih, E and Mendiola Plá, M and Ninokawa, S and Anderson, C and Maluso, P and Keating, J and Burruss, S and Reeves, M and Craugh, LE and Shatz, DV and Bhupathi, A and Spalding, MC and LaRiccia, A and Bird, E and Noorbakhsh, MR and Babowice, J and Nelson, MC and Jacobson, LE and Williams, J and Vella, M and Dellonte, K and Hayward, TZ and Holler, E and Lieser, MJ and Berne, JD and Mederos, DR and Askari, R and Okafor, B and Etchill, E and Fang, R and Roche, SL and Whittenburg, L and Bernard, AC and Haan, JM and Lightwine, KL and Norwood, SH and Murry, J and Gamber, MA and Carrick, MM and Bugaev, N and Tatar, A}, title = {Stop the Bleed-Wait for the Ambulance or Get in the Car and Drive? A Post Hoc Analysis of an EAST Multicenter Trial.}, journal = {The American surgeon}, volume = {}, number = {}, pages = {31348241265135}, doi = {10.1177/00031348241265135}, pmid = {39349054}, issn = {1555-9823}, abstract = {Background: The Stop the Bleed campaign gives bystanders an active role in prehospital hemorrhage control. Whether extending bystanders' role to private vehicle transport (PVT) for urban penetrating trauma improves survival is unknown, but past research has found benefit to police and PVT. We hypothesized that for penetrating trauma in an urban environment, where prehospital procedures have been proven harmful, PVT improves outcomes compared to any EMS or advanced life support (ALS) transport.Methods: Post-hoc analysis of an EAST multicenter trial was performed on adult patients with penetrating torso/proximal extremity trauma at 25 urban trauma centers from 5/2019-5/2020. Patients were allocated to PVT and any EMS or ALS transport using nearest neighbor propensity score matching. Univariate analyses included Wilcoxon signed rank or McNemar's Test and logistic regression.Results: Of 1999 penetrating trauma patients in urban settings, 397 (19.9%) had PVT, 1433 (71.7%) ALS transport, and 169 (8.5%) basic life support (BLS) transport. Propensity matching yielded 778 patients, distributed equally into balanced groups. PVT patients were primarily male (90.5%), Black (71.2%), and sustained gunshot wounds (68.9%). ALS transport had significantly higher ED mortality (3.9% vs 1.9%, P = 0.03). There was no difference in in-hospital mortality rate, hospital LOS, or complications for all EMS or ALS only transport patients.Conclusion: Compared to PVT, ALS, which provides more prehospital procedures than BLS, provided no survival benefit for penetrating trauma patients in urban settings. Bystander education incorporating PVT for early arrival of penetrating trauma patients in urban settings to definitive care merits further investigation.}, } @article {pmid39347895, year = {2024}, author = {Yin, KF and Chen, T and Gu, XJ and Jiang, Z and Su, WM and Duan, QQ and Wen, XJ and Cao, B and Li, JR and Chi, LY and Chen, YP}, title = {Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39347895}, issn = {1559-1182}, support = {2022NSFSC0749//National Natural Science Fund of Sichuan/ ; 2023HXFH032//1·3·5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023YFS0269//Science and Technology Bureau Fund of Sichuan Province/ ; 81971188//National Natural Science Fund of China/ ; C2023124417//National Innovation and Entrepreneurship Training Program for College Students/ ; }, abstract = {Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs.}, } @article {pmid39347334, year = {2024}, author = {Aljehani, NS and Al-Gunaid, ST and Hobani, AH and Alhinti, MF and Khubrani, YA and Abu-Hamoud, LM and Alrayes, AA and Alharbi, LB and Sultan, AA and Turkistani, DA and Naiser, SS and Albraik, L and Alakel, AM and Alotaibi, M and Asiri, AY}, title = {Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e68008}, pmid = {39347334}, issn = {2168-8184}, abstract = {The blood-brain barrier (BBB) presents a significant challenge in treating Alzheimer's disease, as it restricts the delivery of therapeutic medications to brain tissue. Reversible breaking of the BBB using low-intensity focused ultrasound guided by magnetic resonance imaging (MRI) may benefit patients with Alzheimer's disease and other neurological illnesses, such as brain tumors, amyotrophic lateral sclerosis, and Parkinson's disease. This systematic study and meta-analysis aimed to assess aducanumab and the ultrasonography of BBB opening in Alzheimer's patients. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the study was conducted by searching six digital repositories for relevant scholarly literature, focusing on English papers published between 2015 and 2024; the data was extracted using an Excel sheet, and data was analyzed using Revman 5.4.1 software. The study's findings indicate that the groups receiving ultrasound and aducanumab treatment benefited from it; however, overall, the effect was not statistically significant (P=0.29) at 95% CI 0.86 (0.75, 1.00). With regard to side effects, the results indicate that the treatment had fewer side effects compared to the control group; however, the difference was not statistically significant (p=0.94) at 95% CI 0.93 (0.70, 1.22). The study found a positive effect of ultrasound and aducanumab on the treatment groups, but it was not statistically significant. The control group had less side effects than the treatment group. Therefore, future studies should focus on the quantity or combination of the drug that yields more effective results.}, } @article {pmid39346793, year = {2024}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Calcium accumulation or iron deposition: Delving into the temporal sequence of amyotrophic lateral sclerosis pathophysiology in the primary motor cortex.}, journal = {Ibrain}, volume = {10}, number = {3}, pages = {375-377}, pmid = {39346793}, issn = {2769-2795}, abstract = {Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, but an in vivo understanding of its early pathology remains limited. A recent study used topographic layer imaging to investigate iron and calcium accumulation in the primary motor cortex (M1) of patients with ALS compared with controls. Despite the preserved cortical thickness, ALS patients showed increased iron in layer 6 and calcium accumulation in layer 5a and the superficial layer. Calcium accumulation was particularly prominent in the low-myelin borders, potentially preceding the demyelination. This study reveals a novel in vivo pathology in ALS, suggesting that calcium dysregulation may precede iron accumulation and contribute to early M1 cell degeneration. Further investigation using quantitative susceptibility mapping and complementary techniques, such as diffusion kurtosis imaging, along with ultrahigh-field magnetic resonance imaging, into the role of calcium and early intervention strategies is warranted.}, } @article {pmid39346681, year = {2024}, author = {Fisher, RMA and Torrente, MP}, title = {Histone post-translational modification and heterochromatin alterations in neurodegeneration: revealing novel disease pathways and potential therapeutics.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1456052}, pmid = {39346681}, issn = {1662-5099}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal Dementia (FTD), and Amyotrophic lateral sclerosis (ALS) are complex and fatal neurodegenerative diseases. While current treatments for these diseases do alleviate some symptoms, there is an imperative need for novel treatments able to stop their progression. For all of these ailments, most cases occur sporadically and have no known genetic cause. Only a small percentage of patients bear known mutations which occur in a multitude of genes. Hence, it is clear that genetic factors alone do not explain disease occurrence. Chromatin, a DNA-histone complex whose basic unit is the nucleosome, is divided into euchromatin, an open form accessible to the transcriptional machinery, and heterochromatin, which is closed and transcriptionally inactive. Protruding out of the nucleosome, histone tails undergo post-translational modifications (PTMs) including methylation, acetylation, and phosphorylation which occur at specific residues and are connected to different chromatin structural states and regulate access to transcriptional machinery. Epigenetic mechanisms, including histone PTMs and changes in chromatin structure, could help explain neurodegenerative disease processes and illuminate novel treatment targets. Recent research has revealed that changes in histone PTMs and heterochromatin loss or gain are connected to neurodegeneration. Here, we review evidence for epigenetic changes occurring in AD, PD, and FTD/ALS. We focus specifically on alterations in the histone PTMs landscape, changes in the expression of histone modifying enzymes and chromatin remodelers as well as the consequences of these changes in heterochromatin structure. We also highlight the potential for epigenetic therapies in neurodegenerative disease treatment. Given their reversibility and pharmacological accessibility, epigenetic mechanisms provide a promising avenue for novel treatments. Altogether, these findings underscore the need for thorough characterization of epigenetic mechanisms and chromatin structure in neurodegeneration.}, } @article {pmid39345637, year = {2024}, author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC}, title = {Visualizing nuclear pore complex plasticity with Pan-Expansion Microscopy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345637}, issn = {2692-8205}, support = {R21 AR081661/AR/NIAMS NIH HHS/United States ; F31 HL158119/HL/NHLBI NIH HHS/United States ; R35 GM153474/GM/NIGMS NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R01 GM129308/GM/NIGMS NIH HHS/United States ; }, abstract = {Cell-type specific and environmentally-responsive plasticity in nuclear pore complex (NPC) composition and structure is an emerging area of investigation, but its molecular underpinnings remain ill defined. To understand the cause and consequence of NPC plasticity requires technologies to visualize differences within individual NPCs across the thousands in a given nucleus. We evaluate the utility of Pan Expansion Microscopy (Pan-ExM), which enables 16-20 fold isotropic cell enlargement while preserving the proteome, to reveal NPC plasticity. NPCs are robustly identified by deep learning-facilitated segmentation as tripartite structures corresponding to the nucleoplasmic ring, inner ring with central transport channel, and cytoplasmic ring, as confirmed by immunostaining. We demonstrate a range of NPC diameters with a bias for dilated NPCs at the basal nuclear surface, often in local clusters. These diameter biases are eliminated by disrupting linker of nucleoskeleton and cytoskeleton (LINC) complex-dependent connections between the nuclear envelope (NE) and the cytoskeleton, supporting that they reflect local variations in NE tension. Pan-ExM further reveals that the transmembrane nucleoporin/nup POM121 resides specifically at the nuclear ring in multiple model cell lines, surprising given the expectation that it would be a component of the inner ring like other transmembrane nups. Remarkably, however, POM121 shifts from the nuclear ring to the inner ring specifically in aged induced pluripotent stem cell derived neurons (iPSNs) from a patient with C9orf72 amyotrophic lateral sclerosis (ALS). Thus, Pan-ExM allows the visualization of changes in NPC architecture that may underlie early steps in an ALS pathomechanism. Taken together, Pan-ExM is a powerful and accessible tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.}, } @article {pmid39345438, year = {2024}, author = {Elsayyid, M and Tanis, JE and Yu, Y}, title = {In-cell processing enables rapid and in-depth proteome analysis of low-input Caenorhabditis elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345438}, issn = {2692-8205}, support = {P20 GM104316/GM/NIGMS NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; T32 GM133395/GM/NIGMS NIH HHS/United States ; }, abstract = {Caenorhabditis elegans is a widely used genetic model organism, however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming, but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach, which can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LCMS analysis, we identified over 9,400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it with conventional lysis-based methods. Our data suggest equivalent and unbiased performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower input samples, then used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD-1, a gene associated with amyotrophic lateral sclerosis (ALS). Analysis of 8,800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics analysis.}, } @article {pmid39344431, year = {2025}, author = {Quail, NPA and Leighton, DJ and Newton, J and Davidson, S and Kelly, L and McKeown, A and Chandran, S and Pal, S and Gorrie, GH}, title = {Influences of Specialist Palliative Care Team Input, Advance Care Planning, Non-Invasive Ventilation and Gastrostomy Status on Unscheduled Hospital Admissions and Place of Death for People with Motor Neuron Disease: A Retrospective Cohort Analysis.}, journal = {Journal of palliative care}, volume = {40}, number = {1}, pages = {89-97}, doi = {10.1177/08258597241283179}, pmid = {39344431}, issn = {2369-5293}, mesh = {Humans ; Male ; *Motor Neuron Disease/therapy/mortality ; Female ; *Advance Care Planning/statistics & numerical data ; Retrospective Studies ; Aged ; *Gastrostomy/statistics & numerical data ; Middle Aged ; *Palliative Care/statistics & numerical data ; *Noninvasive Ventilation/statistics & numerical data ; Aged, 80 and over ; Scotland ; Cohort Studies ; Hospitalization/statistics & numerical data ; Terminal Care/statistics & numerical data ; Adult ; }, abstract = {Objective: Motor neuron disease is a rapidly progressing neurological condition. People with life-limiting conditions generally prefer to die at home and avoid hospital admissions, with Specialist Palliative Care Team involvement often pivotal. Our aim was to investigate the role of advance care planning, Specialist Palliative Care Team input and other relevant variables on place of death and unscheduled hospital admissions in a Scottish population of people with motor neuron disease. Methods: National CARE-MND audit data, primary and secondary care data, and local Palliative Care records were interrogated. Chi-square, point-biserial correlation and binary logistic regression analysed associations (p < 0.05 statistically significant). Participants (188) were deceased, having a verified motor neuron disease diagnosis between 2015-2017, diagnosis occurring ≥28 days before death. Results: Advance care planning and Specialist Palliative Care Team input of ≥28 days were associated with increased odds of dying outside hospital (BLR:OR 3.937, CI 1.558-9.948, p = 0.004 and OR 2.657, CI 1.135-6.222, p = 0.024 respectively). Non-invasive ventilation decreased the odds of dying outside hospital (BLR:OR 0.311, CI 0.124-0.781, p = 0.013). Having a gastrostomy increased odds of ≥1 admissions in the last year of life (BLR:OR 5.142, CI 1.715-15.417, p = 0.003). Statistical significance was retained with removal of gastrostomy-related complications. Conclusion: Early Specialist Palliative Care input and advance care planning may increase the likelihood of death outside of hospital for persons with motor neuron disease. Further research is warranted into barriers of facilitating death outside of hospital with home non-invasive ventilation use and the association between gastrostomy status and unscheduled admissions.}, } @article {pmid39344228, year = {2024}, author = {Li, P and Tao, Z and Zhao, X}, title = {The Role of Osteopontin (OPN) in Regulating Microglia Phagocytosis in Nervous System Diseases.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {9}, pages = {169}, doi = {10.31083/j.jin2309169}, pmid = {39344228}, issn = {0219-6352}, mesh = {*Osteopontin/metabolism/physiology ; *Microglia/metabolism/physiology ; *Phagocytosis/physiology ; Animals ; Humans ; Nervous System Diseases/metabolism ; }, abstract = {Phagocytosis is the process by which certain cells or organelles internalise foreign substances by engulfing them and then digesting or disposing of them. Microglia are the main resident phagocytic cells in the brain. It is generally believed that microglia/macrophages play a role in guiding the brain's repair and functional recovery processes. However, the resident and invading immune cells of the central nervous system can also exacerbate tissue damage by stimulating inflammation and engulfing viable neurons. The functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon in acute brain injury because it eliminates dead cells and induces an anti-inflammatory response. Osteopontin (OPN) is a phosphorylated glycoprotein induced by injury in various tissues, including brain tissue. In acute brain injuries such as hemorrhagic stroke and ischemic stroke, OPN is generally believed to have anti-inflammatory effects. OPN can promote the reconstruction of the blood-brain barrier and up-regulate the scavenger receptor CD36. But in chronic diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), OPN can cause microglia to engulf neurons and worsen disease progression. We explored the role of OPN in promoting microglial phagocytosis in nervous system disorders.}, } @article {pmid39344189, year = {2024}, author = {Khorshidi, Z and Adibi, I and Ghasemi, M}, title = {Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {}, number = {}, pages = {}, pmid = {39344189}, issn = {1868-1891}, abstract = {INTRODUCTION: One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). Increasing age is one of the risk factors of ALS. Considering that the elderly population in the world is increasing, it is very important to identify useful and effective diagnostic and treatment methods. The purpose of this systematic review is to determine the relationship between chitotriosidase (CHIT1) level and ALS disorder.

CONTENT: Keywords "Amyotrophic Lateral Sclerosis", "Gehrig* Disease", "Charcot Disease", "Guam Disease", ALS, CHIT1 and chitotriosidase were searched in PubMed, Scopus, Web of Science and Science Direct databases without time limit on September 2023. Hundred twenty studies were obtained by searching, and finally, 14 studies were included in this study using the inclusion and exclusion criteria. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. Six studies have reported the amount of CHIT1 level quantitatively. Among these 6 studies, in 5 studies CHIT1 level in disease control was higher than healthy control (not significant) and in only one study CHIT1 level was higher in healthy control compared to disease control (not significant).

SUMMARY AND OUTLOOK: In all 14 studies, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. Therefore, based on the findings of the studies, this study confirms the relationship between CHIT1 increase and ALS disorder.}, } @article {pmid39343990, year = {2024}, author = {Xia, L and Qiu, Y and Li, J and Xu, M and Dong, Z}, title = {The Potential Role of Artemisinins Against Neurodegenerative Diseases.}, journal = {The American journal of Chinese medicine}, volume = {52}, number = {6}, pages = {1641-1660}, doi = {10.1142/S0192415X24500642}, pmid = {39343990}, issn = {1793-6853}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Artemisinins/pharmacology ; *Neuroprotective Agents/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism ; Ferroptosis/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Huntington Disease/drug therapy/metabolism ; Autophagy/drug effects ; }, abstract = {Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.}, } @article {pmid39343443, year = {2024}, author = {O'Brien, D and Shaw, PJ}, title = {New developments in the diagnosis and management of motor neuron disease.}, journal = {British medical bulletin}, volume = {152}, number = {1}, pages = {4-15}, doi = {10.1093/bmb/ldae010}, pmid = {39343443}, issn = {1471-8391}, support = {NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 972-797//AMBRoSIA Biosampling Programme/ ; 764-780//MNDA (Sheffield Care and Research Centre for Motor Neuron Disorders/ ; }, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness.

SOURCES OF DATA: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'.

AREAS OF AGREEMENT: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND.

AREAS OF CONTROVERSY: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe.

GROWING POINTS: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies.

Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease.}, } @article {pmid39342484, year = {2024}, author = {Deneubourg, C and Dafsari, HS and Lowe, S and Martinez-Cotrina, A and Mazaud, D and Park, SH and Vergani, V and Almacellas Barbanoj, A and Maroofian, R and Averdunk, L and Ghayoor-Karimiani, E and Jayawant, S and Mignot, C and Keren, B and Peters, R and Kamath, A and Mattas, L and Verma, S and Silwal, A and Distelmaier, F and Houlden, H and Lignani, G and Antebi, A and Jepson, J and Jungbluth, H and Fanto, M}, title = {Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/15548627.2024.2405956}, pmid = {39342484}, issn = {1554-8635}, abstract = {Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions.Abbreviations: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5: ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC: TSC complex; VS: Vici syndrome.}, } @article {pmid39341837, year = {2024}, author = {Hollingworth, D and Thomas, F and Page, DA and Fouda, MA and De Castro, RL and Sula, A and Mykhaylyk, VB and Kelly, G and Ulmschneider, MB and Ruben, PC and Wallace, BA}, title = {Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8426}, pmid = {39341837}, issn = {2041-1723}, support = {BB/105581//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CC1078/ARC_/Arthritis Research UK/United Kingdom ; mutiple grants//Diamond Light Source/ ; /WT_/Wellcome Trust/United Kingdom ; BB/V0183511//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CF2-100001//Rosetrees Trust/ ; BB/S017844//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; studentship//Wellcome Trust (Wellcome)/ ; }, mesh = {*Riluzole/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Humans ; *Neuroprotective Agents/pharmacology ; Voltage-Gated Sodium Channels/metabolism/chemistry ; HEK293 Cells ; Animals ; Sodium/metabolism ; Motor Neurons/drug effects/metabolism ; }, abstract = {Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na[+] conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.}, } @article {pmid39341656, year = {2024}, author = {Paris, A and Lakatos, A}, title = {Cell and gene therapy for amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {205}, number = {}, pages = {217-241}, doi = {10.1016/B978-0-323-90120-8.00017-4}, pmid = {39341656}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disorder with rapidly progressive skeletal muscle weakness, which can also cause a variable cognitive deficit. Genetic causes are only identified in approximately 10% of all cases, with complex genotype-phenotype associations, making it challenging to identify treatment targets. What further hampers therapeutic development is a broad heterogeneity in mechanisms, possible targets, and disturbances across various cell types, aside from the cortical and spinal motor neurons that lie at the heart of the pathology of ALS. Over the last decade, significant progress in biotechnologic techniques, cell and ribonucleic acid (RNA) engineering, animal models, and patient-specific human stem cell and organoid models have accelerated both mechanistic and therapeutic discoveries. The growing number of clinical trials mirrors this. This chapter reviews the current state of human preclinical models supporting trial strategies as well as recent clinical cell and gene therapy approaches.}, } @article {pmid39341507, year = {2024}, author = {Sivalingam, AM}, title = {Advances in understanding biomarkers and treating neurological diseases - Role of the cerebellar dysfunction and emerging therapies.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102519}, doi = {10.1016/j.arr.2024.102519}, pmid = {39341507}, issn = {1872-9649}, mesh = {Humans ; *Biomarkers/metabolism ; Animals ; *Cerebellar Diseases/therapy/diagnosis/metabolism/genetics ; Genetic Therapy/methods/trends ; Nervous System Diseases/therapy/diagnosis/metabolism ; Cerebellum/metabolism/pathology ; }, abstract = {Cerebellar dysfunction is increasingly recognized as a critical factor in various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Research has revealed distinct cerebellar atrophy patterns in conditions such as AD and multiple system atrophy, and studies in mice have highlighted its impact on motor control and cognitive functions. Emerging research into autism spectrum disorder (ASD) has identified key targets, such as elevated levels of chemokine receptors and ZIC family genes. Biomarkers, including cerebrospinal fluid (CSF), genetic markers, and advances in AI and bioinformatics, are enhancing early diagnosis and personalized treatment across neurodegenerative disorders. Notable advancements include improved diagnostic tools, gene therapy, and novel clinical trials. Despite progress, challenges such as the bloodbrain barrier and neuroinflammation persist. Current therapies for AD, PD, HD, and ALS, including antisense oligonucleotides and stem cell treatments, show promise but require further investigation. A comprehensive approach that integrates diagnostic methods and innovative therapies is essential for effective management and improved patient outcomes.}, } @article {pmid39340928, year = {2024}, author = {Dahl, R and Bezprozvanny, I}, title = {SERCA pump as a novel therapeutic target for treating neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {734}, number = {}, pages = {150748}, doi = {10.1016/j.bbrc.2024.150748}, pmid = {39340928}, issn = {1090-2104}, support = {R01 AG071310/AG/NIA NIH HHS/United States ; R56 AG078337/AG/NIA NIH HHS/United States ; R42 AG062001/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism/antagonists & inhibitors ; Calcium Signaling/drug effects ; Molecular Targeted Therapy/methods ; Allosteric Regulation/drug effects ; }, abstract = {The neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Despite intense research into the causes of these disorders, only marginal progress has been made in the clinic and no cures exist for any of them. Most of the scientific effort has been focused on identification of the major causes of these diseases and on developing ways to target them, such as targeting amyloid accumulation for AD or targeting expression of mutant Huntingtin for HD. Calcium (Ca[2+]) signaling has long been proposed to play an important role in the pathogenesis of neurodegenerative disorders, but blockers of Ca[2+] channels and Ca[2+] signaling proteins have not been translated to clinic primarily due to side effects related to the important roles of target molecules for these compounds at the peripheral tissues. In this review article, we would like to discuss an idea that recently identified positive allosteric modulators (PAMs) of the sarco-endoplasmic reticulum calcium (SERCA) pump may provide a promising approach to develop therapeutic compounds for treatment of these disorders. This hypothesis is supported by the preclinical data obtained with animal models of AD and PD. The first critical test of this idea will be an imminent phase I study that will offer an opportunity to evaluate potential side effects of this class of compounds in humans.}, } @article {pmid39340874, year = {2024}, author = {Xiong, Z and Zeng, Q and Hu, Y and Lai, C and Wu, H}, title = {Optineurin inhibits IBDV replication via interacting with VP1.}, journal = {Veterinary microbiology}, volume = {298}, number = {}, pages = {110261}, doi = {10.1016/j.vetmic.2024.110261}, pmid = {39340874}, issn = {1873-2542}, mesh = {*Virus Replication ; Animals ; *Infectious bursal disease virus/physiology ; *Chickens ; Membrane Transport Proteins/metabolism/genetics ; Cell Cycle Proteins/metabolism/genetics ; Poultry Diseases/virology ; Humans ; Ubiquitination ; Birnaviridae Infections/veterinary/virology ; Cell Line ; Capsid Proteins/metabolism/genetics ; Transcription Factor TFIIIA/metabolism/genetics ; HEK293 Cells ; }, abstract = {Avibirnavirus, specifically Infectious Bursal Disease Virus (IBDV), is a highly contagious pathogen that causes significant economic losses in the poultry industry. The polymerase protein VP1 of IBDV is critical to the viral life cycle, facilitating the synthesis of viral mRNA and the genome. Previous studies have suggested that various host factors influence the regulation of IBDV polymerase activity. In this study, we identified that IBDV infection induces the expression of optineurin (OPTN), a mitophagy receptor and a protein associated with amyotrophic lateral sclerosis (ALS), as well as a negative regulator of interferon I production. The induced expression of OPTN acts as a suppressor of IBDV replication, a function dependent on its ubiquitin-binding domain (UBAN). Furthermore, we demonstrated that OPTN exerts its antiviral effects through direct interactions with VP1 and VP3, which inhibit the polymerase activity of VP1 by preventing K63-linked ubiquitination of VP1. To our knowledge, this study is the first to report that OPTN, upregulated during IBDV infection, functions as a novel antiviral host factor that limits the virus's replicative capacity, offering a potential target for anti-IBDV therapeutic strategies.}, } @article {pmid39340590, year = {2024}, author = {Ghiasvand, K and Amirfazli, M and Moghimi, P and Safari, F and Takhshid, MA}, title = {The role of neuron-like cell lines and primary neuron cell models in unraveling the complexity of neurodegenerative diseases: a comprehensive review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1024}, pmid = {39340590}, issn = {1573-4978}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Neurons/metabolism ; Animals ; Coculture Techniques/methods ; Cell Line ; Models, Biological ; Alzheimer Disease/pathology/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons. As to developing effective therapeutic interventions, it is crucial to understand the underlying mechanisms of NDs. Cellular models have become invaluable tools for studying the complex pathogenesis of NDs, offering insights into disease mechanisms, determining potential therapeutic targets, and aiding in drug discovery. This review provides a comprehensive overview of various cellular models used in ND research, focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Cell lines, such as SH-SY5Y and PC12 cells, have emerged as valuable tools due to their ease of use, reproducibility, and scalability. Additionally, co-culture models, involving the growth of distinct cell types like neurons and astrocytes together, are highlighted for simulating brain interactions and microenvironment. While cell lines cannot fully replicate the complexity of the human brain, they provide a scalable method for examining important aspects of neurodegenerative diseases. Advancements in cell line technologies, including the incorporation of patient-specific genetic variants and improved co-culture models, hold promise for enhancing our understanding and expediting the development of effective treatments. Integrating multiple cellular models and advanced technologies offers the potential for significant progress in unraveling the intricacies of these debilitating diseases and improving patient outcomes.}, } @article {pmid39340541, year = {2024}, author = {Gagliardi, D and Rizzuti, M and Masrori, P and Saccomanno, D and Del Bo, R and Sali, L and Meneri, M and Scarcella, S and Milone, I and Hersmus, N and Ratti, A and Ticozzi, N and Silani, V and Poesen, K and Van Damme, P and Comi, GP and Corti, S and Verde, F}, title = {Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7557-7571}, pmid = {39340541}, issn = {1432-1459}, support = {RF-2018-12366357//Ministero della Salute/ ; RF-2021-12374238//Ministero della Salute/ ; GR-2016-02364373//Ministero della Salute/ ; Ricerca corrente//Ministero della Salute/ ; C1//VIB, KU Leuven/ ; 'Opening the Future' Fund//VIB, KU Leuven/ ; FWO-Vlaanderen//Fund for Scientific Research Flanders/ ; T003519N//TBM grant from FWO-Vlaanderen/ ; G077121N//FWO-Vlaanderen/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/genetics ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Middle Aged ; *Hexosaminidases/cerebrospinal fluid ; Aged ; *MicroRNAs/cerebrospinal fluid ; Prognosis ; Adult ; Cohort Studies ; Disease Progression ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers. NfL, CHIT1 and miR-181b all showed significantly higher levels in ALS subjects compared to controls, with NfL showing the most effective diagnostic performance. Importantly, all three biomarkers were increased compared to neurodegenerative disease controls and, specifically, to patients with Alzheimer's disease (AD; N = 44), with NfL and CHIT1 being also higher in ALS than in alpha-synucleinopathies (N = 22). Notably, ALS patients displayed increased CHIT1 levels despite having, compared to controls, a higher prevalence of a polymorphism lowering CHIT1 expression. While no relationship was found between CSF miR-181b and clinical measures in ALS (disease duration, functional disability, and disease progression rate), CSF NfL was the best independent predictor of disease progression and survival. This study deepens our knowledge of ALS biomarkers, highlighting the relative specificity of CHIT1 for ALS among neurodegenerative diseases and appraising the potential diagnostic utility of CSF miR-181b.}, } @article {pmid39340452, year = {2024}, author = {Tchounwou, C and Jobanputra, AJ and Lasher, D and Fletcher, BJ and Jacinto, J and Bhaduri, A and Best, RL and Fisher, WS and Ewert, KK and Li, Y and Feinstein, SC and Safinya, CR}, title = {Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase-Separated Coacervates.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {40}, number = {40}, pages = {21041-21051}, doi = {10.1021/acs.langmuir.4c02471}, pmid = {39340452}, issn = {1520-5827}, mesh = {*tau Proteins/chemistry/metabolism ; *Liposomes/chemistry ; *Anions/chemistry ; Humans ; Phosphatidylcholines/chemistry ; Phosphatidylserines/chemistry ; Phosphatidylglycerols/chemistry ; Intrinsically Disordered Proteins/chemistry ; }, abstract = {Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein that binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full-length human protein tau and other negatively charged binding substrates, as revealed by differential interference contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase-separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes (i.e. tau-lipoplexes) exhibited distinct types of morphologies. This included large ∼20-30 μm tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles and tau-mediated finite-size assemblies of small liposomes. As the salt concentration was increased to near and above 150 mM for 1:1 electrolytes, AL-tau complexes remained stable, while tau self-coacervate droplets were found to dissolve, indicative of the breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen-facing monolayer of the axon's plasma membrane, suggesting the possibility of transient yet robust interactions near relevant ionic strengths found in neurons.}, } @article {pmid39340290, year = {2024}, author = {Alves, I and Gromicho, M and Oliveira Santos, M and Pinto, S and de Carvalho, M}, title = {Assessing disease progression in ALS: prognostic subgroups and outliers.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2024.2407412}, pmid = {39340290}, issn = {2167-9223}, abstract = {Background: The rate of disease progression, measured by the decline of ALS Functional Rating Scale-Revised (ALSFRS-R) from symptom onset to diagnosis (ΔFS) is a well-established prognostic biomarker for predicting survival. Objectives: This study aims to categorize a large patient cohort based on the initial ΔFS and subsequently investigate survival deviations from the expected prognosis defined by ΔFS. Methods: 1056 ALS patients were stratified into three progression categories based on their ΔFS: slow progressors (below 25th percentile), intermediate progressors (between 25th and 75th percentiles), and fast progressors (above 75th percentile). Survival outcomes were classified as short survivors (<2 years), average survivors (2-5 years), and long survivors (>5 years). Clinical and demographic characteristics within each subgroup were then analyzed. Results: ΔFS stratification yielded cutoff values of <0.29, 0.29-1.03, and >1.03 points/month. Long survivors comprised 26% and 21% were short survivors. Six percent of the fast progressors had a life expectancy of more than 5 years, and none of the clinical and demographic characteristics analyzed could fully explain this discrepancy. Conversely, 13% of intermediate progressors lived less than 2 years, according to a short-diagnostic delay in these patients. Discussion: Our study reaffirms ΔFS as a prognostic biomarker for ALS. We disclosed outliers defying anticipated patterns. The observed shift in progression categories underscores the non-linear nature of disease progression. Genetic and unknown biological reasons may explain these deviations. Further research is needed to fully understand modulation of ALS survival.}, } @article {pmid39338620, year = {2024}, author = {Razzaq, Z and Brahimi, N and Rehman, HZU and Khan, ZH}, title = {Intelligent Control System for Brain-Controlled Mobile Robot Using Self-Learning Neuro-Fuzzy Approach.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {18}, pages = {}, pmid = {39338620}, issn = {1424-8220}, mesh = {*Fuzzy Logic ; *Robotics/methods ; Humans ; *Brain-Computer Interfaces ; *Electroencephalography/methods ; Algorithms ; Brain/physiology ; Neural Networks, Computer ; Machine Learning ; }, abstract = {Brain-computer interface (BCI) provides direct communication and control between the human brain and physical devices. It is achieved by converting EEG signals into control commands. Such interfaces have significantly improved the lives of disabled individuals suffering from neurological disorders-such as stroke, amyotrophic lateral sclerosis (ALS), and spinal cord injury-by extending their movement range and thereby promoting self-independence. Brain-controlled mobile robots, however, often face challenges in safety and control performance due to the inherent limitations of BCIs. This paper proposes a shared control scheme for brain-controlled mobile robots by utilizing fuzzy logic to enhance safety, control performance, and robustness. The proposed scheme is developed by combining a self-learning neuro-fuzzy (SLNF) controller with an obstacle avoidance controller (OAC). The SLNF controller robustly tracks the user's intentions, and the OAC ensures the safety of the mobile robot following the BCI commands. Furthermore, SLNF is a model-free controller that can learn as well as update its parameters online, diminishing the effect of disturbances. The experimental results prove the efficacy and robustness of the proposed SLNF controller including a higher task completion rate of 94.29% (compared to 79.29%, and 92.86% for Direct BCI and Fuzzy-PID, respectively), a shorter average task completion time of 85.31 s (compared to 92.01 s and 86.16 s for Direct BCI and Fuzzy-PID, respectively), and reduced settling time and overshoot.}, } @article {pmid39338563, year = {2024}, author = {Dow, CT and Pierce, ES and Sechi, LA}, title = {Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?.}, journal = {Microorganisms}, volume = {12}, number = {9}, pages = {}, pmid = {39338563}, issn = {2076-2607}, abstract = {Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.}, } @article {pmid39337908, year = {2024}, author = {Wang, R and Chen, L and Zhang, Y and Sun, B and Liang, M}, title = {Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39337908}, issn = {2075-1729}, support = {YJXJ-JZ-2021-0014//Scientific Research Project of Beijing Yicheng Cooperative Development Foundation in 2021-Public welfare projects of rare disease related topics/ ; KM202310858001//R&D Program of Beijing Municipal Education Commission/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease. Current detection methods can only confirm the diagnosis at the onset of the disease, missing the critical window for early treatment. Recent studies using animal models have found that detecting changes in miRNA sites can predict the onset and severity of the disease in its early stages, facilitating early diagnosis and treatment. miRNAs show expression changes in motor neurons that connect the brain, spinal cord, and brain stem, as well as in the skeletal muscle in mouse models of ALS. Clinically, expression changes in some miRNAs in patients align with those in mouse models, such as the upregulation of miR-29b in the brain and the upregulation of miR-206 in the skeletal muscle. This study provides an overview of some miRNA study findings in humans as well as in animal models, including SOD1, FUS, TDP-43, and C9orf72 transgenic mice and wobbler mice, highlighting the potential of miRNAs as diagnostic markers for ALS. miR-21 and miR-206 are aberrantly expressed in both mouse model and patient samples, positioning them as key potential diagnostic markers in ALS. Additionally, miR-29a, miR-29b, miR-181a, and miR-142-3p have shown aberrant expression in both types of samples and show promise as clinical targets for ALS. Finally, miR-1197 and miR-486b-5p have been recently identified as aberrantly expressed miRNAs in mouse models for ALS, although further studies are needed to determine their viability as diagnostic targets.}, } @article {pmid39337696, year = {2024}, author = {Niazi, SK}, title = {Bioavailability as Proof to Authorize the Clinical Testing of Neurodegenerative Drugs-Protocols and Advice for the FDA to Meet the ALS Act Vision.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337696}, issn = {1422-0067}, mesh = {Humans ; *United States Food and Drug Administration ; United States ; *Drug Approval ; *Biological Availability ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Clinical Trials as Topic ; }, abstract = {Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood-brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs.}, } @article {pmid39337560, year = {2024}, author = {Malaguarnera, M and Cabrera-Pastor, A}, title = {Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337560}, issn = {1422-0067}, support = {PI23/00204//Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización de proyectos de I+D+i desarro/ ; CIGE/083//This research was funded by Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educación/Innovación, Universidades, Ciencia y Sociedad Digital, subvenciones para la realización d/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis ; Animals ; Central Nervous System Diseases/metabolism/therapy/diagnosis ; Blood-Brain Barrier/metabolism ; }, abstract = {The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.}, } @article {pmid39337454, year = {2024}, author = {Rizea, RE and Corlatescu, AD and Costin, HP and Dumitru, A and Ciurea, AV}, title = {Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337454}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology/metabolism/genetics ; Humans ; Biomarkers ; Genetic Therapy/methods ; Oxidative Stress ; Animals ; Mitochondria/metabolism ; }, abstract = {This review offers an in-depth examination of amyotrophic lateral sclerosis (ALS), addressing its epidemiology, pathophysiology, clinical presentation, diagnostic techniques, and current as well as emerging treatments. The purpose is to condense key findings and illustrate the complexity of ALS, which is shaped by both genetic and environmental influences. We reviewed the literature to discuss recent advancements in understanding molecular mechanisms such as protein misfolding, mitochondrial dysfunction, oxidative stress, and axonal transport defects, which are critical for identifying potential therapeutic targets. Significant progress has been made in refining diagnostic criteria and identifying biomarkers, leading to earlier and more precise diagnoses. Although current drug treatments provide some benefits, there is a clear need for more effective therapies. Emerging treatments, such as gene therapy and stem cell therapy, show potential in modifying disease progression and improving the quality of life for ALS patients. The review emphasizes the importance of continued research to address challenges such as disease variability and the limited effectiveness of existing treatments. Future research should concentrate on further exploring the molecular foundations of ALS and developing new therapeutic approaches. The implications for clinical practice include ensuring the accessibility of new treatments and that healthcare systems are equipped to support ongoing research and patient care.}, } @article {pmid39337436, year = {2024}, author = {Guo, D and Liu, Z and Zhou, J and Ke, C and Li, D}, title = {Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337436}, issn = {1422-0067}, support = {2023Y9415//Joint Funds for the innovation of science and Technology, Fujian province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Signal Transduction ; Animals ; *Apoptosis ; Ferroptosis ; Neurons/metabolism/pathology ; }, abstract = {Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases.}, } @article {pmid39337251, year = {2024}, author = {Escudier, O and Zhang, Y and Whiting, A and Chazot, P}, title = {Evaluation of a Synthetic Retinoid, Ellorarxine, in the NSC-34 Cell Model of Motor Neuron Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337251}, issn = {1422-0067}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Retinoids/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cell Line ; Humans ; Receptors, AMPA/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Benzoates/pharmacology ; Motor Neuron Disease/drug therapy/metabolism/pathology ; Calcium/metabolism ; Neurites/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease worldwide and is characterized by progressive muscle atrophy. There are currently two approved treatments, but they only relieve symptoms briefly and do not cure the disease. The main hindrance to research is the complex cause of ALS, with its pathogenesis not yet fully elucidated. Retinoids (vitamin A derivatives) appear to be essential in neuronal cells and have been implicated in ALS pathogenesis. This study explores 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethylnyl]benzoic acid (Ellorarxine, or DC645 or NVG0645), a leading synthetic retinoic acid, discussing its pharmacological mechanisms, neuroprotective properties, and relevance to ALS. The potential therapeutic effect of Ellorarxine was analyzed in vitro using the WT and SOD1G93A NSC-34 cell model of ALS at an administered concentration of 0.3-30 nM. Histological, functional, and biochemical analyses were performed. Elorarxine significantly increased MAP2 expression and neurite length, increased AMPA receptor GluA2 expression and raised intracellular Ca[2+] baseline, increased level of excitability, and reduced Ca[2+] spike during depolarization in neurites. Ellorarxine also displayed both antioxidant and anti-inflammatory effects. Overall, these results suggest Ellorarxine shows relevance and promise as a novel therapeutic strategy for treatment of ALS.}, } @article {pmid39336788, year = {2024}, author = {Tourtourikov, I and Todorov, T and Angelov, T and Chamova, T and Tournev, I and Mitev, V and Todorova, A}, title = {Genetic Modifiers of ALS: The Impact of Chromogranin B P413L in a Bulgarian ALS Cohort.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336788}, issn = {2073-4425}, support = {Grant No. D-148/ 03.08.2023//Medical University of Sofia/ ; National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0004-C01//European Union-NextGenerationEU/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Bulgaria ; Middle Aged ; Aged ; Adult ; *Genetic Predisposition to Disease ; *Chromogranin B/genetics ; Age of Onset ; Alleles ; Genotype ; Polymorphism, Single Nucleotide ; Cohort Studies ; Gene Frequency ; Kaplan-Meier Estimate ; }, abstract = {This study investigated the role of the CHGB P413L variant (rs742710) in sporadic amyotrophic lateral sclerosis (sALS) within the Bulgarian population. We analyzed 150 patients with sALS (85 male and 65 female) for the presence of this variant, its potential impact on disease susceptibility, and age of onset. Genotyping was performed using PCR amplification and direct Sanger sequencing. Statistical analyses included comparisons with control data from GnomAD v2.1.1, one-way ANOVA, and Kaplan-Meier survival analysis. Results revealed a higher frequency of the minor T allele in patients with sALS compared to all control groups and a statistically significant increase in carrier genotypes compared to non-Finnish Europeans (χ[2] = 15.4572, p = 0.000440). However, the impact on age of onset was less clear, with no statistically significant differences observed across genotypes or between carriers and non-carriers of the T allele. Kaplan-Meier analysis suggested a potential 2.5-year-earlier onset in T allele carriers, but the small sample size of carriers limits the reliability of this finding. Our study provides evidence for an association between the CHGB P413L variant and sALS susceptibility in the Bulgarian population, while its effect on age of onset remains uncertain, highlighting the need for further research in larger, diverse cohorts.}, } @article {pmid39336748, year = {2024}, author = {Chami, AA and Bedja-Iacona, L and Richard, E and Lanznaster, D and Marouillat, S and Veyrat-Durebex, C and Andres, CR and Corcia, P and Blasco, H and Vourc'h, P}, title = {N-Terminal Fragments of TDP-43-In Vitro Analysis and Implication in the Pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336748}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; HEK293 Cells ; Protein Domains ; Cell Survival/genetics ; }, abstract = {Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells. The N-terminal domain (NTD) alone was not sufficient to produce aggregates. Fragments containing the NTD and all or part of the RRM1 domain produced nuclear aggregates without affecting cell viability. Only large fragments also containing the RRM2 domain, with or without the glycine-rich domain, produced cytoplasmic aggregates. Of these, only NTFs containing even a very short portion of the glycine-rich domain caused a reduction in cell viability. Our results provide insights into the involvement of different TDP-43 domains in the formation of nuclear or cytoplasmic aggregates and support the idea that work on the development of therapeutic molecules targeting TDP-43 must also take into account NTFs and, in particular, those containing even a small part of the glycine-rich domain.}, } @article {pmid39336146, year = {2024}, author = {Duranti, E and Villa, C}, title = {From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders.}, journal = {Biology}, volume = {13}, number = {9}, pages = {}, pmid = {39336146}, issn = {2079-7737}, abstract = {Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes.}, } @article {pmid39335997, year = {2024}, author = {Dork, J and Mangan, E and Burns, L and Dimenstein, E}, title = {Affective Instability: Impact of Fluctuating Emotions on Regulation and Psychological Well-Being.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39335997}, issn = {2076-328X}, abstract = {Previous research has focused on understanding the occurrence of intense and fluctuating emotions and the ability to manage these emotions and affective states. These phenomena have been, respectively, labeled as affective instability and emotion regulation and have been studied among individuals diagnosed with borderline personality disorder (BPD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and post-traumatic stress disorder (PTSD). Previous findings suggest that affective instability may be associated with poorer psychological well-being. The present study aims to investigate the general tendency of affective instability and capacity for emotional regulation among college students, regardless of a previous psychological diagnosis, and to understand the relationship between these processes and psychological well-being. Three questionnaires were administered to measure levels of affective instability, the ability to manage fluctuating affective states, and overall psychological well-being. The findings suggest that (1) individuals with diagnoses experience affective lability and difficulty regulating emotions at a greater rate than those without, (2) higher affective lability scores are consistent with more significant emotion dysregulation and lower overall psychological well-being, and (3) scores on the Affective lability Scale (ALS) and the Difficulties in Emotional Regulation Scale (DERS) are reliable predictors of one's estimated Global Assessment of Functioning (GAF) scores. Although causation has not been established, the evidence suggests that individuals with diagnoses experience greater difficulty in regulating their emotions, have greater affective lability, and experience diminished psychological well-being and day-to-day functionality. Certain anecdotal evidence suggests that emotional lability can be endogenous and affect multiple aspects of an individual's social, occupational, and personal life. By revising the existing literature and the present findings, the authors provide insights into the significance of endogenous factors in the context of affective lability and offer suggestions for future research.}, } @article {pmid39335582, year = {2024}, author = {Carata, E and Muci, M and Mariano, S and Panzarini, E}, title = {BV2 Microglial Cell Activation/Polarization Is Influenced by Extracellular Vesicles Released from Mutated SOD1 NSC-34 Motoneuron-like Cells.}, journal = {Biomedicines}, volume = {12}, number = {9}, pages = {}, pmid = {39335582}, issn = {2227-9059}, abstract = {Microglia-mediated neuroinflammation is a key player in the pathogenesis of amyotrophic lateral sclerosis (ALS) as it can contribute to the progressive degeneration of motor neurons (MNs). Here, we investigated the role of mSOD1 NSC-34 MN-like cell-derived extracellular vesicles (EVs) in inducing the activation of BV2 microglial cells. NSC-34-released EVs were isolated by culture medium differential ultracentrifugation to obtain two fractions, one containing small EVs (diameter < 200 nm) and the other containing large EVs (diameter > 200 nm). BV2 cells were incubated with the two EV fractions for 12, 24, and 48 h to evaluate 1) the state of microglial inflammation through RT-PCR of IL-1β, IL-6, IL-4, and IL-10 and 2) the expression of proteins involved in inflammasome activation (IL-β and caspase 1), cell death (caspase 3), and glial cell recruitment (CXCR1), and presence of the TGFβ cytokine receptor (TGFβ-R2). The obtained results suggest a mSOD1 type-dependent polarization of BV2 cells towards an early neurotoxic phenotype and a late neuroprotective status, with an appearance of mixed M1 and M2 microglia subpopulations. A significant role in driving microglial cell activation is played by the TGFβ/CX3CR1 axis. Therefore, targeting the dysregulated microglial response and modulating neuroinflammation could hold promise as a therapeutic strategy for ALS.}, } @article {pmid39335395, year = {2024}, author = {Ore, A and Angelastro, JM and Giulivi, C}, title = {Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {14}, number = {9}, pages = {}, pmid = {39335395}, issn = {2076-3425}, abstract = {The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.}, } @article {pmid39334855, year = {2024}, author = {Hasan, A and Staveley, BE}, title = {Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334855}, issn = {2218-273X}, support = {RGPIN-2016-04828//Natural Sciences and Engineering Research Council/ ; }, mesh = {Animals ; *Aging/genetics/metabolism ; Cytoskeletal Proteins ; *Drosophila melanogaster/genetics/metabolism ; *Drosophila Proteins/metabolism/genetics ; Dynamins/genetics/metabolism ; GTP-Binding Proteins ; Longevity/genetics ; Mitochondrial Proteins/genetics/metabolism ; Phenotype ; *Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Membrane Proteins/metabolism ; }, abstract = {The relationship of Amyotrophic Lateral Sclerosis, Parkinson's disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.}, } @article {pmid39334843, year = {2024}, author = {Lucchi, C and Simonini, C and Rustichelli, C and Avallone, R and Zucchi, E and Martinelli, I and Biagini, G and Mandrioli, J}, title = {Reduced Levels of Neurosteroids in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334843}, issn = {2218-273X}, support = {Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project//University of Modena and Reggio Emilia/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Humans ; Middle Aged ; Male ; Female ; *Neurosteroids/cerebrospinal fluid ; Case-Control Studies ; Aged ; Biomarkers/cerebrospinal fluid ; Pregnanolone/cerebrospinal fluid ; Adult ; Pregnenolone/cerebrospinal fluid ; Progesterone/cerebrospinal fluid ; Testosterone/cerebrospinal fluid ; Chromatography, Liquid ; Tandem Mass Spectrometry ; }, abstract = {Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on motor neuron degeneration. This single-center case-control study included 37 patients with amyotrophic lateral sclerosis (ALS) and 28 healthy controls. Cerebrospinal fluid (CSF) neurosteroid levels were quantified using liquid chromatography-electrospray tandem mass spectrometry and compared between the two cohorts. Neurosteroid concentrations have been correlated with neuroinflammation and neurodegeneration biomarkers detected through an automated immunoassay, along with disease features and progression. Pregnenolone, progesterone, allopregnanolone, pregnanolone, and testosterone levels were significantly lower in ALS patients' CSF compared to healthy controls. A significant inverse correlation was found between neurofilament and neurosteroid levels. Neurosteroid concentrations did not correlate with disease progression, phenotype, genotype, or survival prediction. Our study suggests the independence of the disease features and its progression, from the dysregulation of neurosteroids in ALS patients' CSF. This neurosteroid reduction may relate to disease pathogenesis or be a consequence of disease-related processes, warranting further research. The inverse correlation between neurosteroids and neurofilament levels may indicate a failure of compensatory neuroprotective mechanisms against neurodegeneration.}, } @article {pmid39334720, year = {2024}, author = {Munteanu, C and Galaction, AI and Turnea, M and Blendea, CD and Rotariu, M and Poștaru, M}, title = {Redox Homeostasis, Gut Microbiota, and Epigenetics in Neurodegenerative Diseases: A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {39334720}, issn = {2076-3921}, abstract = {Neurodegenerative diseases encompass a spectrum of disorders marked by the progressive degeneration of the structure and function of the nervous system. These conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS), often lead to severe cognitive and motor deficits. A critical component of neurodegenerative disease pathologies is the imbalance between pro-oxidant and antioxidant mechanisms, culminating in oxidative stress. The brain's high oxygen consumption and lipid-rich environment make it particularly vulnerable to oxidative damage. Pro-oxidants such as reactive nitrogen species (RNS) and reactive oxygen species (ROS) are continuously generated during normal metabolism, counteracted by enzymatic and non-enzymatic antioxidant defenses. In neurodegenerative diseases, this balance is disrupted, leading to neuronal damage. This systematic review explores the roles of oxidative stress, gut microbiota, and epigenetic modifications in neurodegenerative diseases, aiming to elucidate the interplay between these factors and identify potential therapeutic strategies. We conducted a comprehensive search of articles published in 2024 across major databases, focusing on studies examining the relationships between redox homeostasis, gut microbiota, and epigenetic changes in neurodegeneration. A total of 161 studies were included, comprising clinical trials, observational studies, and experimental research. Our findings reveal that oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases, with gut microbiota composition and epigenetic modifications significantly influencing redox balance. Specific bacterial taxa and epigenetic markers were identified as potential modulators of oxidative stress, suggesting novel avenues for therapeutic intervention. Moreover, recent evidence from human and animal studies supports the emerging concept of targeting redox homeostasis through microbiota and epigenetic therapies. Future research should focus on validating these targets in clinical settings and exploring the potential for personalized medicine strategies based on individual microbiota and epigenetic profiles.}, } @article {pmid39333504, year = {2024}, author = {Cozzi, M and Magri, S and Tedesco, B and Patelli, G and Ferrari, V and Casarotto, E and Chierichetti, M and Pramaggiore, P and Cornaggia, L and Piccolella, M and Galbiati, M and Rusmini, P and Crippa, V and Mandrioli, J and Pareyson, D and Pisciotta, C and D'Arrigo, S and Ratti, A and Nanetti, L and Mariotti, C and Sarto, E and Pensato, V and Gellera, C and Di Bella, D and Cristofani, RM and Taroni, F and Poletti, A}, title = {Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {692}, pmid = {39333504}, issn = {2041-4889}, support = {GGP19128//Fondazione Telethon (Telethon Foundation)/ ; 23236//AFM-Téléthon (French Muscular Dystrophy Association)/ ; PRIN n. 2022EFLFL8//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; PRIN n. P2022B5J32//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; Scientific Exchange Grant n. 9643//European Molecular Biology Organization (EMBO)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; RF-2018-12367768//Ministero della Salute (Ministry of Health, Italy)/ ; RRC 2023//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; *Kinesins/metabolism/genetics ; Mitochondria/metabolism/genetics ; *Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism/pathology ; *Neurodevelopmental Disorders/genetics/metabolism/pathology ; }, abstract = {Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.}, } @article {pmid39332091, year = {2024}, author = {Sharma, O and Kaur Grewal, A and Khan, H and Gurjeet Singh, T}, title = {Exploring the nexus of cGAS STING pathway in neurodegenerative terrain: A therapeutic odyssey.}, journal = {International immunopharmacology}, volume = {142}, number = {Pt B}, pages = {113205}, doi = {10.1016/j.intimp.2024.113205}, pmid = {39332091}, issn = {1878-1705}, mesh = {Humans ; *Membrane Proteins/metabolism/genetics ; Animals ; *Neurodegenerative Diseases/drug therapy/immunology/metabolism ; *Nucleotidyltransferases/metabolism/genetics ; *Signal Transduction ; Immunity, Innate ; }, abstract = {By detecting and responding to cytosolic DNA, the cGAS STING pathway regulates the innate immune responses bymediatinginflammatory reactions and antiviral defense. Thederegulation and modification of this system have been linked to variousneurodegenerative diseases like AD, PD and ALS. Accumulation of tau protein and Aβ aggregates to activate the pathway and releases neuroinflammatory cytokines which accelerates neuronal dysfunction and cognitive impairment as the symptom of AD. Similarly, in PD Alpha-synuclein aggregates activate the cGAS STING pathway and regulate the neuroinflammation and oxidative stress. In ALS, mutation of the genes causes the activation of the pathway which leads to motor neuron degeneration. Alteration of the cGAS STING pathway also leads to mitochondrial dysfunction and impaired autophagy. Preclinical investigations of AD, PD, and ALS animal models showed that STING pathway inhibitors reduced inflammation and improved neurological outcomes and modulators of the cGAS STING pathway may treat these neurodegenerative disorders. In this review we focus on the fact thatneuroinflammation, neuronal dysfunction, and various disease progressions can be treated byaltering the cGAS STING pathway. Understanding the processes and creating specific interventions for this route may offer new treatments for these terrible illnesses.}, } @article {pmid39330700, year = {2024}, author = {Everett, WH and Bucelli, RC}, title = {Tofersen for SOD1 ALS.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {5}, pages = {149-160}, pmid = {39330700}, issn = {1758-2032}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/antagonists & inhibitors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in SOD1 make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of SOD1 mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.}, } @article {pmid39329756, year = {2024}, author = {Trainito, A and Muscarà, C and Gugliandolo, A and Chiricosta, L and Salamone, S and Pollastro, F and Mazzon, E and D'Angiolini, S}, title = {Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study.}, journal = {Cells}, volume = {13}, number = {18}, pages = {}, pmid = {39329756}, issn = {2073-4409}, support = {Current Research Funds 2024//Ministero della Salute/ ; }, mesh = {*Ion Channels/metabolism/genetics ; Animals ; *Synapses/metabolism/drug effects ; *Transcriptome/drug effects/genetics ; Mice ; Cell Line ; Gene Expression Profiling ; Cannabinoids/pharmacology ; Humans ; Gene Expression Regulation/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission.}, } @article {pmid39329381, year = {2024}, author = {Lee, I and Vestrucci, M and Lee, S and Rosenbaum, M and Mitsumoto, H}, title = {Blood glycated hemoglobin level is not associated with disease progression in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2024.2407409}, pmid = {39329381}, issn = {2167-9223}, abstract = {Objective: A high glycemic index and high glycemic load diet has been associated with slower progression of amyotrophic lateral sclerosis (ALS), suggesting a benefit from high blood glucose levels. We examined the association between average blood glucose level and ALS progression in two independent cohorts. Methods: Sporadic ALS patients enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS) who completed a 3-month follow-up visit and had available blood samples were included. Hemoglobin A1c (HbA1c) was measured from whole blood collected at the 3-month follow-up. From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we included ALS patients with one or more HbA1c measurements at enrollment and available death information. Associations between HbA1c with revised ALS functional rating scale (ALSFRS-R)/ALSFRS total score change, and tracheostomy-free survival/survival were examined in these cohorts using linear regression, linear mixed-effects models, and Cox proportional hazard models, adjusted for covariates. Results: In the ALS COSMOS cohort (n = 193), HbA1c level was not significantly associated with the change in the ALSFRS-R total score from baseline to the 3-month follow-up (p = 0.8) nor baseline to the 6-month follow-up (p = 0.4). No significant association was found between HbA1c level and tracheostomy-free survival (p = 0.8). In the PRO-ACT cohort (n = 928), no significant association was found between HbA1c level and the rate of ALSFRS decline in the first 200 days (p = 0.81 for interaction) nor between HbA1c level and survival (p = 0.45). Interpretation: We did not find convincing evidence that mean blood glucose level is associated with disease progression among ALS patients.}, } @article {pmid39328853, year = {2024}, author = {Ali, M and Ramadan, A and Surani, S}, title = {Obstructive sleep apnea-hypopnea syndrome immunological relationship.}, journal = {World journal of clinical cases}, volume = {12}, number = {27}, pages = {6011-6014}, pmid = {39328853}, issn = {2307-8960}, abstract = {Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a complex disorder characterized by symptoms resulting from intermittent hypoxia and hypopnea, with research indicating a crucial role of immune system dysregulation and genetic variations in its pathogenesis. A recent Zhao et al study utilizes Mendelian randomization analysis to explore the causal relationship between immune cell characteristics and OSAHS. The study identifies specific lymphocyte subsets associated with OSAHS, providing valuable insights into the disease's pathophysiology and potential targets for therapeutic intervention. The findings underscore the significance of genetic and immunological factors in sleep disorders, offering a fresh perspective on OSAHS's complexities. Compared to existing literature, Zhao et al's study stands out for its focus on genetic markers and specific immune responses associated with OSAHS, expanding upon previous research primarily centered on systemic inflammation. In conclusion, the study represents a significant advancement in the field, shedding light on the causal role of immune cells in OSAHS and paving the way for future research and targeted treatments.}, } @article {pmid39328135, year = {2024}, author = {Sharma, S and Mehan, S and Khan, Z and Tiwari, A and Kumar, A and Gupta, GD and Narula, AS and Kalfin, R}, title = {Exploring the Neuroprotective Potential of Icariin through Modulation of Neural Pathways in the Treatment of Neurological Diseases.}, journal = {Current molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665240317650240924041923}, pmid = {39328135}, issn = {1875-5666}, abstract = {Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin.}, } @article {pmid39328012, year = {2024}, author = {Cui, Y and Chen, J and Li, H and Zheng, D and Shi, X}, title = {The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70018}, pmid = {39328012}, issn = {2162-3279}, support = {2023A03J0438//Science and Technology Program of Guangzhou/ ; 2020A1515010063//Natural Science Foundation of Guangdong Province/ ; 2023A1515011047//Natural Science Foundation of Guangdong Province/ ; //Guangzhou Research-oriented Hospital/ ; //Guangzhou High-level Clinical Key Specialty/ ; 2022A1515220119//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2021-2023//Guangzhou Municipal Key Discipline in Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis ; *Epilepsy/genetics/epidemiology/etiology ; *Genome-Wide Association Study ; Causality ; }, abstract = {OBJECTIVES: Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method.

METHODS: We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10[-5] as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy.

RESULTS: The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p = .130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P = .300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p = .019). Moreover, the investigation of reverse causalities did not reveal significant results.

CONCLUSIONS: The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.}, } @article {pmid39327888, year = {2024}, author = {Fitri, HU and Saputra, R and Suhardita, K and Suarta, IM and Oktasari, M and Aminah, S and Laras, PB}, title = {Digging deeper: A critique of the mediation study of spirituality in ALS patients.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-2}, doi = {10.1017/S1478951524001275}, pmid = {39327888}, issn = {1478-9523}, } @article {pmid39327260, year = {2024}, author = {Wang, L and Liu, H and Li, L}, title = {Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.}, journal = {Journal of Zhejiang University. Science. B}, volume = {}, number = {}, pages = {1-5}, doi = {10.1631/jzus.B2300853}, pmid = {39327260}, issn = {1862-1783}, support = {81970431//the National Natural Science Foundation of China/ ; 2023JJ50136//the Hunan Provincial Natural Science Foundation of China/ ; }, abstract = {Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.}, } @article {pmid39327159, year = {2024}, author = {Vassallu, F and Igaz, LM}, title = {TDP-43 nuclear condensation and neurodegenerative proteinopathies.}, journal = {Trends in neurosciences}, volume = {47}, number = {11}, pages = {849-850}, doi = {10.1016/j.tins.2024.09.003}, pmid = {39327159}, issn = {1878-108X}, mesh = {Animals ; Humans ; Cell Nucleus/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Neurodegenerative Diseases/metabolism ; *TDP-43 Proteinopathies/metabolism/genetics/pathology ; }, abstract = {RNA-binding proteins (RBPs) can undergo phase separation and form condensates, processes that, in turn, can be critical for their functionality. In a recent study, Huang, Ellis, and colleagues show that cellular stress can trigger transient alterations in nuclear TAR DNA-binding protein 43 (TDP-43), leading to changes crucial for proper neuronal function. These findings have implications for understanding neurological TDP-43 proteinopathies.}, } @article {pmid39326369, year = {2024}, author = {Suzuki, Y and Adachi, T and Yoshida, K and Sakuwa, M and Hanajima, R}, title = {Psychiatric symptoms and TDP-43 pathology in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123249}, doi = {10.1016/j.jns.2024.123249}, pmid = {39326369}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/psychology ; Male ; Female ; Aged ; *DNA-Binding Proteins/metabolism ; Middle Aged ; Mental Disorders/etiology/pathology/metabolism ; Brain/pathology/metabolism ; Aged, 80 and over ; Neurons/pathology/metabolism ; }, abstract = {BACKGROUND: ALS is not a pure motor neuron disease but co-occurs with cognitive impairment and psychiatric symptoms. The neuropathological origin of the psychiatric symptoms is unclear. This study examined the association between the psychiatric symptoms and neuropathology of ALS.

METHODS: We investigated the clinicopathological characteristics of 15 autopsy cases of ALS, including neuronal loss, gliosis, and the burden of TDP-43 pathology. We divided TDP-43-positive structures by morphology into four categories (neuronal cytoplasmic inclusion, dystrophic neurite, dot, and glial cytoplasmic inclusion) and gave each a semiquantitative score in nine brain regions. Braak neurofibrillary tangle stage, Thal amyloid phase, Lewy-related pathology, and argyrophilic grains were also assessed.

RESULTS: Of the 15 ALS patients, seven had presented with psychiatric symptoms and eight had not. Significantly higher TDP-43 pathology scores were found in the group with psychiatric symptoms in the temporal tip, transentorhinal cortex, entorhinal cortex, subiculum, and the hippocampal CA1 region and dentate gyrus. Cognitive impairment was not significantly associated with the degree of TDP-43 pathology. There were no significant differences in the degree of neuronal loss/gliosis or in other concurrent pathologies between patients with and without psychiatric symptoms. Morphological evaluation showed that neuronal cytoplasmic inclusions, dystrophic neurites, and dots tended to be more common in the group with psychiatric symptoms.

CONCLUSION: Psychiatric symptoms in ALS may be related to TDP-43 pathology in the perforant pathway. (224 words).}, } @article {pmid39324867, year = {2024}, author = {Li, J and Gao, C and Wang, Q and Liu, J and Xie, Z and Zhao, Y and Yu, M and Zheng, Y and Lv, H and Zhang, W and Yuan, Y and Meng, L and Deng, J and Wang, Z}, title = {Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16493}, pmid = {39324867}, issn = {1468-1331}, support = {82071409//National Natural Science Foundation of China/ ; 82101469//National Natural Science Foundation of China/ ; 82171846//National Natural Science Foundation of China/ ; U20A20356//National Natural Science Foundation of China/ ; 2022-4-40716//Capitals Funds for Health Improvement and Research/ ; 20220484017//Beijing Nova Program/ ; 20230484403//Beijing Nova Program/ ; 2023CX05//Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital/ ; 2023HQ03//National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; Male ; Female ; *DNA, Mitochondrial/blood/genetics ; Middle Aged ; Aged ; *Interleukin-6/blood ; *Cell-Free Nucleic Acids/blood ; *Superoxide Dismutase-1/blood/genetics ; Mutation ; Adult ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients.

METHODS: The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed.

RESULTS: Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 10[5] mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = -0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = -0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038).

CONCLUSION: Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.}, } @article {pmid39323877, year = {2024}, author = {Engelberg-Cook, E and Shah, JS and Teixeira da Silva Hucke, A and Vera-Garcia, DV and Dagher, JE and Donahue, MH and Belzil, VV and Oskarsson, B}, title = {Prognostic Factors and Epidemiology of Amyotrophic Lateral Sclerosis in Southeastern United States.}, journal = {Mayo Clinic proceedings. Innovations, quality & outcomes}, volume = {8}, number = {5}, pages = {482-492}, pmid = {39323877}, issn = {2542-4548}, abstract = {OBJECTIVE: To assess the performance of known survival predictors and evaluate their stratification capability in patients with amyotrophic lateral sclerosis (ALS).

PATIENTS AND METHODS: We analyzed demographic and clinical variables collected at the Mayo Clinic, Florida ALS center during the first clinical visit of 1442 (100%) patients with ALS.

RESULTS: Our cohort had a median (interquartile range [IQR]) age at diagnosis of 64.8 (57-72) years; 1350 (92%) were non-Hispanic White; and 771 (53.5%) were male. The median (IQR) diagnostic delay was 10.1 (6-18) months, body mass index was 25.4 (23-49), and forced vital capacity was 72% (52%-87%). Approximately 12% of patients tested carried a pathologic C9orf72 hexanucleotide repeat expansion. Median (IQR) ALS functional rating scale-revised score was 35 (29-40) and ALS cognitive behavioral screen score was 15 (12-17). The median (IQR) survival after diagnosis was 17.2 (9-31) months, and survival from symptom onset was 30 (20-48) months. We found that older age decreased forced vital capacity, and fast-progressing ALS functional rating scale-revised scores significantly (P<.0001) influence survival curves and associated hazard risk.

CONCLUSION: Although results obtained from our cohort are consistent with other reports (eg, men with spinal onset experience a longer survival than women with bulbar onset), they remind us of the complexity of the disease's natural history and the limited prognostic power of the most common clinical predictors.}, } @article {pmid39323817, year = {2024}, author = {Zeng, A and Huang, Y and Xin, J and Li, J and Qiu, W and Zhang, M}, title = {Progress and recommendations of developing occupational exposure limits for noise-A systematic review.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37878}, pmid = {39323817}, issn = {2405-8440}, abstract = {OBJECTIVE: Noise exposure limit is one of the critical measures to prevent noise-induced hearing loss (NIHL). This review aimed to review the progress and recommendations for developing occupational exposure limits (OELs) for workplace noise.

METHODS: A systematic review was used. Thirty-eight national or international organizations' noise exposure standards (including OEL) and laws, regulations, and guidelines for noise exposure control were analyzed. Articles on recommendations for revising noise OEL standards between 2000 and 2023 were selected.

RESULTS: The definition of different noise types (especially for non-steady and impulsive noise) varied worldwide, and the used 8-h OEL varied from 80 to 90 dB(A). Maximum sound pressure level (Lmax) and noise dose for industrial noise and peak sound pressure level (Lpeak) for impulsive noise have been incorporated into the OELs. Countries developed noise risk management measures based on OELs, action levels (ALs), and exposure risk ratio or classification. The risk of co-exposure to noise and ototoxic organic substances and the effects of noise on susceptible populations were concerns in EU country standards. Scholars suggested revising the existing noise exposure standards based on noise's temporal structure (expressed by kurtosis), effective noise level, impulsive noise OEL, action level, and key factors of risk assessment.

CONCLUSIONS: Indicators such as Lmax, noise dose, Lpeak, and action level can be incorporated into noise OELs. Developing noise OEL standards should consider the co-exposure of noise and ototoxic substances, HPD's noise attenuation, susceptible groups, and noise's temporal structure.}, } @article {pmid39323783, year = {2024}, author = {You, J and Maksimovic, K and Metri, MN and Schoeppe, A and Chen, K and Lee, J and Santos, JR and Youssef, MMM and Salter, MW and Park, J}, title = {Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37926}, pmid = {39323783}, issn = {2405-8440}, abstract = {Microglia have been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Dectin-1, encoded by the Clec7a gene, is highly upregulated in a specific microglial response state called disease-associated microglia (DAM) in various neurodegenerative conditions. However, the role of Dectin-1 in ALS is undetermined. Here, we show that Clec7a mRNA upregulation occurs in central nervous system (CNS) regions that exhibit neurodegeneration in a MATR3 S85C knock-in mouse model (Matr3 [S85C/S85C]) of ALS. Furthermore, a significant increase in the number of Dectin-1[+] microglia coincides with the onset of motor deficits, and this number increases with disease progression. We demonstrate that the knockout of Dectin-1 does not affect survival, motor function, neurodegeneration, or microglial responses in Matr3 [S85C/S85C] mice. These findings suggest that Dectin-1 does not play a role in modifying ALS onset or progression.}, } @article {pmid39322357, year = {2024}, author = {Mehta, RI and Ranjan, M and Haut, MW and Carpenter, JS and Rezai, AR}, title = {Focused Ultrasound for Neurodegenerative Diseases.}, journal = {Magnetic resonance imaging clinics of North America}, volume = {32}, number = {4}, pages = {681-698}, doi = {10.1016/j.mric.2024.03.001}, pmid = {39322357}, issn = {1557-9786}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; Ultrasonic Therapy/methods ; Brain/diagnostic imaging ; Animals ; }, abstract = {Neurodegenerative diseases are a leading cause of death and disability and pose a looming global public health crisis. Despite progress in understanding biological and molecular factors associated with these disorders and their progression, effective disease modifying treatments are presently limited. Focused ultrasound (FUS) is an emerging therapeutic strategy for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these contexts, applications of FUS include neuroablation, neuromodulation, and/or blood-brain barrier opening with and without facilitated intracerebral drug delivery. Here, the authors review preclinical evidence and current and emerging applications of FUS for neurodegenerative diseases and summarize future directions in the field.}, } @article {pmid39321879, year = {2024}, author = {Lei, T and Zhang, X and Fu, G and Luo, S and Zhao, Z and Deng, S and Li, C and Cui, Z and Cao, J and Chen, P and Yang, H}, title = {Advances in human cellular mechanistic understanding and drug discovery of brain organoids for neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102517}, doi = {10.1016/j.arr.2024.102517}, pmid = {39321879}, issn = {1872-9649}, mesh = {Humans ; *Organoids/drug effects/pathology ; *Neurodegenerative Diseases/pathology/drug therapy ; *Drug Discovery/methods ; *Brain/pathology/drug effects ; Animals ; }, abstract = {The prevalence of neurodegenerative diseases (NDs) is increasing rapidly as the aging population accelerates, and there are still no treatments to halt or reverse the progression of these diseases. While traditional 2D cultures and animal models fail to translate into effective therapies benefit patients, 3D cultured human brain organoids (hBOs) facilitate the use of non-invasive methods to capture patient data. The purpose of this study was to review the research and application of hBO in disease models and drug screening in NDs. The pluripotent stem cells are induced in multiple stages to form cerebral organoids, brain region-specific organoids and their derived brain cells, which exhibit complex brain-like structures and perform electrophysiological activities. The brain region-specific organoids and their derived neurons or glial cells contribute to the understanding of the pathogenesis of NDs and the efficient development of drugs, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Glial-rich brain organoids facilitate the study of glial function and neuroinflammation, including astrocytes, microglia, and oligodendrocytes. Further research on the maturation enhancement, vascularization and multi-organoid assembly of hBO will help to enhance the research and application of NDs cellular models.}, } @article {pmid39319809, year = {2024}, author = {Karra, R and Rice, AD and Hardcastle, A and V Lara, J and Hollen, A and Glenn, M and Munn, R and Hannan, P and Arcaris, B and Derksen, D and Spaite, DW and Gaither, JB}, title = {Telemedical Direction to Optimize Resource Utilization in a Rural Emergency Medical Services System.}, journal = {The western journal of emergency medicine}, volume = {25}, number = {5}, pages = {777-783}, pmid = {39319809}, issn = {1936-9018}, mesh = {Humans ; Retrospective Studies ; *Telemedicine ; *Emergency Medical Services ; *Rural Health Services ; Female ; *Emergency Medical Technicians ; Male ; Chest Pain/therapy ; Middle Aged ; Pilot Projects ; Adult ; }, abstract = {BACKGROUND: Telemedicine remains an underused tool in rural emergency medical servces (EMS) systems. Rural emergency medical technicians (EMT) and paramedics cite concerns that telemedicine could increase Advanced Life Support (ALS) transports, extend on-scene times, and face challenges related to connectivity as barriers to implementation. Our aim in this project was to implement a telemedicine system in a rural EMS setting and assess the impact of telemedicine on EMS management of patients with chest pain while evaluating some of the perceived barriers.

METHODS: This study was a mixed-methods, retrospective review of quality assurance data collected prior to and after implementation of a telemedicine program targeting patients with chest pain. We compared quantitative data from the 12-month pre-implementation phase to data from 15 months post-implementation. Patients were included if they had a chief complaint of chest pain or a 12-lead electrocardiogram had been obtained. The primary outcome was the rate of ALS transport before and after program implementation. Secondary outcomes included EMS call response times and EMS agency performance on quality improvement benchmarks. Qualitative data were also collected after each telemedicine encounter to evaluate paramedic/EMT and EMS physician perception of call quality.

RESULTS: The telemedicine pilot project was implemented in September 2020. Overall, there were 58 successful encounters. For this analysis, we included 38 patients in both the pre-implementation period (September 9, 2019-September 10, 2020) and the post-implementation period (September 11, 2020-December 5, 2021). Among this population, the ALS transport rate was 42% before and 45% after implementation (odds ratio 1.11; 95% confidence interval 0.45-2.76). The EMS median out-of-service times were 47 minutes before, and 33 minutes after (P = 0.07). Overall, 64% of paramedics/EMTs and 89% of EMS physicians rated the telemedicine call quality as "good."

CONCLUSION: In this rural EMS system, a telehealth platform was successfully used to connect paramedics/EMTs to board-certified EMS physicians over a 15-month period. Telemedicine use did not alter rates of ALS transports and did not increase on-scene time. The majority of paramedics/EMTs and EMS physicians rated the quality of the telemedicine connection as "good."}, } @article {pmid39318842, year = {2024}, author = {Emary, PC and Turner, AJ}, title = {Cervical spondylotic myelopathy in a 68-year-old man diagnosed with amyotrophic lateral sclerosis.}, journal = {The Journal of the Canadian Chiropractic Association}, volume = {68}, number = {2}, pages = {172-176}, pmid = {39318842}, issn = {0008-3194}, abstract = {Owing to similar clinical presentations, cervical spondylotic myelopathy can mimic other neurological disorders. In this imaging case review (ICR), we describe a case of cervical spondylotic myelopathy in a patient diagnosed with amyotrophic lateral sclerosis. The key clinical features, imaging findings and differential diagnoses of cervical spondylotic myelopathy compared with amyotrophic lateral sclerosis are also presented.}, } @article {pmid39318236, year = {2024}, author = {Majewski, S and Klein, P and Boillée, S and Clarke, BE and Patani, R}, title = {Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.24622}, pmid = {39318236}, issn = {1098-1136}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Substantial advances in technology are permitting a high resolution understanding of the salience of glia, and have helped us to transcend decades of predominantly neuron-centric research. In particular, recent advances in 'omic' technologies have enabled unique insights into glial biology, shedding light on the cellular and molecular aspects of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques to attempt to understand the role of glia in ALS across different model systems and post mortem tissue. We also address caveats that should be considered when interpreting such studies, and how some of these may be mitigated through either using a multi-omic approach and/or careful low throughput, high fidelity orthogonal validation with particular emphasis on functional validation. Finally, we consider emerging technologies and their potential relevance in deepening our understanding of glia in ALS.}, } @article {pmid39317854, year = {2024}, author = {Khoshdooz, S and Abbasi, H and Abbasi, MM}, title = {Iron-Status Indicators and HFE Gene Polymorphisms in Individuals with Amyotrophic Lateral Sclerosis: An Umbrella Review of Meta-analyses and Systematic Reviews.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {39317854}, issn = {1559-0720}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Recent meta-analyses and systematic reviews suggest that HFE gene polymorphisms and iron-associated biomarkers may play a key role in the risk and occurrence of ALS. This umbrella study aimed to explore the roles of HFE gene polymorphisms and iron-associated biomarkers in individuals with ALS. A thorough search of three online scientific databases, namely Scopus, Web of Science, and PubMed, was conducted from their inception until September 13, 2024. The screening and selection processes were executed based on the PICO framework and eligibility criteria, followed by two independent reviewers. The Assessment of Multiple Systematic Reviews (AMSTAR)-2 and GRADE tools were utilized to assess the methodological quality and the certainty of evidence. Through an advanced search, 101 records were retrieved, of which eight meta-analyses and systematic reviews were selected for this umbrella review. A significant increase in iron concentrations was found in individuals with ALS compared to healthy controls (SMD, 0.26; 95% CI - 0.05, 0.57). Conversely, selected meta-analyses reported that serum transferrin concentrations in ALS patients were lower compared to healthy controls (SMD, - 0.15; 95% CI - 0.36, 0.05). Furthermore, mutations in H63D polymorphisms resulted in a 13% significant increase in the risk of ALS (OR, 1.13; 95% CI 1.05, 1.22). Our umbrella study of meta-analyses and systematic reviews reveals that individuals with ALS have lower serum concentrations of transferrin compared to healthy controls. Additionally, the H63D polymorphism in the HFE gene is associated with a slight increase in the risk of ALS. Future research should investigate broader aspects of iron-related biomarkers and HFE genes to elucidate their roles in ALS pathogenesis. Registration: Our umbrella study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42024559032 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024559032).}, } @article {pmid39317352, year = {2024}, author = {Kleinerova, J and Garcia-Gallardo, A and Tacheva, A and Bede, P}, title = {Subcortical grey matter involvement in ALS and PLS - vulnerable hubs of cortico-cortical and cortico-basal circuits: extrapyramidal, cognitive, bulbar and respiratory correlates.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2405130}, pmid = {39317352}, issn = {2167-9223}, abstract = {Evidence from neuroimaging studies suggests that the cardinal clinical manifestations of ALS stem from the dysfunction of specific neural networks. The majority of cortico-cortical and cortico-basal networks are physiologically relayed by deep cerebral and cerebellar grey matter nuclei which have been increasingly implicated in the pathophysiology of ALS. A series of recent human imaging papers revealed volume reductions, shape deformations, metabolic alterations and more recently, susceptibility changes in hippocampal subfields, thalamic, striatal, amygdalar and cerebellar nuclei. Thalamic changes have been identified in presymptomatic mutation carriers long before symptom onset and longitudinal studies have consistently confirmed progressive subcortical degeneration during the symptomatic phase of the disease. The dysfunction of circuits relayed by specific subcortical nuclei has been associated with apathy, amnestic deficits, limbic symptoms, extrapyramidal manifestations, sensory disturbances, pseudobulbar affect and cerebellar deficits. In light of emerging imaging data, the clinical heterogeneity of ALS is probably best approached from a network integrity perspective. Accordingly, the comprehensive assessment of subcortical grey matter nuclei seems imperative to untangle complex clinical phenomena in ALS.}, } @article {pmid39316747, year = {2024}, author = {de Calbiac, H and Renault, S and Haouy, G and Jung, V and Roger, K and Zhou, Q and Campanari, ML and Chentout, L and Demy, DL and Marian, A and Goudin, N and Edbauer, D and Guerrera, C and Ciura, S and Kabashi, E}, title = {Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.}, journal = {Autophagy}, volume = {20}, number = {10}, pages = {2164-2185}, pmid = {39316747}, issn = {1554-8635}, mesh = {*Motor Neurons/metabolism/pathology ; Animals ; *C9orf72 Protein/genetics/metabolism ; *Zebrafish ; *Mitophagy/genetics ; *Apoptosis/genetics ; Humans ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Dipeptides/pharmacology/metabolism ; Loss of Function Mutation/genetics ; Mitochondria/metabolism ; Disease Models, Animal ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.}, } @article {pmid39316061, year = {2024}, author = {Yang, W and Liu, X and Fan, D}, title = {Low CD3 level is a risk factor for amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2407408}, pmid = {39316061}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by neuronal degeneration of the spinal cord and brain and believed to be related to the immune system. In this study, our aim is to use Mendelian randomization (MR) to search for immune markers related to ALS. A total of 731 immune cell traits were included in this study. MR analysis was used to identify the causality between 731 immune cell traits (with 3,757 Europeans) and ALS (with 138,086 Europeans). Colocalization analysis was used to verify the found causality, protein-protein interaction prediction was used to look for the interacting proteins that are known to be involved in ALS. We found low expression levels of CD3 on central memory CD8+ T cell is risk factor for ALS (OR = 0.90, 95% CI: 0.86-0.95, P = 0.0000303). CD3 can interact with three ALS-related proteins: VCP, HLA-DRA and HLA-DRB5, which are associated with adaptive immune response. Our study reported for the first time that low-level CD3 is a risk factor for ALS and the possible mechanism, which could provide a potential strategy for ALS diagnosis and therapy.}, } @article {pmid39316038, year = {2024}, author = {Olsen, CG and Malmberg, VN and Fahlström, M and Alstadhaug, KB and Bjørnå, IK and Braathen, GJ and Bråthen, G and Demic, N and Hallerstig, E and Hogenesch, I and Horn, MA and Kampman, MT and Kleveland, G and Ljøstad, U and Maniaol, A and Morsund, ÅH and Nakken, O and Schlüter, K and Schuler, S and Seim, E and Flemmen, HØ and Tysnes, OB and Holmøy, T and Høyer, H}, title = {Amyotrophic lateral sclerosis caused by the C9orf72 expansion in Norway - prevalence, ancestry, clinical characteristics and sociodemographic status.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2405118}, pmid = {39316038}, issn = {2167-9223}, abstract = {OBJECTIVE: The most common genetic cause of amyotrophic lateral sclerosis (ALS) is the C9orf72 expansion. A high incidence of this expansion has been detected in Sweden and Finland. This Norwegian population-based study aimed to identify the prevalence, geographic distribution, ancestry, and relatedness of ALS patients with a C9orf72 expansion (C9pos). Further, we compared C9pos and C9neg patients' clinical presentation, family history of ALS and other neurodegenerative disorders, and sociodemographic status.

METHODS: We recruited ALS patients from all 17 Departments of neurology in Norway. Blood samples and questionnaires regarding clinical characteristics, sociodemographic status and family history of ALS, and other neurodegenerative disorders were collected. The C9orf72 expansion was examined for all patients.

RESULTS: The study enrolled 500 ALS patients, 8.8% of whom were C9pos, with half being sporadic ALS cases. The proportion of C9pos cases differed between regions, ranging from 17.9% in the Northern region to 1.9% in the Western region. The majority of C9pos patients had non-Finnish European descent and were not closely related. C9pos patients exhibited a significantly shorter mean survival time, had a higher frequency of relatives with ALS or dementia, and were more often unmarried/single and childless than C9neg patients.

CONCLUSION: C9pos patients constitute a large portion of the Norwegian ALS population. Ancestry and relatedness do not adequately explain regional differences. Relying on clinical information to identify C9pos patients has proven to be challenging. Half of C9pos patients were reported as having sporadic ALS, underlining the importance of carefully assessing family history and the need for genetic testing.}, } @article {pmid39315390, year = {2024}, author = {Douglas, AGL and Thompson, AG and Turner, MR and Talbot, K}, title = {Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000792}, pmid = {39315390}, issn = {2632-6140}, abstract = {BACKGROUND: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected by C9orf72 using available family history information, allowing the calculation of personalised risk estimates.

METHODS: Published aggregated age-of-onset data for C9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years.

RESULTS: This method allows family-specific penetrance to be estimated from family history and at-risk relatives' personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases.

CONCLUSIONS: Family history remains the best indicator of penetrance in C9orf72 expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.}, } @article {pmid39315308, year = {2024}, author = {Abati, E and Gagliardi, D and Manini, A and Del Bo, R and Ronchi, D and Meneri, M and Beretta, F and Sarno, A and Rizzo, F and Monfrini, E and Di Fonzo, A and Pellecchia, MT and Brusati, A and Silani, V and Comi, GP and Ratti, A and Verde, F and Ticozzi, N and Corti, S}, title = {Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae312}, pmid = {39315308}, issn = {2632-1297}, abstract = {The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.}, } @article {pmid39315251, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39315251}, issn = {2693-5015}, support = {R56 NS112296/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10[S59L], and human cell models expressing CHCHD10[S59L], we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10[S59L]. Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10[S59L]-induced diseases.

METHODS: An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10[S59L] mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance.

RESULTS: We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10[S59L]-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10[S59L]-induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H[S81L]. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10[S59L].

CONCLUSION: These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10[S59L]-induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.}, } @article {pmid39314515, year = {2025}, author = {He, D and Wang, X and Hao, M and Shen, D and Yang, X and Liu, M and Li, Y and Wang, J and Cui, L}, title = {Mutational and transcriptional profiling of cuproptosis-associated genes in amyotrophic lateral sclerosis.}, journal = {Genes & diseases}, volume = {12}, number = {1}, pages = {101208}, pmid = {39314515}, issn = {2352-3042}, } @article {pmid39314491, year = {2024}, author = {Guerra San Juan, I and Brunner, J and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314491}, issn = {2692-8205}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the microtubule binding motor protein, kinesin family member 5A (KIF5A), cause the fatal motor neuron disease, Amyotrophic Lateral Sclerosis. While KIF5 family members transport a variety of cargos along axons, it is still unclear which cargos are affected by KIF5A mutations. We generated KIF5A null mutant human motor neurons to investigate the impact of KIF5A loss on the transport of various cargoes and its effect on motor neuron function at two different timepoints in vitro. The absence of KIF5A resulted in reduced neurite complexity in young motor neurons (DIV14) and significant defects in axonal regeneration capacity at all developmental stages. KIF5A loss did not affect neurofilament transport but resulted in decreased mitochondria motility and anterograde speed at DIV42. More prominently, KIF5A depletion strongly reduced anterograde transport of SFPQ-associated RNA granules in DIV42 motor neuron axons. We conclude that KIF5A most prominently functions in human motor neurons to promote axonal regrowth after injury as well as to anterogradely transport mitochondria and, to a larger extent, SFPQ-associated RNA granules in a time-dependent manner.}, } @article {pmid39314333, year = {2024}, author = {Guha, A and Si, Y and Smith, R and Kazamel, M and Jiang, N and Smith, KA and Thalacker-Mercer, A and Singh, BK and Ho, R and Andrabi, SA and Pereira, JDTDS and Salgado, JS and Agrawal, M and Velic, EH and King, PH}, title = {The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314333}, issn = {2692-8205}, support = {I01 BX002466/BX/BLRD VA/United States ; I01 BX006231/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; R21 NS111275/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1[G93A] mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1[G93A] or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.}, } @article {pmid39314138, year = {2025}, author = {Lv, Y and Li, H}, title = {Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2556-2570}, doi = {10.4103/NRR.NRR-D-24-00286}, pmid = {39314138}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.}, } @article {pmid39313512, year = {2024}, author = {Khan, AF and Iturria-Medina, Y}, title = {Beyond the usual suspects: multi-factorial computational models in the search for neurodegenerative disease mechanisms.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {386}, pmid = {39313512}, issn = {2158-3188}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; *Neuroimaging/methods ; *Brain/diagnostic imaging/physiopathology ; Disease Progression ; Biomarkers ; Alzheimer Disease/diagnostic imaging/physiopathology ; Computer Simulation ; }, abstract = {From Alzheimer's disease to amyotrophic lateral sclerosis, the molecular cascades underlying neurodegenerative disorders remain poorly understood. The clinical view of neurodegeneration is confounded by symptomatic heterogeneity and mixed pathology in almost every patient. While the underlying physiological alterations originate, proliferate, and propagate potentially decades before symptomatic onset, the complexity and inaccessibility of the living brain limit direct observation over a patient's lifespan. Consequently, there is a critical need for robust computational methods to support the search for causal mechanisms of neurodegeneration by distinguishing pathogenic processes from consequential alterations, and inter-individual variability from intra-individual progression. Recently, promising advances have been made by data-driven spatiotemporal modeling of the brain, based on in vivo neuroimaging and biospecimen markers. These methods include disease progression models comparing the temporal evolution of various biomarkers, causal models linking interacting biological processes, network propagation models reproducing the spatial spreading of pathology, and biophysical models spanning cellular- to network-scale phenomena. In this review, we discuss various computational approaches for integrating cross-sectional, longitudinal, and multi-modal data, primarily from large observational neuroimaging studies, to understand (i) the temporal ordering of physiological alterations, i(i) their spatial relationships to the brain's molecular and cellular architecture, (iii) mechanistic interactions between biological processes, and (iv) the macroscopic effects of microscopic factors. We consider the extents to which computational models can evaluate mechanistic hypotheses, explore applications such as improving treatment selection, and discuss how model-informed insights can lay the groundwork for a pathobiological redefinition of neurodegenerative disorders.}, } @article {pmid39313484, year = {2024}, author = {Funai, A and Hayashi, K and Kawata, A and Nakayama, Y and Matsuda, C and Haraguchi, M and Takahashi, K and Komori, T}, title = {An autopsy report of a long-survival case of familial amyotrophic lateral sclerosis with SOD1 G93S gene mutation: Lack of SOD1-positive inclusion in the remaining neurons.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/neup.13004}, pmid = {39313484}, issn = {1440-1789}, support = {22H03398//Japan Society for the Promotion of Science/ ; }, abstract = {We describe the case of a 70-year-old Japanese man with familial amyotrophic lateral sclerosis (fALS) associated with a p.Gly93Ser mutation in the copper/zinc superoxide dismutase (SOD1) gene. This mutation is one of the relatively rare SOD1 mutations, with only one previous autopsy report, and is known for its longer disease duration. As previously reported, the patient had weakness in the lower limbs at age 33, followed by dysphagia, dysesthesia in the lower limbs, and autonomic dysfunction. He required mechanical ventilation at age 44 and died of acute pancreatitis at age 70. Neuropathologically, multisystem degeneration was observed beyond lesions typical of familial ALS with posterior column involvement. In addition, there was no SOD1-positive inclusion in the remaining motor neurons. The absence of SOD1-positive inclusion is a rare feature observed predominantly in long survival cases with SOD1 gene mutations. We hypothesize that the considerably lower amount of abnormal SOD1 protein in the motor neuron cells might explain our patient's extraordinarily long clinical course.}, } @article {pmid39313211, year = {2025}, author = {Rahimi, M and Al Masry, Z and Templeton, JM and Schneider, S and Poellabauer, C}, title = {A Comprehensive Multifunctional Approach for Measuring Parkinson's Disease Severity.}, journal = {Applied clinical informatics}, volume = {16}, number = {1}, pages = {11-23}, pmid = {39313211}, issn = {1869-0327}, mesh = {Humans ; *Parkinson Disease/diagnosis/physiopathology ; Male ; Female ; *Severity of Illness Index ; Aged ; Middle Aged ; Neuropsychological Tests ; Machine Learning ; }, abstract = {OBJECTIVES: This research study aims to advance the staging of Parkinson's disease (PD) by incorporating machine learning to assess and include a broader multifunctional spectrum of neurocognitive symptoms in the staging schemes beyond motor-centric assessments. Specifically, we provide a novel framework to modernize and personalize PD staging more objectively by proposing a hybrid feature scoring approach.

METHODS:  We recruited 37 individuals diagnosed with PD, each of whom completed a series of tablet-based neurocognitive tests assessing motor, memory, speech, executive functions, and tasks ranging in complexity from single to multifunctional. Then, the collected data were used to develop a hybrid feature scoring system to calculate a weighted vector for each function. We evaluated the current PD staging schemes and developed a new approach based on the features selected and extracted using random forest and principal component analysis.

RESULTS:  Our findings indicate a substantial bias in current PD staging systems toward fine motor skills, that is, other neurological functions (memory, speech, executive function, etc.) do not map into current PD stages as well as fine motor skills do. The results demonstrate that a more accurate and personalized assessment of PD severity could be achieved by including a more exhaustive range of neurocognitive functions in the staging systems either by involving multiple functions in a unified staging score or by designing a function-specific staging system.

CONCLUSION:  The proposed hybrid feature score approach provides a comprehensive understanding of PD by highlighting the need for a staging system that covers various neurocognitive functions. This approach could potentially lead to more effective, objective, and personalized treatment strategies. Further, this proposed methodology could be adapted to other neurodegenerative conditions such as Alzheimer's disease or amyotrophic lateral sclerosis.}, } @article {pmid39312574, year = {2024}, author = {Plessis-Belair, J and Ravano, K and Han, E and Janniello, A and Molina, C and Sher, RB}, title = {NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.}, journal = {PLoS genetics}, volume = {20}, number = {9}, pages = {e1011411}, pmid = {39312574}, issn = {1553-7404}, support = {R01 AG079898/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *beta Karyopherins/metabolism/genetics ; *Active Transport, Cell Nucleus/genetics ; Mice ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Disease Models, Animal ; Mutation ; ran GTP-Binding Protein/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Cell Nucleus/metabolism/genetics ; Frontotemporal Dementia/genetics/metabolism/pathology ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Alzheimer Disease/genetics/metabolism/pathology ; }, abstract = {Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTD\FTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.}, } @article {pmid39312484, year = {2024}, author = {Okada, K and Ito, D and Morimoto, S and Kato, C and Oguma, Y and Warita, H and Suzuki, N and Aoki, M and Kuramoto, J and Kobayashi, R and Shinozaki, M and Ikawa, M and Nakahara, J and Takahashi, S and Nishimoto, Y and Shibata, S and Okano, H}, title = {Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {11}, pages = {3933-3948}, pmid = {39312484}, issn = {1460-2156}, support = {21H02812//Japan Society for the Promotion of Science/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; //Takeda Science Foundation/ ; //The Yukihiko Miyata Memorial Trust for ALS Research/ ; //Yoshio Koide/ ; //Japan ALS Association/ ; //Daiichi Sankyo Foundation of Life Science/ ; //Keio Medical Association and Keio University Grant-in-Aid for Encouragement of Young Medical Scientists/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *RNA-Binding Protein FUS/genetics/metabolism ; Mice ; Humans ; *Nuclear Pore Complex Proteins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Nuclear Lamina/metabolism ; Disease Models, Animal ; Male ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Female ; Mutation ; }, abstract = {Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.}, } @article {pmid39311426, year = {2024}, author = {Azzolino, D and Piras, R and Zulueta, A and Lucchi, T and Lunetta, C}, title = {Amyotrophic lateral sclerosis as a disease model of sarcopenia.}, journal = {Age and ageing}, volume = {53}, number = {9}, pages = {}, doi = {10.1093/ageing/afae209}, pmid = {39311426}, issn = {1468-2834}, mesh = {Humans ; *Sarcopenia/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Muscle, Skeletal/pathology/physiopathology ; Aging/pathology ; Animals ; Age Factors ; Aged ; Risk Factors ; }, abstract = {Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.}, } @article {pmid39311315, year = {2024}, author = {Ortiz-Corredor, F and Correa-Arrieta, C and Forero Diaz, JJ and Castellar-Leones, S and Gil-Salcedo, A}, title = {Profiles of disease progression and predictors of mortality in Colombian patients with amyotrophic lateral sclerosis: a comprehensive longitudinal study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2024.2405587}, pmid = {39311315}, issn = {2167-9223}, abstract = {Objective: This study aimed to assess the prognostic value of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) in predicting mortality and characterizing disease progression patterns in ALS patients in Colombia. Methods: We conducted a retrospective longitudinal analysis of 537 ALS patients from the Roosevelt Institute Rehabilitation Service between October 2008 and October 2022. The study excluded nine patients due to incomplete data, resulting in 528 individuals in the analysis. ALS diagnoses were confirmed using the revised El Escorial and Gold Coast criteria. Disease progression was assessed using the ALSFRS-R, and mortality data were sourced from follow-up calls and a national database. Statistical analysis included Cox proportional hazards models to identify mortality predictors and Growth Mixture Modeling (GMM) to explore ALS progression trajectories. Results: The majority of the cohort (63.8%) deceased within the 84-month follow-up period. Survival analysis revealed that each point increase in the ALSFRS-R rate was associated with a 2.22-fold (95% CI =1.99-2.48, p < 0.001) increased risk of mortality. In the population with data from two clinical visits, the ALSFRS-R rate based on initial assessments predicted mortality more effectively over 36 months than the rate based on two evaluations. GMM identified three distinct progression trajectories: slow, intermediate, and rapid decliners. Conclusions: The ALSFRS-R rate, derived from self-reported symptom onset, significantly predicts mortality, underscoring its value in clinical assessments. This study highlights the heterogeneity in disease progression among Colombian ALS patients, indicating the necessity for personalized treatment approaches based on individual progression trajectories. Further studies are needed to refine these predictive models and improve patient management and outcomes.}, } @article {pmid39311028, year = {2024}, author = {Driver, MD and Postema, J and Onck, PR}, title = {The Effect of Dipeptide Repeat Proteins on FUS/TDP43-RNA Condensation in C9orf72 ALS/FTD.}, journal = {The journal of physical chemistry. B}, volume = {128}, number = {39}, pages = {9405-9417}, pmid = {39311028}, issn = {1520-5207}, mesh = {*RNA-Binding Protein FUS/chemistry/metabolism/genetics ; *C9orf72 Protein/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Dipeptides/chemistry/metabolism ; *RNA/chemistry/metabolism ; Humans ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism ; }, abstract = {Condensation of RNA binding proteins (RBPs) with RNA is essential for cellular function. The most common familial cause of the diseases ALS and FTD is C9orf72 repeat expansion disorders that produce dipeptide repeat proteins (DPRs). We explore the hypothesis that DPRs disrupt the native condensation behavior of RBPs and RNA through molecular interactions resulting in toxicity. FUS and TDP43 are two RBPs known to be affected in ALS/FTD. We use our previously developed 1-bead-per-amino acid and a newly developed 3-bead-per-nucleotide molecular dynamics model to explore ternary phase diagrams of FUS/TDP43-RNA-DPR systems. We show that the most toxic arginine containing DPRs (R-DPRs) can disrupt the RBP condensates through cation-π interactions and can strongly sequester RNA through electrostatic interactions. The native droplet morphologies are already modified at small additions of R-DPRs leading to non-native FUS/TDP43-encapsulated condensates with a marbled RNA/DPR core.}, } @article {pmid39310990, year = {2024}, author = {Vallejo Herrera, MJ and Vallejo Herrera, V and Del Toro Ortega, A and Tapia Guerrero, MJ}, title = {[Radiological versus endoscopic gastrostomy in patients with amyotrophic lateral sclerosis].}, journal = {Nutricion hospitalaria}, volume = {41}, number = {6}, pages = {1160-1164}, doi = {10.20960/nh.05190}, pmid = {39310990}, issn = {1699-5198}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Gastrostomy/methods/adverse effects ; Middle Aged ; Retrospective Studies ; Male ; Female ; *Enteral Nutrition/methods ; Aged ; Deglutition Disorders/etiology ; Adult ; Treatment Outcome ; Radiography ; }, abstract = {IIntroduction: patients with amyotrophic lateral sclerosis (ALS) require nutritional support, in most cases with enteral nutrition through gastrostomy, either endoscopic (PEG) or radiological (PRG). Objectives: to analyze the characteristics of patients with ALS at the time of PEG/PRG placement, and to compare the efficacy and safety of PRG versus PEG. Methods: a retrospective descriptive study. All patients with ALS who required gastrostomy in the last 3 years (2021-2023) in our hospital were recruited (4 PEG and 6 PRG). Demographic and nutritional parameters were analyzed. Results: ten patients were included, with an average age of 57 years. All patients presented with dysphagia and received oral or tube supplements prior to gastrostomy placement. The average duration of enteral nutrition was approximately 50 months, with a mortality rate of 30 % at 12 months after gastrostomy. The success rate of PEG and PRG was similar, with no complications. All patients developed deterioration of respiratory function, even after nutritional support. Conclusion: gastrostomy should be indicated as soon as a patient is at risk of aspiration pneumonia or when weight loss begins. Although the nutritional benefit of gastrostomy is well established, there is currently a delay between diagnosis and placement of approximately 4 years. PRG appears to be safer than PEG in patients with ALS and respiratory failure.}, } @article {pmid39310519, year = {2024}, author = {Albadawi, EA}, title = {Microstructural Changes in the Corpus Callosum in Neurodegenerative Diseases.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e67378}, pmid = {39310519}, issn = {2168-8184}, abstract = {The corpus callosum, the largest white matter structure in the brain, plays a crucial role in interhemispheric communication and cognitive function. This review examines the microstructural changes observed in the corpus callosum across various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). New neuroimaging studies, mainly those that use diffusion tensor imaging (DTI) and advanced tractography methods, were put together to show how changes have happened in the organization of white matter and the connections between them. Some of the most common ways the corpus callosum breaks down are discussed, including less fractional anisotropy, higher mean diffusivity, and atrophy in certain regions. The relationship between these microstructural changes and cognitive decline, motor dysfunction, and disease progression is explored. Additionally, we consider the potential of corpus callosum imaging as a biomarker for early disease detection and monitoring. Studies show that people with these disorders have lower fractional anisotropy and higher mean diffusivity in the corpus callosum, often in ways that are specific to the disease. These changes often happen before gray matter atrophy and are linked to symptoms, which suggests that the corpus callosum could be used as an early sign of neurodegeneration. The review also highlights the implications of these findings for understanding disease mechanisms and developing therapeutic strategies. Future directions, including the application of advanced imaging techniques and longitudinal studies, are discussed to elucidate the role of corpus callosum degeneration in neurodegenerative processes. This review underscores the importance of the corpus callosum in understanding the pathophysiology of neurodegenerative diseases and its potential as a target for therapeutic interventions.}, } @article {pmid39307464, year = {2024}, author = {Kalykaki, M and Rubio-Tomás, T and Tavernarakis, N}, title = {The role of mitochondria in cytokine and chemokine signalling during ageing.}, journal = {Mechanisms of ageing and development}, volume = {222}, number = {}, pages = {111993}, doi = {10.1016/j.mad.2024.111993}, pmid = {39307464}, issn = {1872-6216}, mesh = {Humans ; *Mitochondria/metabolism ; *Aging/metabolism ; *Signal Transduction ; *Inflammation/metabolism ; *Cytokines/metabolism ; Animals ; Chemokines/metabolism ; Cellular Senescence/physiology ; }, abstract = {Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPR[mt], in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.}, } @article {pmid39307154, year = {2024}, author = {Pal, S and Chataway, J and Swingler, R and Macleod, MR and Carragher, NO and Hardingham, G and Selvaraj, BT and Smith, C and Wong, C and Newton, J and Lyle, D and Stenson, A and Dakin, RS and Ihenacho, A and Colville, S and Mehta, AR and Stallard, N and Carpenter, JR and Parker, RA and Keerie, C and Weir, CJ and Virgo, B and Morris, S and Waters, N and Gray, B and MacDonald, D and MacDonald, E and Parmar, MKB and Chandran, S and , }, title = {Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1097-1107}, doi = {10.1016/S1474-4422(24)00326-0}, pmid = {39307154}, issn = {1474-4465}, mesh = {Humans ; *Trazodone/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; *Memantine/therapeutic use ; Double-Blind Method ; *Motor Neuron Disease/drug therapy ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.

METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.

FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.

INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result.

FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.}, } @article {pmid39307005, year = {2024}, author = {Austin, JM and Bailey, R and Velazquez, SG and Sainath, H and Jackson, C}, title = {Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123243}, doi = {10.1016/j.jns.2024.123243}, pmid = {39307005}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Medical Marijuana/therapeutic use ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Treatment Outcome ; Disease Progression ; Cohort Studies ; Adult ; Anxiety/drug therapy/etiology ; }, abstract = {Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.}, } @article {pmid39305776, year = {2024}, author = {Lichtfouse, J and Courtier, A and Vergunst, AC and Giannoni, P}, title = {Effects of environmental concentrations of toxins BMAA and its isomers DAB and AEG on zebrafish larvae.}, journal = {Ecotoxicology and environmental safety}, volume = {285}, number = {}, pages = {117045}, doi = {10.1016/j.ecoenv.2024.117045}, pmid = {39305776}, issn = {1090-2414}, mesh = {Animals ; *Zebrafish ; *Amino Acids, Diamino/toxicity ; *Cyanobacteria Toxins ; *Water Pollutants, Chemical/toxicity ; *Larva/drug effects ; Aminobutyrates/toxicity ; Glycine/toxicity/analogs & derivatives ; Embryo, Nonmammalian/drug effects ; Toxicity Tests, Acute ; Embryonic Development/drug effects ; Isomerism ; }, abstract = {The increasing concern over the environmental presence of β-N-Methylamino-L-alanine (BMAA), a toxin primarily produced by cyanobacteria and diatoms, has stimulated numerous studies to evaluate the risk for exposed populations, mainly aquatic organisms and humans. This study focuses on the toxicity of environmental concentrations of BMAA and its isomers, l-2,4 diaminobutyric acid dihydrochloride (DAB) and N-(2-aminoethyl) glycine (AEG) on zebrafish embryo development (ng.L[-1]). Presence of BMAA in various environments, including aquatic sources, air, and desert crusts, has raised concerns due to its potential link to neurodegenerative diseases such as the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Despite its known toxicity at high concentrations, there is limited information on the effects of environmental concentrations of BMAA and its isomers. These isomers are often found in association with BMAA and have been detected in seafood intended for human consumption, indicating potential risks from bioaccumulation and biomagnification. Zebrafish embryos have been chosen as a model due to their relevance for embryonic development and toxicity studies. The study employed fish embryo acute toxicity tests and behavioural analyses to specifically assess the sublethal effects of BMAA, DAB, and AEG. The results demonstrated larval mortality rates between 0 % and 3.75 %, while morphological defects were detected across all tested concentrations for each molecule. Behavioural analyses showed alterations in swimming behaviour. Unexpectedly, the changes in morphology and locomotion of the zebrafish larvae were detected more frequently at the lowest concentrations tested, suggesting potential non-monotonic dose responses. Overall, this research underscores the environmental risks associated with BMAA and its isomers, highlighting the importance of continuous monitoring and understanding of their sublethal effects on aquatic organisms and potential implications for human health. Further studies are warranted to elucidate the mechanisms of toxicity, evaluate long-term effects, and assess the risks associated with chronic exposure to these toxins.}, } @article {pmid39297678, year = {2024}, author = {Paoletti, O and Hyeraci, G and Finochietti, M and Celani, MG and Bacigalupo, I and Lombardi, N and Crescioli, G and Tuccori, M and Cascini, S and Gini, R and Addis, A and Kirchmayer, U and , }, title = {Pharmacological and non-pharmacological treatments in amyotrophic lateral sclerosis: an Italian real-world data study.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16470}, pmid = {39297678}, issn = {1468-1331}, support = {//Agenzia Italiana del Farmaco, Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/drug therapy ; Italy/epidemiology ; *Riluzole/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; Neuroprotective Agents/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the use patterns of pharmacological and non-pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions.

METHODS: Amyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital- and disease-specific co-payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3-year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2 years before and 1 year after the index date: prevalent, incident, former users and non-users. Use of symptomatic pharmacological and non-pharmacological therapies was described across these categories during 12 months after the index date. Determinants of riluzole use were also investigated.

RESULTS AND CONCLUSIONS: A total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65-74 years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12 months after the index date, also symptomatic therapies increased, in riluzole users and non-users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole.}, } @article {pmid39297377, year = {2024}, author = {Akyuz, E and Aslan, FS and Gokce, E and Ilmaz, O and Topcu, F and Kakac, S}, title = {Extracellular vesicle and CRISPR gene therapy: Current applications in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6057-6090}, doi = {10.1111/ejn.16541}, pmid = {39297377}, issn = {1460-9568}, mesh = {Humans ; *Genetic Therapy/methods ; *Extracellular Vesicles/metabolism/genetics ; *CRISPR-Cas Systems ; *Huntington Disease/therapy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; Animals ; Gene Editing/methods ; Neurodegenerative Diseases/therapy/genetics ; }, abstract = {Neurodegenerative diseases are characterized by progressive deterioration of the nervous system. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are prominently life-threatening examples of neurodegenerative diseases. The complexity of the pathophysiology in neurodegenerative diseases causes difficulties in diagnosing. Although the drugs temporarily help to correct specific symptoms including memory loss and degeneration, a complete treatment has not been found yet. New therapeutic approaches have been developed to understand and treat the underlying pathogenesis of neurodegenerative diseases. With this purpose, clustered-regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technology has recently suggested a new treatment option. Editing of the genome is carried out by insertion and deletion processes on DNA. Safe delivery of the CRISPR/Cas system to the targeted cells without affecting surrounding cells is frequently investigated. Extracellular vesicles (EVs), that is exosomes, have recently been used in CRISPR/Cas studies. In this review, CRISPR/Cas and EV approaches used for diagnosis and/or treatment in AD, PD, ALS, and HD are reviewed. CRISPR/Cas and EV technologies, which stand out as new therapeutic approaches, may offer a definitive treatment option in neurodegenerative diseases.}, } @article {pmid39305312, year = {2024}, author = {Torres, P and Rico-Rios, S and Ceron-Codorniu, M and Santacreu-Vilaseca, M and Seoane-Miraz, D and Jad, Y and Ayala, V and Mariño, G and Beltran, M and Miralles, MP and Andrés-Benito, P and Fernandez-Irigoyen, J and Santamaria, E and López-Otín, C and Soler, RM and Povedano, M and Ferrer, I and Pamplona, R and Wood, MJA and Varela, MA and Portero-Otin, M}, title = {TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {45}, pmid = {39305312}, issn = {1432-0533}, support = {PI 20-00155//Instituto de Salud Carlos III/ ; 23-00176//Instituto de Salud Carlos III/ ; Programa Margarita Salas//Ministerio de Universidades/ ; SGR//Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya/ ; Ayuda Unzue//Fundación Luzon/ ; }, mesh = {Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Microtubule-Associated Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cysteine Endopeptidases/metabolism/genetics ; Male ; Spinal Cord/metabolism/pathology ; Autophagy/physiology ; Mice, Knockout ; RNA Splicing/genetics ; Female ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Oligonucleotides, Antisense/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b[-/-] mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.}, } @article {pmid39305271, year = {2024}, author = {Panzetta, ME and Valdivia, RH}, title = {Akkermansia in the gastrointestinal tract as a modifier of human health.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2406379}, pmid = {39305271}, issn = {1949-0984}, support = {R01 AI142376/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Akkermansia/physiology ; Animals ; *Gastrointestinal Tract/microbiology ; Gastrointestinal Diseases/microbiology ; }, abstract = {Akkermansia sp are common members of the human gut microbiota. Multiple reports have emerged linking the abundance of A. muciniphila to health benefits and disease risk in humans and animals. This review highlights findings linking Akkermansia species in the gastrointestinal (GI) tract to health outcomes across a spectrum of disorders, encompassing those that affect the digestive, respiratory, urinary, and central nervous systems. The mechanism through which Akkermansia exerts a beneficial versus a detrimental effect on health is likely dependent on the genetic makeup of the host metabolic capacity and immunomodulatory properties of the strain, the competition or cooperation with other members of the host microbiota, as well as synergy with co-administered therapies.}, } @article {pmid39304897, year = {2024}, author = {Ortiz, DA and Peregrín, N and Valencia, M and Vinueza-Gavilanes, R and Marín-Ordovas, E and Ferrero, R and Nicolás, MJ and González-Aseguinolaza, G and Arrasate, M and Aragón, T}, title = {GCN2 inhibition reduces mutant SOD1 clustering and toxicity and delays disease progression in an amyotrophic lateral sclerosis mouse model.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {49}, pmid = {39304897}, issn = {2047-9158}, support = {BFU2017-90043-P//Ministerio de Ciencia e Innovación, Gobierno de España/ ; PID2020-120497RB-I00//Ministerio de Ciencia y Universidades, Gobierno de España/ ; Proyecto Intramural IdisNa 2022//Navarra Institute for Health Research (IdiSNA)/ ; Proyectos I+D, 2017//Fundación para la Investigación Médica Aplicada/ ; AC Predoctoral Fellowship//Fundación para la Investigación Médica Aplicada/ ; 270-2018-922//República de Panamá, Programa de Becas IFARHU-SENACYT/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Animals ; *Disease Progression ; *Disease Models, Animal ; Mice ; *Superoxide Dismutase-1/genetics ; *Mice, Transgenic ; Protein Serine-Threonine Kinases/genetics/antagonists & inhibitors ; Humans ; Mutation/genetics ; }, } @article {pmid39302099, year = {2024}, author = {Haider, R and Shipley, B and Surewicz, K and Hinczewski, M and Surewicz, WK}, title = {Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {10}, pages = {e5179}, pmid = {39302099}, issn = {1469-896X}, support = {F30 AG071339/AG/NIA NIH HHS/United States ; F30 AG071339-03/NH/NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; T32 NS077888/NH/NIH HHS/United States ; T32 GM007250/NH/NIH HHS/United States ; RF1 AG061797/NH/NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Phosphorylation ; *Protein Domains ; Molecular Dynamics Simulation ; Amino Acid Substitution ; Liquid-Liquid Extraction ; Phase Separation ; }, abstract = {C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404 and (especially) at S409/S410 is, in fact, accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that phosphomimetic Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, unlike the LLPS of unmodified protein, LLPS of the phosphomimetic variants displays a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically relevant C-terminal phosphorylation on the LLPS of TDP-43 in a more complex cellular environment.}, } @article {pmid39302063, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Mureau, N and Emond, P and Pisella, PJ and Blasco, H and Corcia, P}, title = {Exploring amyotrophic lateral sclerosis through the visual system: A systematic review.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16475}, pmid = {39302063}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; Vision Disorders/etiology/physiopathology ; Visual Pathways/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: The human visual system relies on neural networks throughout the brain that are easily accessible for tests exploring eye structures and movements. Over the past two decades, investigations have been carried out on both afferent and efferent components of the visual system in people with amyotrophic lateral sclerosis (ALS). This approach might represent an innovative biomarker research strategy to better characterise the phenotypic variability of ALS. The purpose of this review was to determine whether exploring the visual system of patients with ALS (pwALS) is an effective strategy.

METHODS: The Medline and Web of science databases were searched for studies with terms relating to ALS and vision. Of 1146 references identified, 43 articles were included.

RESULTS: In this review article, both afferent and efferent components of the visual system were found to be impaired in pwALS in the absence of visual complaint, thereby contributing to the hypothesis that ALS is a multisystem disease with sensory involvement. Of note, some areas of the eye remain unexplored (i.e., tears, and retinal function using electroretinography).

CONCLUSIONS: According to the findings available in the literature, investigating the oculomotor system and exploring the ocular surface could represent two key promising strategies to identify new diagnostic biomarkers in pwALS. Further longitudinal studies are needed to identify relevant indicators of disease progression and response to therapeutic intervention.}, } @article {pmid39301564, year = {2024}, author = {Barnard, J and Hunt, R and Yucel, M and Mazaud, D and Smith, BN and Fanto, M}, title = {Human TDP43 is required for ALS‑related annexin A11 toxicity in Drosophila.}, journal = {Biomedical reports}, volume = {21}, number = {5}, pages = {165}, pmid = {39301564}, issn = {2049-9442}, abstract = {Genomics allows identification of genes and mutations associated with amyotrophic lateral sclerosis (ALS). Mutations in annexin A11 (ANXA11) are responsible for ~1% of all familial ALS and fronto-temporal dementia cases. The present study used the fruit fly, Drosophila melanogaster, to assess the mechanism of toxicity of ANXA11 mutants in residues that are conserved in the fly ANXB11 protein, the closest homolog to human ANXA11. In immune fluorescence, lifespan and negative geotaxis assays ANXA11 mutants, while displaying some degree of alteration in localization and function, did not exert any relevant organism toxicity in Drosophila. However, they showed a specific interaction with human TAR DNA-binding protein (TDP43). The present study illustrated that the ANXA11 mutants interact with human TDP43, but not the fly TAR DNA-binding protein-43 homolog (TBPH) or other ALS-associated genes such as super oxide dismutase 1, to shorten lifespan and increase negative geotaxis defects. This sheds light both on the mechanisms underlying ALS, further elucidating the intricate molecular network implicated in ALS and placing ANXA11 as a key player in its pathology, and on the complexity of using Drosophila as a model organism for researching genes in ALS.}, } @article {pmid39300745, year = {2024}, author = {Guo, Y and Ma, G and Wang, Y and Lin, T and Hu, Y and Zang, T}, title = {Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.}, journal = {Aging cell}, volume = {23}, number = {11}, pages = {e14271}, pmid = {39300745}, issn = {1474-9726}, support = {62371161//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Longevity/genetics ; *Neurodegenerative Diseases/genetics ; *Epigenesis, Genetic ; *Aging/genetics ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; }, abstract = {The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.}, } @article {pmid39302926, year = {2024}, author = {Chung, YM and Hu, CS and Sun, E and Tseng, HC}, title = {Morphological multiparameter filtration and persistent homology in mitochondrial image analysis.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310157}, pmid = {39302926}, issn = {1932-6203}, mesh = {Humans ; *Mitochondria/metabolism/genetics ; *Membrane Transport Proteins/genetics/metabolism ; *Image Processing, Computer-Assisted/methods ; Cell Cycle Proteins/genetics/metabolism ; Transcription Factor TFIIIA/genetics/metabolism ; Mutation ; Software ; }, abstract = {The complexity of branching and curvilinear morphology of a complete mitochondrial network within each cell is challenging to analyze and quantify. To address this challenge, we developed an image analysis technique using persistent homology with a multiparameter filtration framework, combining image processing techniques in mathematical morphology. We show that such filtrations contain both topological and geometric information about complex cellular organelle structures, which allows a software program to extract meaningful features. Using this information, we also develop a connectivity index that describes the morphology of the branching patterns. As proof of concept, we utilize this approach to study how mitochondrial networks are altered by genetic changes in the Optineurin gene. Mutations in the autophagy gene Optineurin (OPTN) are associated with primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), and Paget's disease of the bone, but the pathophysiological mechanism is unclear. We utilized the proposed mathematical morphology-based multiparameter filtration and persistent homology approach to analyze and quantitatively compare how changes in the OPTN gene alter mitochondrial structures from their normal interconnected, tubular morphology into scattered, fragmented pieces.}, } @article {pmid39300574, year = {2024}, author = {Ashkaran, F and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Mutation/metal deficiency in the "electrostatic loop" enhanced aggregation process in apo/holo SOD1 variants: implications for ALS diseases.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {177}, pmid = {39300574}, issn = {2661-801X}, abstract = {Despite the many mechanisms it has created to prevent unfolding and aggregation of proteins, many diseases are caused by abnormal folding of proteins, which are called misfolding diseases. During this process, proteins undergo structural changes and become stable, insoluble beta-sheet aggregates called amyloid fibrils. Mutations/disruptions in metal ion homeostasis in the ALS-associated metalloenzyme superoxide dismutase (SOD1) reduce conformational stability, consistent with the protein aggregation hypothesis for neurodegenerative diseases. However, the exact mechanism of involvement is not well understood. Hence, to understand the role of mutation/ metal deficiency in SOD1 misfolding and aggregation, we investigated the effects of apo/holo SOD1 variants on structural properties using biophysical/experimental techniques. The MD results support the idea that the mutation/metal deficiency can lead to a change in conformation. The increased content of β-sheet structures in apo/holo SOD1 variants can be attributed to the aggregation tendency, which was confirmed by FTIR spectroscopy and dictionary of secondary structure in proteins (DSSP) results. Thermodynamic studies of GdnHCl showed that metal deficiency/mutation/intramolecular S-S reduction together are required to initiate misfolding/aggregation of SOD1. The results showed that apo/holo SOD1 variants under destabilizing conditions induced amyloid aggregates at physiological pH, which were detected by ThT/ANS fluorescence, as well as further confirmation of amyloid/amorphous species by TEM. This study confirms that mutations in the electrostatic loop of SOD1 lead to structural abnormalities, including changes in hydrophobicity, reduced disulfide bonds, and an increased propensity for protein denaturation. This process facilitates the formation of amyloid/amorphous aggregates ALS-associated.}, } @article {pmid39300421, year = {2024}, author = {Koçkaya, PD and Alvur, TM and Odabaşı, O}, title = {Empowering medical students: bridging gaps with high-fidelity simulations; a mixed-methods study on self-efficacy.}, journal = {BMC medical education}, volume = {24}, number = {1}, pages = {1026}, pmid = {39300421}, issn = {1472-6920}, mesh = {Humans ; *Self Efficacy ; *Students, Medical/psychology ; Prospective Studies ; *Clinical Competence ; Male ; Female ; Cardiopulmonary Resuscitation/education ; Simulation Training ; Adult ; Emergency Medicine/education ; High Fidelity Simulation Training ; Young Adult ; Focus Groups ; Education, Medical, Undergraduate/methods ; Empowerment ; }, abstract = {BACKGROUND: High-fidelity simulations play a crucial role in preparing for high-mortality events like cardiopulmonary arrest, emphasizing the need for rapid and accurate intervention. Proficiency in cardiopulmonary resuscitation(CPR) requires a strong self-efficacy(SE); training for both is crucial. This study assesses the impact of Advanced Life Support(ALS) simulation on SE changes in final-year medical students.

METHODS: This mixed-methods prospective simulation study involved medical students in emergency medicine internships, examining self-efficacy perceptions regarding ALS technical skills(ALS-SEP). A comparison was made between students who underwent scenario-based ALS simulation training and those who did not. Competencies in chest compression skills were assessed, and the concordance between ALS-SEP scores and observed CPR performances were evaluated. Focus group interviews were conducted and analyzed using content analysis techniques.

RESULTS: The study involved 80 students, with 53 in the experimental group(EG) and 27 in the control group(CG). The EG, underwent simulation training, showed a significantly higher ALS-SEP change than the CG(p < 0.05). However, there was low concordance between pre-simulation SEP and actual performance. Compression skills success rates were inadequate. Qualitative analysis revealed main themes as"learning"(32.6%), "self-efficacy"(29%), "simulation method"(21.3%), and "development"(16.5%).

DISCUSSION: Post-simulation, students reported improved SEP and increased readiness for future interventions. The findings and qualitative statements support the effectiveness of simulation practices in bridging the gap between SEP and performance. Utilizing simulation-based ALS training enhances learners' belief in their capabilities, raises awareness of their competencies, and encourages reflective thinking. Given the importance of high SEP for ALS, simulation trainings correlating self-efficacy perception and performance may significantly reduce potential medical errors stemming from a disparity between perceived capability and actual performance.}, } @article {pmid39300071, year = {2024}, author = {Castelli, S and Desideri, E and Laureti, L and Felice, F and De Cristofaro, A and Scaricamazza, S and Lazzarino, G and Ciriolo, MR and Ciccarone, F}, title = {N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {686}, pmid = {39300071}, issn = {2041-4889}, support = {GR-2019-1236998//Ministero della Salute (Ministry of Health, Italy)/ ; MNESYS PNRR - MUR PE00000006//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *Glycolysis/drug effects ; *Muscle Fibers, Skeletal/metabolism/drug effects ; Mice ; *Aspartic Acid/metabolism/analogs & derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Oxidation-Reduction ; Cell Line ; Mice, Transgenic ; }, abstract = {N-acetylaspartate (NAA) is a neuronal metabolite that can be extruded in extracellular fluids and whose blood concentration increases in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Aspartoacylase (ASPA) is the enzyme responsible for NAA breakdown. It is abundantly expressed in skeletal muscle and most other human tissues, but the role of NAA catabolism in the periphery is largely neglected. Here we demonstrate that NAA treatment of differentiated C2C12 muscle cells increases lipid turnover, mitochondrial biogenesis and oxidative metabolism at the expense of glycolysis. These effects were ascribed to NAA catabolism, as CRISPR/Cas9 ASPA KO cells are insensitive to NAA administration. Moreover, the metabolic switch induced by NAA was associated with an augmented resistance to atrophic stimuli. Consistently with in vitro results, SOD1-G93A ALS mice show an increase in ASPA levels in those muscles undergoing the glycolytic to oxidative switch during the disease course. The impact of NAA on the metabolism and resistance capability of myotubes supports a role for this metabolite in the phenotypical adaptations of skeletal muscle in neuromuscular disorders.}, } @article {pmid39299905, year = {2024}, author = {Hetz, C and Thielen, P and Matus, S and Nassif, M and Court, F and Kiffin, R and Martinez, G and Cuervo, AM and Brown, RH and Glimcher, LH}, title = {Corrigendum: XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.}, journal = {Genes & development}, volume = {38}, number = {15-16}, pages = {785}, doi = {10.1101/gad.352249.124}, pmid = {39299905}, issn = {1549-5477}, } @article {pmid39299508, year = {2024}, author = {Shetty, P and Ren, Y and Dillon, D and Mcleod, A and Nishijima, D and Taylor, SL and , }, title = {Derivation of a clinical decision rule for termination of resuscitation in non-traumatic pediatric out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {204}, number = {}, pages = {110400}, doi = {10.1016/j.resuscitation.2024.110400}, pmid = {39299508}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Child ; *Clinical Decision Rules ; *Cardiopulmonary Resuscitation/methods ; Child, Preschool ; Emergency Medical Services/methods ; Medical Futility ; Adolescent ; Infant ; Resuscitation Orders ; Withholding Treatment/standards ; }, abstract = {AIM: Prehospital termination of resuscitation (ToR) rules are used to predict medical futility in adult out-of-hospital cardiac arrest (OHCA), however, the available evidence for pediatric patients is limited. The primary aim of this study is to derive a Pediatric Termination of Resuscitation (PToR) prediction rule for use in pediatric non-traumatic OHCA patients.

METHODS: We analyzed a retrospective cohort of pediatric OHCA patients within the CARES database over a 10-year period (2013-2022). We split the dataset into training and test datasets and fit logistic regressions with Least Absolute Shrinkage and Selection Operator (LASSO) to select predictor variables and estimate predictive test characteristics for the primary outcome of death and a secondary composite outcome of death or survival to hospital discharge with unfavorable neurologic status.

RESULTS: We analyzed a sample of 21,240 children where 2,326 (11.0%) survived to hospital discharge, and 1,894 (8.9%) survived to hospital discharge with favorable neurologic status. We derived a PToR rule for death demonstrating a specificity of 99.1% and a positive predictive value (PPV) of 99.8% and a PToR rule for death or survival with poor neurologic status with a specificity of 99.7% and PPV of 99.9% within the test dataset.

CONCLUSION: We derived a clinical prediction rule with high specificity and positive predictive value in prehospital settings utilizing Advanced Life Support (ALS) providers which may inform termination of resuscitation considerations in pediatric patients. Further prospective and validation studies will be necessary to define the appropriateness and applicability of these PToR criteria for routine use.}, } @article {pmid39299489, year = {2024}, author = {Le, NT and Chu, N and Joshi, G and Higgins, NR and Nebie, O and Adelakun, N and Butts, M and Monteiro, MJ}, title = {Prion protein pathology in Ubiquilin 2 models of ALS.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106674}, pmid = {39299489}, issn = {1095-953X}, support = {K22 CA241105/CA/NCI NIH HHS/United States ; R01 NS098243/NS/NINDS NIH HHS/United States ; R35 GM151124/GM/NIGMS NIH HHS/United States ; RF1 NS098243/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Mutation ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism/pathology ; Prion Proteins/metabolism/genetics ; Inclusion Bodies/metabolism/pathology ; Neurons/metabolism/pathology ; Mice, Transgenic ; }, abstract = {Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrP[C]) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrP[C] with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrP[C] protein degradation and leads to mislocalization of PrP[C] in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrP[C] bind together in a complex. The abnormalities in PrP[C] caused by UBQLN2 mutations may be relevant in disease pathogenesis.}, } @article {pmid39299156, year = {2024}, author = {Caswell, G and Wilson, E}, title = {The impact of home mechanical ventilation on the time and manner of death for those with Motor neurone disease (MND): A qualitative study of bereaved family members.}, journal = {Social science & medicine (1982)}, volume = {360}, number = {}, pages = {117345}, doi = {10.1016/j.socscimed.2024.117345}, pmid = {39299156}, issn = {1873-5347}, mesh = {Humans ; *Motor Neuron Disease/psychology/complications ; *Qualitative Research ; Male ; Female ; *Respiration, Artificial/psychology ; Middle Aged ; *Family/psychology ; United Kingdom ; Aged ; *Bereavement ; Attitude to Death ; Adult ; Terminal Care/psychology/methods ; Home Care Services ; Time Factors ; Aged, 80 and over ; }, abstract = {Motor neurone disease (MND) is a progressive neurodegenerative disorder which is ultimately terminal. It causes muscle weakness which can lead to the need for assistance in breathing, for some with the disease. This paper draws on qualitative research using semi-structured interviews with 32 people bereaved by the death of a family member with MND who was dependent on home mechanical ventilation, from across the United Kingdom. Interviews explored how the end-of-life of a person who had used non-invasive ventilation to assist their breathing was experienced by participants, who had cared about, and for them. Four themes are used to examine the impact of dependent ventilation technology on the experience of dying on the part of bereaved family members. Themes are: accompanied dying, planned withdrawal of ventilation, blurred time of death, time post-death. The perception and experience of time was a key component across all four themes. Ventilator technology played a critical role in sustaining life, but it could also contribute to a complex dynamic where the realities of death were mediated or obscured. This raises ethical, emotional, and existential considerations, both for the individuals receiving ventilator support and their families, as well as for healthcare professionals involved in end-of-life care.}, } @article {pmid39299050, year = {2024}, author = {Eshak, D and Arumugam, M}, title = {Unveiling therapeutic biomarkers and druggable targets in ALS: An integrative microarray analysis, molecular docking, and structural dynamic studies.}, journal = {Computational biology and chemistry}, volume = {113}, number = {}, pages = {108211}, doi = {10.1016/j.compbiolchem.2024.108211}, pmid = {39299050}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Molecular Docking Simulation ; *Biomarkers/metabolism/analysis/blood ; Microarray Analysis ; Molecular Dynamics Simulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a debilitating neurodegenerative disorder characterized by the progressive degeneration of nerve cells in the brain and spinal cord. Despite extensive research, its precise etiology remains elusive, and early diagnosis is challenging due to the absence of specific tests. This study aimed to identify potential blood-based biomarkers for early ALS detection and monitoring using datasets from whole blood samples (GSE112680) and oligodendrocytes, astrocytes, and fibroblasts (GSE87385) obtained from the NCBI-GEO repository. Through bioinformatics analysis, including protein-protein interactions and molecular pathway analyses, we identified differentially expressed genes (DEGs) associated with ALS. Notably, ALS2, ADH7, ALDH8A1, ALDH3B1, ABHD2, ABHD17B, ABHD12, ABHD13, PGAM2, AURKB, ANAPC11, VAPA, UNC45B, and TNNT2 emerged as top-ranked DEGs, implicated in drug metabolism, protein depalmytilation, and the AKT/mTOR signaling pathways. Among these, AurKB established as a potential therapeutic biomarker with relevance to various neurological conditions. Consequently, AurKB was selected for identifying potential therapeutic molecules and utilized for in silico structural characterization studies. Exploration of the IMPATT database led to the discovery of a lead compound similar to Fostamatinib, currently used for AurKB. Initial molecular docking and MMGBSA-based binding energy analysis were followed by molecular dynamics simulation (MDS) and free energy landscape (FEL) analysis to validate the ligand's binding efficacy and understand dynamic processes within the biological system. The identified potential biomarkers and lead molecule provide novel insights into the correlation between blood cell transcripts and ALS pathology, paving the way for blood-based diagnostic tools for early ALS detection and ongoing disease monitoring.}, } @article {pmid39297270, year = {2024}, author = {Doğan, V and Şenormanci, Ö}, title = {Validity and Reliability of the Affective Lability Scale-18 (ALS-18) Turkish Form in the Non-Clinical Group.}, journal = {Turk psikiyatri dergisi = Turkish journal of psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.5080/u27329}, pmid = {39297270}, issn = {2651-3463}, abstract = {OBJECTIVE: Affective lability, which is an important aspect of mood dysregulation, is seen in many psychiatric conditions. The aim of this study is to examine the psychometric properties of the Affective Lability Scale-18 in the Turkish sample of the non-clinical group.

METHOD: A total of 615 individuals (312 females and 303 males) who did not have a past or current psychiatric disorder were included in the study. The participants were administered sociodemographic data form, Affective Lability Scale-18, Difficulties in Emotion Regulation Scale, and Beck Depression Inventory. The participants were divided into 4 groups; a pilot group, EFA (exploratory factor analysis) group, CFA (confirmatory factor analysis) group and test-retest group.

RESULTS: The factor analysis conducted for the construct validity of the scale, revealed similar results to that of the original scale. The Cronbach's alpha internal consistency coefficient was 0.92 for the EFA group and 0.92 for the CFA group. The test-retest reliability coefficient was 0.82. Difficulties in Emotion Regulation Scale (DERS) and Beck's Depression Inventory (BDI) were used tp measure validity. The correlation between the total scores of participants on the ALS-18 and their scores on the DERS and BDI was determined to be positive and moderate (r=0.38, r=41).

CONCLUSION: The Affective Lability Scale-18 in the Turkish sample, three sub-dimensions, anxiety/depression, depression/elevation, anger and the general factor all have sufficient internal consistency and it has been demonstrated that the scale can be applied in our country to evaluate the situations in which affect variability is evaluated.}, } @article {pmid39296960, year = {2024}, author = {Keilholz, AN and Pathak, I and Smith, CL and Osman, KL and Smith, L and Oti, G and Golzy, M and Ma, L and Lever, TE and Nichols, NL}, title = {Tongue exercise ameliorates structural and functional upper airway deficits in a rodent model of hypoglossal motor neuron loss.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1441529}, pmid = {39296960}, issn = {1664-2295}, abstract = {INTRODUCTION: Tongue weakness and atrophy can lead to deficits in the vital functions of breathing and swallowing in patients with motor neuron diseases (MNDs; e.g., amyotrophic lateral sclerosis (ALS) and pseudobulbar palsy), often resulting in aspiration pneumonia, respiratory failure, and death. Available treatments for patients with MNDs are largely palliative; thus, there is a critical need for therapies targeting preservation of upper airway function and suggesting a role for tongue exercise in patients with MNDs. Here, we leveraged our inducible rodent model of hypoglossal (XII) motor neuron degeneration to investigate the effects of a strength endurance tongue exercise program on upper airway structure and function. Our model was created through intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue to induce targeted death of XII motor neurons.

METHODS: Rats in this study were allocated to 4 experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) +/- tongue exercise. Following tongue exercise exposure, we evaluated the effect on respiratory function (via plethysmography), macrostructure [via magnetic resonance imaging (MRI) of the upper airway and tongue], and ultrafine structure [via ex vivo magnetic resonance spectroscopy (MRS) of the tongue] with a focus on lipid profiles.

RESULTS: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to CTB-SAP + exercise rats and control rats +/- tongue exercise, which was ameliorated with tongue exercise. Additionally, CTB-SAP + sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP + exercise rats or control rats +/- tongue exercise.

CONCLUSION: These findings provide further evidence that a strength endurance tongue exercise program may be a viable therapeutic treatment option in patients with XII motor neuron degeneration in MNDs such as ALS. Future directions will focus on investigating the underlying mechanism responsible for tongue exercise-induced plasticity in the hypoglossal-tongue axis, particularly inflammatory associated factors such as BDNF.}, } @article {pmid39296911, year = {2024}, author = {Odat, RM and Alomari, O and Elgenidy, A}, title = {Evaluation of the gold cost criteria as a diagnostic criteria of amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {37}, number = {}, pages = {100524}, pmid = {39296911}, issn = {2405-6502}, } @article {pmid39295200, year = {2024}, author = {Zhang, Z and He, X and Wang, J and Cui, J and Shi, B}, title = {The correlation between social support, coping style, advance care planning readiness, and quality of life in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2024.2400520}, pmid = {39295200}, issn = {2167-9223}, abstract = {OBJECTIVE: The primary goal for clinical healthcare professionals is to enhance the quality of life (QOL) of patients with amyotrophic lateral sclerosis (ALS). This study aimed to explore the correlation between social support, coping style, advance care planning (ACP) readiness, and QOL in patients with ALS. We also sought to analyze the mediating effect of coping style and ACP readiness between social support and QOL, and to provide insights for developing targeted interventions to improve patients' QOL.

METHODS: A cross-sectional design was used, with participants recruited through convenience sampling in Tianjin, China. Statistical analysis included the t-test, analysis of variance, correlation analysis, and mediating effect analysis.

RESULTS: The study included 215 participants. The QOL of patients with ALS was at a medium level, with significant correlations between social support, coping style, ACP readiness, and QOL (all p < 0.01). The direct effect of social support on QOL was 0.403 (p = 0.018), accounting for 41.85% of the total effect. The total indirect effect of social support on QOL through coping style and ACP readiness was 0.560 (p < 0.001), accounting for 58.15% of the total effect. The chain mediating effect involving facing, avoiding, and ACP readiness accounted for 16.72%.

CONCLUSION: Social support directly influenced QOL and had an indirect impact through coping style and ACP readiness. Healthcare professionals can improve the QOL of patients with ALS by enhancing social support, disease-coping ability, and ACP readiness in clinical practice.}, } @article {pmid39295118, year = {2024}, author = {Berry, JD and Paganoni, S and Harms, MB and Shneider, N and Andrews, J and Miller, TM and Babu, S and Sherman, AV and Harris, BT and Provenzano, FA and Phatnani, HP and Shefner, J and Garret, MA and Ladha, SS and Tsou, AY and Mohan, P and Igne, C and , and Bowser, R}, title = {Access for ALL in ALS: A large-scale, inclusive, collaborative consortium to unlock the molecular and genetic mechanisms of amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {6}, pages = {1140-1150}, doi = {10.1002/mus.28244}, pmid = {39295118}, issn = {1097-4598}, support = {OT2 NS136938/NS/NINDS NIH HHS/United States ; OT2 NS136939/NS/NINDS NIH HHS/United States ; 1OT2NS136939-01//National Institute of Neurological Disorders and Stroke, NIH/ ; 1OT2NS136938-01//National Institute of Neurological Disorders and Stroke, NIH/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; United States ; Biomedical Research ; National Institutes of Health (U.S.) ; }, abstract = {Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.}, } @article {pmid39294194, year = {2024}, author = {Luthi-Carter, R and Cappelli, S and Le Roux-Bourdieu, M and Tentillier, N and Quinn, JP and Petrozziello, T and Gopalakrishnan, L and Sethi, P and Choudhary, H and Bartolini, G and Gebara, E and Stuani, C and Font, L and An, J and Ortega, V and Sage, J and Kosa, E and Trombetta, BA and Simeone, R and Seredenina, T and Afroz, T and Berry, JD and Arnold, SE and Carlyle, BC and Adolfsson, O and Sadri-Vakili, G and Buratti, E and Bowser, R and Agbas, A}, title = {Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21837}, pmid = {39294194}, issn = {2045-2322}, support = {BB-2022-C5//Target ALS Foundation/ ; Industry-Led Consortium Project Grant//Target ALS Foundation/ ; }, mesh = {Humans ; *Blood Platelets/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/blood/metabolism ; *Biological Specimen Banks ; Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; Biomarkers/blood ; Cytosol/metabolism ; }, abstract = {The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system.}, } @article {pmid39293800, year = {2024}, author = {Gao, J and Chai, N and Wang, T and Han, Z and Chen, J and Lin, G and Wu, Y and Bi, L}, title = {A new technique of percutaneous minimally invasive surgery assisted by magnetic resonance neurography.}, journal = {Bone & joint open}, volume = {5}, number = {9}, pages = {776-784}, pmid = {39293800}, issn = {2633-1462}, abstract = {AIMS: In order to release the contracture band completely without damaging normal tissues (such as the sciatic nerve) in the surgical treatment of gluteal muscle contracture (GMC), we tried to display the relationship between normal tissue and contracture bands by magnetic resonance neurography (MRN) images, and to predesign a minimally invasive surgery based on the MRN images in advance.

METHODS: A total of 30 patients (60 hips) were included in this study. MRN scans of the pelvis were performed before surgery. The contracture band shape and external rotation angle (ERA) of the proximal femur were also analyzed. Then, the minimally invasive GMC releasing surgery was performed based on the images and measurements, and during the operation, incision lengths, surgery duration, intraoperative bleeding, and complications were recorded; the time of the first postoperative off-bed activity was also recorded. Furthermore, the patients' clinical functions were evaluated by means of Hip Outcome Score (HOS) and Ye et al's objective assessments, respectively.

RESULTS: The contracture bands exhibited three typical types of shape - feather-like, striped, and mixed shapes - in MR images. Guided by MRN images, we designed minimally invasive approaches directed to each hip. These approaches resulted in a shortened incision length in each hip (0.3 cm (SD 0.1)), shorter surgery duration (25.3 minutes (SD 5.8)), less intraoperative bleeding (8.0 ml (SD 3.6)), and shorter time between the end of the operation and the patient's first off-bed activity (17.2 hours (SD 2.0)) in each patient. Meanwhile, no serious postoperative complications occurred in all patients. The mean HOS-Sports subscale of patients increased from 71.0 (SD 5.3) to 94.83 (SD 4.24) at six months postoperatively (p < 0.001). The follow-up outcomes from all patients were "good" and "excellent", based on objective assessments.

CONCLUSION: Preoperative MRN analysis can be used to facilitate the determination of the relationship between contracture band and normal tissues. The minimally invasive surgical design via MRN can avoid nerve damage and improve the release effect.}, } @article {pmid39293008, year = {2024}, author = {Ramirez, V and Kittrell, P and Jackson, C and Clegg, A and Allegretti, A}, title = {Sexual Intimacy in Persons with Amyotrophic Lateral Sclerosis and their Partners: A Pilot Study.}, journal = {Journal of allied health}, volume = {53}, number = {3}, pages = {212-217}, pmid = {39293008}, issn = {1945-404X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Pilot Projects ; Male ; Female ; Middle Aged ; *Sexual Partners/psychology ; Aged ; Sexual Behavior ; Adult ; Quality of Life ; }, abstract = {OBJECTIVE: The objective of this study was to describe concerns experienced among persons with amyotrophic lateral sclerosis (PALS) and their partners regarding sexual intimacy, as well as preferences regarding discussion of the topic with healthcare providers.

METHODS: A total of 27 survey responses including 13 PALS and 14 partners were received. Surveys included both quantitative and qualitative data addressing the importance of sexual intimacy to quality of life, assistance required to participate in sexual intimacy, concerns for safety, and preferred timing and method of discussing/receiving information from healthcare professionals.

RESULTS: 100% of respondents stated they had never been asked about sexual intimacy by any healthcare provider. 92% of participants agreed ALS had affected their ability to express sexual intimacy. Participants discussed loss of intimacy as due to muscle weakness, respiratory concerns, and role change among other contributors to the overall experienced change in expression of sexual intimacy. With regards to their preferred method of receiving/discussing information on the effect of ALS on sexual intimacy, 48% of participants preferred use of an online video series, 44% chose a pamphlet, 24% chose a one-on-one discussion with a healthcare provider, and 12% chose a private conversation with their partner and healthcare provider.

CONCLUSIONS: The findings greatly illustrate the difficulties and concerns experienced with sexual intimacy among PALS and their partners as well as the preferred methods for receiving information on the topic.}, } @article {pmid39292705, year = {2024}, author = {Minnella, A and McCusker, KP and Amagata, A and Trias, B and Weetall, M and Latham, JC and O'Neill, S and Wyse, RK and Klein, MB and Trimmer, JK}, title = {Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0309893}, pmid = {39292705}, issn = {1932-6203}, mesh = {Animals ; *Ferroptosis/drug effects ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Humans ; *Parkinson Disease/drug therapy/metabolism/pathology ; Rats ; Mice ; alpha-Synuclein/metabolism ; Lipid Peroxidation/drug effects ; Neurons/drug effects/metabolism/pathology ; Fibroblasts/drug effects/metabolism ; Arachidonate 15-Lipoxygenase/metabolism ; Cells, Cultured ; Male ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.}, } @article {pmid39292682, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Pei, X and Chen, Z and Huang, Y and Zhao, S and Guo, T and Liu, Z}, title = {Immediate efficacy of auricular acupuncture combined with active exercise in the treatment of acute lumbar sprains in 10 minutes: Protocol of a randomized controlled trial.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0308801}, pmid = {39292682}, issn = {1932-6203}, mesh = {Humans ; Adult ; Male ; Female ; *Acupuncture, Ear/methods ; Middle Aged ; *Exercise Therapy/methods ; Low Back Pain/therapy ; Treatment Outcome ; Sprains and Strains/therapy ; Prospective Studies ; Lumbosacral Region ; Range of Motion, Articular ; Young Adult ; Adolescent ; Combined Modality Therapy ; Lumbar Vertebrae/physiopathology ; Pain Measurement ; }, abstract = {BACKGROUND: Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes.

METHODS: This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle.

DISCUSSION: This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical.

TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.}, } @article {pmid39292611, year = {2024}, author = {Xu, Z and Tang, J and Gong, Y and Zhang, J and Zou, Y}, title = {Atomistic Insights into the Stabilization of TDP-43 Protofibrils by ATP.}, journal = {Journal of chemical information and modeling}, volume = {64}, number = {19}, pages = {7639-7649}, doi = {10.1021/acs.jcim.4c01140}, pmid = {39292611}, issn = {1549-960X}, mesh = {*Adenosine Triphosphate/metabolism ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism ; Humans ; Protein Stability ; Hydrogen Bonding ; }, abstract = {The aberrant accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates in the cytoplasm of motor neurons is the main pathological hallmark of amyotrophic lateral sclerosis (ALS). Previous experiments reported that adenosine triphosphate (ATP), the universal energy currency for all living cells, could induce aggregation and enhance the folding of TDP-43 fibrillar aggregates. However, the significance of ATP on TDP-43 fibrillation and the mechanism behind it remain elusive. In this work, we conducted multiple atomistic molecular dynamics (MD) simulations totaling 20 μs to search the critical nucleus size of TDP-43282-360 and investigate the impact of ATP molecules on preformed protofibrils. The results reveal that the trimer is the critical nucleus for TDP-43282-360 fibril formation and the tetramer is the minimal stable nucleus. When ATP molecules bind to the TDP-43282-360 trimer and tetramer, they can consolidate the TDP-43282-360 protofibrils by increasing the content of the β-sheet structure and promoting the formation of hydrogen bonds (H-bonds). Binding site analyses show that the N-terminus of TDP-43282-360 protofibrils is the main binding site of ATP, and R293 dominates the direct binding of ATP. Further analyses reveal that the π-π, cation-π, salt bridge, and H-bonding interactions together contribute to the binding of ATP to TDP-43282-360 protofibrils. This study decoded the detailed stabilization mechanism of protofibrillar TDP-43282-360 oligomers by ATP, and may provide new avenues for the development of drug design against ALS.}, } @article {pmid39292414, year = {2024}, author = {Ataman, R and Alhasani, R and Auneau-Enjalbert, L and Quigley, A and Michael, HU and Ahmed, S}, title = {The psychometric properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system in neurorehabilitation populations: a systematic review.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {106}, pmid = {39292414}, issn = {2509-8020}, support = {36053//Canadian Foundation of Innovation and the Ministry of Health of Quebec/ ; }, mesh = {Humans ; *Nervous System Diseases/rehabilitation/psychology/diagnosis ; *Neurological Rehabilitation/methods ; *Psychometrics/methods ; *Quality of Life/psychology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To systematically review the literature of existing evidence on the measurement properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system among neurorehabilitation populations.

DATA SOURCES: The Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guided this systematic review in which we searched nine electronic databases and registries, and hand-searched reference lists of included articles.

STUDY SELECTION: Two independent reviewers screened selected articles and extracted data from 28 included studies.

DATA EXTRACTION: COSMIN's approach guided extraction and synthesizing measurement properties evidence (insufficient, sufficient), and the modified GRADE approach guided synthesizing evidence quality (very-low, low, moderate, high) by diagnosis.

DATA SYNTHESIS: Neuro-QoL has sufficient measurement properties when used by individuals with Huntington's disease, Multiple Sclerosis, Parkinson's disease, stroke, lupus, cognitive decline, and amyotrophic lateral sclerosis. The strongest evidence is for the first four conditions, where test-retest reliability, construct validity, and responsiveness are nearly always sufficient (GRADE: moderate-high). Structural validity is assessed only in multiple sclerosis and stroke but is often insufficient (GRADE: moderate-high). Criterion validity is sufficient in some stroke and Huntington's disease domains (GRADE: high). Item response theory analyses were reported for some stroke domains only. There is limited, mixed evidence for responsiveness and measurement error (GRADE: moderate-high), and no cross-cultural validity evidence CONCLUSIONS: Neuro-QoL domains can describe and evaluate patients with Huntington's disease, multiple sclerosis, Parkinson's disease, and stroke, but predictive validity evidence would be beneficial. In the other conditions captured in this review, a limited number of Neuro-QoL domains have evidence for descriptive use only. For these conditions, further evidence of structural validity, measurement error, cross-cultural validity and predictive validity would enhance the use and interpretation of Neuro-QoL.}, } @article {pmid39292338, year = {2024}, author = {Zhang, H and Gao, C and Yang, D and Nie, L and He, K and Chen, C and Li, S and Huang, G and Zhou, L and Huang, X and Wu, D and Liu, J and Huang, Z and Wang, J and Li, W and Zhang, Z and Yang, X and Zou, L}, title = {Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1[G93A] Transgenic Mice Via Activation of Mitophagy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39292338}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1[G93A] transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1[G93A] mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1[G93A] mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.}, } @article {pmid39291248, year = {2024}, author = {Senerchia, G and Dubbioso, R}, title = {Non-invasive brain stimulation therapy in amyotrophic lateral sclerosis: are we ready for clinical use?.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101055}, pmid = {39291248}, issn = {2666-7762}, } @article {pmid39291166, year = {2024}, author = {Gianferrari, G and Cuoghi Costantini, R and Crippa, V and Carra, S and Bonetto, V and Pansarasa, O and Cereda, C and Zucchi, E and Martinelli, I and Simonini, C and Vicini, R and Fini, N and Trojsi, F and Passaniti, C and Ticozzi, N and Doretti, A and Diamanti, L and Fiamingo, G and Conte, A and Dalla Bella, E and D'Errico, E and Scarian, E and Pasetto, L and Antoniani, F and Galli, V and Casarotto, E and , and D'Amico, R and Poletti, A and Mandrioli, J}, title = {Colchicine treatment in amyotrophic lateral sclerosis: safety, biological and clinical effects in a randomized clinical trial.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae304}, pmid = {39291166}, issn = {2632-1297}, abstract = {In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.}, } @article {pmid39290830, year = {2024}, author = {Noches, V and Campos-Melo, D and Droppelmann, CA and Strong, MJ}, title = {Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1417961}, pmid = {39290830}, issn = {1662-5099}, abstract = {The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.}, } @article {pmid39290715, year = {2024}, author = {Huang, L and Liu, M and Tang, J and Gong, Z and Li, Z and Yang, Y and Zhang, M}, title = {The role of ALDH2 rs671 polymorphism and C-reactive protein in the phenotypes of male ALS patients.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1397991}, pmid = {39290715}, issn = {1662-4548}, abstract = {BACKGROUND: The aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients.

METHODS: Clinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects.

RESULTS: Male patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (β = 0.274, 95% CI = 0.048-0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = -1.790, 95% CI = -4.555--0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses.

CONCLUSION: The ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients.}, } @article {pmid39289761, year = {2024}, author = {van der Geest, AT and Jakobs, CE and Ljubikj, T and Huffels, CFM and Cañizares Luna, M and Vieira de Sá, R and Adolfs, Y and de Wit, M and Rutten, DH and Kaal, M and Zwartkruis, MM and Carcolé, M and Groen, EJN and Hol, EM and Basak, O and Isaacs, AM and Westeneng, HJ and van den Berg, LH and Veldink, JH and Schlegel, DK and Pasterkamp, RJ}, title = {Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {152}, pmid = {39289761}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; ALS-on-a-chip//Stichting ALS Nederland/ ; MUS-ALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; INTEGRALS//E-Rare/ ; TRIAGE//JPND/ ; EScORIAL/ERC_/European Research Council/International ; }, mesh = {Humans ; *Organoids/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics ; *Induced Pluripotent Stem Cells/pathology ; *Synapses/pathology/genetics ; Male ; Female ; Cerebral Cortex/pathology ; DNA Repeat Expansion/genetics ; }, abstract = {A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.}, } @article {pmid39289471, year = {2024}, author = {Jawdat, O and Rucker, J and Nakano, T and Takeno, K and Statland, J and Pasnoor, M and Dimachkie, MM and Sabus, C and Badawi, Y and Hunt, SL and Tomioka, NH and Gunewardena, S and Bloomer, C and Wilkins, HM and Herbelin, L and Barohn, RJ and Nishimune, H}, title = {Resistance exercise in early-stage ALS patients, ALSFRS-R, Sickness Impact Profile ALS-19, and muscle transcriptome: a pilot study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21729}, pmid = {39289471}, issn = {2045-2322}, support = {P30 GM122731/GM/NIGMS NIH HHS/United States ; R01NS078214/NS/NINDS NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; R01 NS078214/NS/NINDS NIH HHS/United States ; U54 HD090216/HD/NICHD NIH HHS/United States ; S10 OD021743/OD/NIH HHS/United States ; 19K24690//Japan Society for the Promotion of Science/ ; UL1 TR002366/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Pilot Projects ; Male ; *Resistance Training ; Female ; Middle Aged ; *Transcriptome ; *Muscle Strength ; Aged ; Adult ; Quadriceps Muscle/metabolism/physiopathology ; Muscle, Skeletal/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients' muscle transcriptome.}, } @article {pmid39289025, year = {2024}, author = {Dunlop, CL and Kilpatrick, C and Jones, L and Bonet, M and Allegranzi, B and Brizuela, V and Graham, W and Thompson, A and Cheshire, J and Lissauer, D}, title = {Adapting the WHO hand hygiene 'reminders in the workplace' to improve acceptability for healthcare workers in maternity settings worldwide: a mixed methods study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e083132}, pmid = {39289025}, issn = {2044-6055}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Hand Hygiene ; *Focus Groups ; Female ; *World Health Organization ; *Health Personnel/psychology ; Workplace ; Attitude of Health Personnel ; Reminder Systems ; Adult ; Male ; Cross Infection/prevention & control ; Surveys and Questionnaires ; Hospitals, Maternity ; Developing Countries ; Guideline Adherence ; Interviews as Topic ; }, abstract = {INTRODUCTION: Hand hygiene is key in preventing healthcare-associated infections, but it is challenging in maternity settings due to high patient turnover, frequent emergencies and volume of aseptic procedures. We sought to investigate if adaptions to the WHO hand hygiene reminders could improve their acceptability in maternity settings globally, and use these findings to develop new reminders specific to maternity settings.

METHODS: Informed by Sekhon et al's acceptability framework, we conducted an online survey, semi-structured interviews and a focus group examining the three WHO central hand hygiene reminders ('your five moments of hand hygiene', 'how to hand wash' and 'how to hand rub') and their acceptability in maternity settings. A convergent mixed-methods study design was followed. Findings were examined overall and by country income status. A WHO expert working group tested the integrated findings, further refined results and developed recommendations to improve acceptability for use in the global maternity community. Findings were used to inform the development of two novel and acceptable hand hygiene reminders for use in high-income country (HIC) and low- and middle-income country (LMIC) maternity settings.

RESULTS: Participation in the survey (n=342), semi-structured interviews (n=12) and focus group (n=7) spanned 51 countries (14 HICs and 37 LMICs). The highest scoring acceptability constructs were clarity of the intervention (intervention coherence), confidence in performance (self-efficacy), and alignment with personal values (ethicality). The lowest performing were perceived difficulty (burden) and how the intervention made the participant feel (affective attitude). Overfamiliarity reduced acceptability in HICs (perceived effectiveness). In LMICs, resource availability was a barrier to implementation (opportunity cost). Two new reminders were developed based on the findings, using inclusive female images, and clinical examples from maternity settings.

CONCLUSION: Following methodologically robust adaptation, two novel and inclusive maternity-specific hand hygiene reminders have been developed for use in both HIC and LMICs.}, } @article {pmid39288267, year = {2024}, author = {Liu, H and Zhao, XF and Lu, YN and Hayes, LR and Wang, J}, title = {CRISPR/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {21}, pages = {}, pmid = {39288267}, issn = {1558-8238}, support = {R01 NS123538/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *CRISPR-Cas Systems ; Mice ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *DNA Repeat Expansion/genetics ; *Mice, Transgenic ; Protein Biosynthesis ; Induced Pluripotent Stem Cells/metabolism ; RNA/genetics/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {A hexanucleotide GGGGCC repeat expansion in the non-coding region of the C9orf72 gene is the most common genetic mutation identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The resulting repeat RNA and dipeptide repeat proteins from non-conventional repeat translation have been recognized as important markers associated with the diseases. CRISPR/Cas13d, a powerful RNA-targeting tool, has faced challenges in effectively targeting RNA with stable secondary structures. Here we report that CRISPR/Cas13d can be optimized to specifically target GGGGCC repeat RNA. Our results demonstrate that the CRISPR/Cas13d system can be harnessed to significantly diminish the translation of poly-dipeptides originating from the GGGGCC repeat RNA. This efficacy has been validated in various cell types, including induced pluripotent stem cells and differentiated motor neurons originating from C9orf72-ALS patients, as well as in C9orf72 repeat transgenic mice. These findings demonstrate the application of CRISPR/Cas13d in targeting RNA with intricate higher-order structures and suggest a potential therapeutic approach for ALS and FTD.}, } @article {pmid39287680, year = {2024}, author = {Castelnovo, V and Canu, E and Aiello, EN and Curti, B and Sibilla, E and Torre, S and Freri, F and Tripodi, C and Lumaca, L and Spinelli, EG and Schito, P and Russo, T and Falzone, Y and Verde, F and Silani, V and Ticozzi, N and Sturm, VE and Rankin, KP and Gorno-Tempini, ML and Poletti, B and Filippi, M and Agosta, F}, title = {How to detect affect recognition alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7208-7221}, pmid = {39287680}, issn = {1432-1459}, support = {StG-2016_714388_NeuroTRACK//FP7 Ideas: European Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests ; Recognition, Psychology/physiology ; Cognitive Dysfunction/diagnosis/etiology/physiopathology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To define the clinical usability of an affect recognition (AR) battery-the Comprehensive Affect Testing System (CATS)-in an Italian sample of patients with amyotrophic lateral sclerosis (ALS).

METHODS: 96 ALS patients and 116 healthy controls underwent a neuropsychological assessment including the AR subtests of the abbreviated version of the CATS (CATS-A). CATS-A AR subtests and their global score (CATS-A AR Quotient, ARQ) were assessed for their factorial, convergent, and divergent validity. The diagnostic accuracy of each CATS-A AR measure in discriminating ALS patients with cognitive impairment from cognitively normal controls and patients was tested via receiver-operating characteristics analyses. Optimal cut-offs were identified for CATS-A AR measures yielding an acceptable AUC value (≥ .70). The ability of CATS-A ARQ to discriminate between different ALS cognitive phenotypes was also tested. Gray-matter (GM) volumes of controls, ALS with normal (ALS-nARQ), and impaired ARQ score (ALS-iARQ) were compared using ANCOVA models.

RESULTS: CATS-A AR subtests and ARQ proved to have moderate-to-strong convergent and divergent validity. Almost all considered CATS-A measures reached acceptable accuracy and diagnostic power (AUC range = .79-.83). ARQ showed to be the best diagnostic measure (sensitivity = .80; specificity = .75) and discriminated between different ALS cognitive phenotypes. Compared to ALS-nARQ, ALS-iARQ patients showed reduced GM volumes in the right anterior cingulate, right middle frontal, left inferior temporal, and superior occipital regions.

CONCLUSIONS: The AR subtests of the CATS-A, and in particular the CATS-A ARQ, are sound measures of AR in ALS. AR deficits may be a valid marker of frontotemporal involvement in these patients.}, } @article {pmid39287519, year = {2024}, author = {Wendebourg, MJ and Kesenheimer, E and Sander, L and Weigel, M and Weidensteiner, C and Haas, T and Madoerin, P and Diebold, M and Deigendesch, N and Neuhaus, D and Naumann, N and Neuwirth, C and Braun, N and Weber, M and Granziera, C and Scheurer, E and Lenz, C and Schweikert, K and Sinnreich, M and Lieb, J and Bieri, O and Schlaeger, R}, title = {The Lateral Corticospinal Tract Sign: An MRI Marker for Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {312}, number = {3}, pages = {e231630}, doi = {10.1148/radiol.231630}, pmid = {39287519}, issn = {1527-1315}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Prospective Studies ; *Pyramidal Tracts/diagnostic imaging/pathology ; Sensitivity and Specificity ; }, abstract = {Background Radially sampled averaged magnetization inversion-recovery acquisition (rAMIRA) imaging shows hyperintensity in the lateral corticospinal tract (CST) in patients with motor neuron diseases. Purpose To systematically determine the accuracy of the lateral corticospinal tract sign for detecting patients with amyotrophic lateral sclerosis (ALS) at rAMIRA MRI. Materials and Methods This study included prospectively acquired data from participants in ALS and other motor neuron disease imaging studies at the University Hospital Basel, Switzerland. All participants underwent 3-T axial two-dimensional rAMIRA imaging at four cervical intervertebral disk levels. The lateral CST sign was defined as spinal cord white matter hyperintensity dorsolateral to the anterior horns, with higher signal intensity than in the dorsal columns on axial rAMIRA images. Marker accuracy was assessed in a study data set and in an independent validation data set. Postmortem rAMIRA imaging and histopathologic analysis were performed in one participant who died during the study. Results Participants with ALS (study data set: 38 participants [mean age, 61 years; IQR, 15 years], 22 male participants; validation data set: 10 participants [mean age, 61 years; IQR, 21 years], seven male participants), post-polio syndrome (study data set: 25 participants [mean age, 68 years; IQR, 8 years], 12 male participants), spinal muscular atrophy (study data set: 10 participants [mean age, 43 years; IQR, 14 years], eight male participants; validation data set: five participants [mean age, 38 years; IQR, 19 years], two male participants), and healthy control participants (study data set: 60 participants [mean age, 57 years; IQR, 20 years], 36 male participants; validation data set: 10 participants [mean age, 44 years; IQR, 17 years], seven male participants) were included. The sensitivity and specificity of rAMIRA for ALS were 60% (23 of 38) and 97% (91 of 94) in the study data set and 100% (10 of 10) and 93% (14 of 15) in the validation data set, respectively. Histopathologic analysis showed distinct loss of myelinated axons in the localization of the hyperintensities observed at rAMIRA imaging performed in situ and after organ extraction. Conclusion The recently defined marker at rAMIRA MRI may be a promising tool for assessing upper motor neuron degeneration in the lateral CST in patients with ALS. Clinical trials registration no. NCT03561623, NCT05764434, NCT06137612 © RSNA, 2024 Supplemental material is available for this article.}, } @article {pmid39287472, year = {2024}, author = {Kasperkiewicz, M}, title = {Letter to the Editor: Comment on Bocanegra-Oyola et al's "Clinical Characteristics of Ocular Mucous Membrane Pemphigoid: A Systematic Review and Meta-Analysis".}, journal = {Ocular immunology and inflammation}, volume = {32}, number = {10}, pages = {2622-2623}, doi = {10.1080/09273948.2024.2404105}, pmid = {39287472}, issn = {1744-5078}, mesh = {Humans ; Diagnosis, Differential ; *Pemphigoid, Benign Mucous Membrane/diagnosis ; Meta-Analysis as Topic ; }, abstract = {The work by Bocanegra-Oyola et al. provides a qualitative analysis and meta-analysis of ocular pemphigoid characteristics. This correspondence discusses the need for diagnostic process optimization to better differentiate between ocular pemphigoid and its mimicker pseudopemphigoid.}, } @article {pmid39286440, year = {2024}, author = {Kew, SYN and Mok, SY and Goh, CH}, title = {Machine learning and brain-computer interface approaches in prognosis and individualized care strategies for individuals with amyotrophic lateral sclerosis: A systematic review.}, journal = {MethodsX}, volume = {13}, number = {}, pages = {102765}, pmid = {39286440}, issn = {2215-0161}, abstract = {Amyotrophic lateral sclerosis (ALS) characterized by progressive degeneration of motor neurons is a debilitating disease, posing substantial challenges in both prognosis and daily life assistance. However, with the advancement of machine learning (ML) which is renowned for tackling many real-world settings, it can offer unprecedented opportunities in prognostic studies and facilitate individuals with ALS in motor-imagery tasks. ML models, such as random forests (RF), have emerged as the most common and effective algorithms for predicting disease progression and survival time in ALS. The findings revealed that RF models had an excellent predictive performance for ALS, with a testing R2 of 0.524 and minimal treatment effects of 0.0717 for patient survival time. Despite significant limitations in sample size, with a maximum of 18 participants, which may not adequately reflect the population diversity being studied, ML approaches have been effectively applied to ALS datasets, and numerous prognostic models have been tested using neuroimaging data, longitudinal datasets, and core clinical variables. In many literatures, the constraints of ML models are seldom explicitly enunciated. Therefore, the main objective of this research is to provide a review of the most significant studies on the usage of ML models for analyzing ALS. This review covers a variation of ML algorithms involved in applications in ALS prognosis besides, leveraging ML to improve the efficacy of brain-computer interfaces (BCIs) for ALS individuals in later stages with restricted voluntary muscular control. The key future advances in individualized care and ALS prognosis may include the advancement of more personalized care aids that enable real-time input and ongoing validation of ML in diverse healthcare contexts.}, } @article {pmid39286389, year = {2024}, author = {Willman, M and Patel, G and Lucke-Wold, B}, title = {T lymphocyte proportion in Alzheimer's disease prognosis.}, journal = {World journal of clinical cases}, volume = {12}, number = {26}, pages = {6001-6003}, pmid = {39286389}, issn = {2307-8960}, abstract = {Bai et al investigate the predictive value of T lymphocyte proportion in Alzheimer's disease (AD) prognosis. Through a retrospective study involving 62 AD patients, they found that a decrease in T lymphocyte proportion correlated with a poorer prognosis, as indicated by higher modified Rankin scale scores. While the study highlights the potential of T lymphocyte proportion as a prognostic marker, it suggests the need for larger, multicenter studies to enhance generalizability and validity. Additionally, future research could use cognitive exams when evaluating prognosis and delve into immune mechanisms underlying AD progression. Despite limitations inherent in retrospective designs, Bai et al's work contributes to understanding the immune system's role in AD prognosis, paving the way for further exploration in this under-researched area.}, } @article {pmid39283513, year = {2024}, author = {Koopmann, A and Hoffmann, S and Riegler, A and Cordes, J and Kiefer, F}, title = {[Factors influencing hospital readmission rates in alcohol use disorder].}, journal = {Der Nervenarzt}, volume = {}, number = {}, pages = {}, pmid = {39283513}, issn = {1433-0407}, abstract = {BACKGROUND: According to data from the Federal Statistical Office, the diagnosis of alcohol use disorder (AUD) (F 10) is the second most common main diagnosis for hospital treatment. Those affected by this disorder are often repeatedly hospitalized at short intervals due to relapses; however, little is known about the factors that influence readmission rates after initial treatment.

AIM OF THE STUDY: The aim of this retrospective analysis is to analyze the effects of treatment type (qualified withdrawal treatment (QE) versus physical detoxification) and discharge mode on the probability of readmission in alcohol-dependent patients after inpatient treatment.

MATERIAL AND METHODS: Data from 981 male and female alcohol-dependent patients who completed either qualified withdrawal treatment (QE) (68% men; mean age 47.6 years) or inpatient detoxification (74% men; mean age 48.0 years) were analyzed. Predictors of regular discharge were determined separately for both types of treatment using stepwise logistic regression.

RESULTS: Patients who had completed a qualified withdrawal treatment were significantly more likely to be regularly discharged. Regular completion of the qualified withdrawal treatment (QE) led to a relative reduction in the readmission rate of 25.64% within 1 year compared to a physical detoxification.

CONCLUSION: In order to prevent readmission and chronic courses of alcohol use disorder (AUD), qualified withdrawal treatment should always be recommended to affected patients instead of physical detoxification. Aktuelle Daten des Statistischen Bundesamtes für das Jahr 2022 zeigen, dass die Diagnose "Psychische und Verhaltensstörungen durch Alkohol (F 10.X)" die zweithäufigste Hauptdiagnose bei Krankenhausbehandlungen darstellt [13]. Im Gesundheitssystem entstehen durch dieses Erkrankungsbild und seine somatischen und psychischen Folgeerkrankungen jährlich ca. 10 Mrd. € direkte Kosten [13]. Dieser Sachverhalt wird dadurch kontrastiert, dass die Krankenkassen die qualifizierte Entzugsbehandlung (QE) als leitliniengerechte Goldstandardtherapie [4] wiederholt infrage stellen [10].}, } @article {pmid39283487, year = {2024}, author = {Zufiría, M and Pikatza-Menoio, O and Garciandia-Arcelus, M and Bengoetxea, X and Jiménez, A and Elicegui, A and Levchuk, M and Arnold-García, O and Ondaro, J and Iruzubieta, P and Rodríguez-Gómez, L and Fernández-Pelayo, U and Muñoz-Oreja, M and Aiastui, A and García-Verdugo, JM and Herranz-Pérez, V and Zulaica, M and Poza, JJ and Ruiz-Onandi, R and Fernández-Torrón, R and Espinal, JB and Bonilla, M and Lersundi, A and Fernández-Eulate, G and Riancho, J and Vallejo-Illarramendi, A and Holt, IJ and Sáenz, A and Malfatti, E and Duguez, S and Blázquez, L and López de Munain, A and Gerenu, G and Gil-Bea, F and Alonso-Martín, S}, title = {Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {43}, pmid = {39283487}, issn = {1432-0533}, support = {CB06/05/1126//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; PI2020/08-1//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; P18/01066//Instituto de Salud Carlos III/ ; PI19/00175//Instituto de Salud Carlos III/ ; PI21/00153//Instituto de Salud Carlos III/ ; PI22/00433//Instituto de Salud Carlos III/ ; IJC2019-039965-I//Instituto de Salud Carlos III/ ; 2020-CIEN-000057-01//Diputación Foral de Gipuzkoa/ ; 2021-CIEN-000020-01//Diputación Foral de Gipuzkoa/ ; 2019-FELL-000010-01//Diputación Foral de Gipuzkoa/ ; 2020-FELL-000016-02-01//Diputación Foral de Gipuzkoa/ ; 2021-FELL-000013-02-01//Diputación Foral de Gipuzkoa/ ; BIO17/ND/023/BD//EiTB Maratoia/ ; 2015111122//Osasun Saila, Eusko Jaurlaritzako/ ; 2017222027//Osasun Saila, Eusko Jaurlaritzako/ ; 2018111042//Osasun Saila, Eusko Jaurlaritzako/ ; 2019222020//Osasun Saila, Eusko Jaurlaritzako/ ; 2020111032//Osasun Saila, Eusko Jaurlaritzako/ ; 2020333043//Osasun Saila, Eusko Jaurlaritzako/ ; 2021333050//Osasun Saila, Eusko Jaurlaritzako/ ; PRE_2015_1_0023//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2019_1_0339//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0122//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0191//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0119//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0095//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2021_1_0125//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0253//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; NEURODEGENPROT//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PIF18/317//Euskal Herriko Unibertsitatea/ ; RYC2018-024397-I//Spanish National Plan for Scientific and Technical Research and Innovation/ ; RF/2019/001//Ikerbasque, Basque Foundation for Science/ ; RF/2023/010//Ikerbasque, Basque Foundation for Science/ ; PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; BIO19/ROCHE/017/BD//Roche España/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; *Muscle, Skeletal/metabolism/pathology ; *Forkhead Box Protein O1/metabolism/genetics ; DNA-Binding Proteins/genetics/metabolism ; Male ; RNA-Binding Protein FUS/genetics/metabolism ; Female ; Drosophila ; Muscle Development/physiology ; Middle Aged ; Aged ; Motor Neurons/metabolism/pathology ; Myoblasts/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.}, } @article {pmid39282230, year = {2024}, author = {Tsai, YC and Brown, KA and Bernardi, MT and Harting, J and Clelland, CD}, title = {Single-Molecule Sequencing of the C9orf72 Repeat Expansion in Patient iPSCs.}, journal = {Bio-protocol}, volume = {14}, number = {17}, pages = {e5060}, pmid = {39282230}, issn = {2331-8325}, abstract = {A hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). C9orf72 repeat expansions are currently identified with long-range PCR or Southern blot for clinical and research purposes, but these methods lack accuracy and sensitivity. The GC-rich and repetitive content of the region cannot be amplified by PCR, which leads traditional sequencing approaches to fail. We turned instead to PacBio single-molecule sequencing to detect and size the C9orf72 repeat expansion without amplification. We isolated high molecular weight genomic DNA from patient-derived iPSCs of varying repeat lengths and then excised the region containing the C9orf72 repeat expansion from naked DNA with a CRISPR/Cas9 system. We added adapters to the cut ends, capturing the target region for sequencing on PacBio's Sequel, Sequel II, or Sequel IIe. This approach enriches the C9orf72 repeat region without amplification and allows the repeat expansion to be consistently and accurately sized, even for repeats in the thousands. Key features • This protocol is adapted from PacBio's previous "no-amp targeted sequencing utilizing the CRISPR-Cas9 system." • Optimized for sizing C9orf72 repeat expansions in patient-derived iPSCs and applicable to DNA from any cell type, blood, or tissue. • Requires high molecular weight naked DNA. • Compatible with Sequel I and II but not Revio.}, } @article {pmid39281855, year = {2024}, author = {Jones, VM and Thompson, LDR and Pettus, JR and Green, DC and Lefferts, JA and Shah, PS and Tsongalis, GJ and Sajed, DP and Guilmette, JM and Lewis, JS and Fisch, AS and Tafe, LJ and Kerr, DA}, title = {Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39281855}, issn = {2693-5015}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored.

METHODS: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing.

RESULTS: Fifteen lesions (3 to 42 mm) were identified predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AMLs contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four ALs contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included surface ulceration, vascular thrombosis, chronic inflammation, and myxoid change; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin and/or desmin) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2.

CONCLUSION: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AMLs. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.}, } @article {pmid39280885, year = {2024}, author = {Robinson, SE and Findlay, AR and Li, S and Wang, F and Schiava, M and Daw, J and Diaz-Manera, J and Chou, TF and Weihl, CC}, title = {Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200191}, pmid = {39280885}, issn = {2376-7839}, abstract = {OBJECTIVES: Multisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity.

METHODS: Patients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein.

RESULTS: Among the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = -0.94, p = 0.01).

DISCUSSION: Previous studies have reported that VCP pathogenic variants are "hyperactive." Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.}, } @article {pmid39280794, year = {2024}, author = {Ren, K and Wang, Q and Jiang, D and Liu, E and Alsmaan, J and Jiang, R and Rutkove, SB and Tian, F}, title = {A comprehensive review of electrophysiological techniques in amyotrophic lateral sclerosis research.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1435619}, pmid = {39280794}, issn = {1662-5102}, support = {R01 NS055099/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is characterized by progressive motor neuron degeneration, leading to widespread weakness and respiratory failure. While a variety of mechanisms have been proposed as causes of this disease, a full understanding remains elusive. Electrophysiological alterations, including increased motor axon excitability, likely play an important role in disease progression. There remains a critical need for non-animal disease models that can integrate electrophysiological tools to better understand underlying mechanisms, track disease progression, and evaluate potential therapeutic interventions. This review explores the integration of electrophysiological technologies with ALS disease models. It covers cellular and clinical electrophysiological tools and their applications in ALS research. Additionally, we examine conventional animal models and highlight advancements in humanized models and 3D organoid technologies. By bridging the gap between these models, we aim to enhance our understanding of ALS pathogenesis and facilitate the development of new therapeutic strategies.}, } @article {pmid39280372, year = {2024}, author = {Nishiwaki, T and Oya, A and Fujie, A and Kanaji, A}, title = {Higher Incidence of Venous Thromboembolism in Anterolateral Approach in Lateral Position Compared to Anterolateral Supine and Direct Anterior Approaches in Minimally Invasive Total Hip Arthroplasty.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66831}, pmid = {39280372}, issn = {2168-8184}, abstract = {INTRODUCTION: Venous thromboembolism (VTE) remains a major complication after total hip arthroplasty (THA), irrespective of the surgical approach. This study investigated the incidence of VTE in patients undergoing THA through intermuscular minimally invasive surgical techniques, which included a direct anterior approach (DAA), an anterolateral approach (AL), and an anterolateral supine approach (ALS), at a single institution.

METHODS: A hundred consecutive patients treated with each surgical approach were evaluated. Plasma D-dimer levels one month preoperatively and one day postoperatively, operative time, and intraoperative blood loss were recorded, and the presence of VTE was evaluated based on multidetector-row computed tomography performed the day after surgery. Student's t-test and Pearson's chi-square test or one-way analysis of variance were used in statistical analysis.

RESULTS: No differences among the groups in terms of age, height, weight, operative time, intraoperative bleeding, and preoperative and postoperative D-dimer levels were observed. The overall incidence of VTE was 21%. The incidences of VTE were 30% in AL, 17% in ALS, and 16% in DAA, representing a significantly higher rate in AL than in ALS and DAA (P=0.025). The incidences of VTE on the operated side were 19% in AL, 13% in ALS, and 12% in DAA, with no statistically significant differences. The incidences of VTE on the non-operated side were 22% in AL, 9% in ALS, and 8% in DAA; these differences were statistically significant (P=0.0045).

DISCUSSION: Results showed that the incidence of VTE was significantly higher in AL than in ALS and DAA, especially for the non-operated side.}, } @article {pmid39280119, year = {2024}, author = {Banack, SA and Dunlop, RA and Mehta, P and Mitsumoto, H and Wood, SP and Han, M and Cox, PA}, title = {A microRNA diagnostic biomarker for amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae268}, pmid = {39280119}, issn = {2632-1297}, abstract = {Blood-based diagnostic biomarkers for amyotrophic lateral sclerosis will improve patient outcomes and positively impact novel drug development. Critical to the development of such biomarkers is robust method validation, optimization and replication with adequate sample sizes and neurological disease comparative blood samples. We sought to test an amyotrophic lateral sclerosis biomarker derived from diverse samples to determine if it is disease specific. Extracellular vesicles were extracted from blood plasma obtained from individuals diagnosed with amyotrophic lateral sclerosis, primary lateral sclerosis, Parkinson's disease and healthy controls. Immunoaffinity purification was used to create a neural-enriched extracellular vesicle fraction. MicroRNAs were measured across sample cohorts using real-time polymerase chain reaction. A Kruskal-Wallis test was used to assess differences in plasma microRNAs followed by post hoc Mann-Whitney tests to compare disease groups. Diagnostic accuracy was determined using a machine learning algorithm and a logistic regression model. We identified an eight-microRNA diagnostic signature for blood samples from amyotrophic lateral sclerosis patients with high sensitivity and specificity and an area under the curve calculation of 98% with clear statistical separation from neurological controls. The eight identified microRNAs represent disease-related biological processes consistent with amyotrophic lateral sclerosis. The direction and magnitude of gene fold regulation are consistent across four separate patient cohorts with real-time polymerase chain reaction analyses conducted in two laboratories from diverse samples and sample collection procedures. We propose that this diagnostic signature could be an aid to neurologists to supplement current clinical metrics used to diagnose amyotrophic lateral sclerosis.}, } @article {pmid39279312, year = {2024}, author = {Banaszak-Ziemska, M and Rojek, A and Niedziela, M}, title = {Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.}, journal = {Endokrynologia Polska}, volume = {75}, number = {4}, pages = {428-437}, doi = {10.5603/ep.100030}, pmid = {39279312}, issn = {2299-8306}, mesh = {Humans ; *Pregnancy-Associated Plasma Protein-A/genetics/metabolism/analysis ; Female ; *Insulin-Like Growth Factor I/genetics/analysis/metabolism ; Male ; Child ; Adolescent ; *Insulin-Like Growth Factor Binding Protein 5/genetics ; Carrier Proteins/genetics ; Glycoproteins/genetics/blood ; Growth Disorders/genetics/blood ; Mutation ; Child, Preschool ; }, abstract = {INTRODUCTION: Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs).

MATERIAL AND METHODS: The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA).

RESULTS: The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found.

CONCLUSIONS: Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.}, } @article {pmid39279053, year = {2024}, author = {Lin, PH and Yao, HY and Huang, L and Fu, CC and Yao, XL and Lian, C and Zhang, SF and Lai, WD and Lin, GY and Liao, S and Yang, J and Mao, ZF and Liu, D and Long, BY and Yue, JJ and Gao, C and Long, YM}, title = {Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {9}, pages = {e70042}, pmid = {39279053}, issn = {1755-5949}, support = {2022A1515110143//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010225//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022-LCYJ-YYDZX-04//Multi-center Project of The Second Affiliated Hospital of Guangzhou Medical University/ ; }, mesh = {Humans ; *Glial Fibrillary Acidic Protein/cerebrospinal fluid/immunology ; Female ; Male ; *Aquaporin 4/immunology ; Middle Aged ; *Astrocytes/immunology/metabolism/pathology ; Retrospective Studies ; Adult ; *Biomarkers/cerebrospinal fluid/blood ; Aged ; *Immunoglobulin G/cerebrospinal fluid/blood ; Neurofilament Proteins/cerebrospinal fluid/blood ; Autoantibodies/cerebrospinal fluid/blood ; Young Adult ; Adolescent ; }, abstract = {OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies.

METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA).

RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient.

DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.}, } @article {pmid39278909, year = {2024}, author = {Reis, ALG and Maximino, JR and Lage, LAPC and Gomes, HR and Pereira, J and Brofman, PRS and Senegaglia, AC and Rebelatto, CLK and Daga, DR and Paiva, WS and Chadi, G}, title = {Proteomic analysis of cerebrospinal fluid of amyotrophic lateral sclerosis patients in the presence of autologous bone marrow derived mesenchymal stem cells.}, journal = {Stem cell research & therapy}, volume = {15}, number = {1}, pages = {301}, pmid = {39278909}, issn = {1757-6512}, support = {401922/2014-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 836458/2016//Ministério da Saúde/ ; 1701/22//Financiadora de Estudos e Projetos/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/therapy/metabolism ; Apolipoprotein A-I/cerebrospinal fluid/metabolism ; Apolipoproteins E/metabolism/genetics/cerebrospinal fluid ; Bone Marrow Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/metabolism ; Protein Interaction Maps ; *Proteomics/methods ; *Transplantation, Autologous ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS.

METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 10[6] cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129.

RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects.

CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients.

TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.}, } @article {pmid39277385, year = {2024}, author = {Porri, A and Panozzo, S and Tekeste Sisay, M and Scarabel, L and Lerchl, J and Milani, A}, title = {3D structure of acetolactate synthase explains why the Asp-376-Glu point mutation does not give the same resistance level to different imidazolinone herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106070}, doi = {10.1016/j.pestbp.2024.106070}, pmid = {39277385}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/chemistry ; *Herbicides/pharmacology/chemistry ; *Herbicide Resistance/genetics ; *Imidazoles/pharmacology/chemistry ; *Amaranthus/drug effects/genetics ; *Point Mutation ; Sorghum/genetics/drug effects ; Molecular Docking Simulation ; Plant Proteins/genetics/metabolism/chemistry ; Nicotinic Acids/pharmacology ; Niacin/analogs & derivatives ; }, abstract = {Resistance to ALS-inhibiting herbicides has dramatically increased worldwide due to the persisting evolution of target site mutations that reduce the affinity between the herbicide and the target. We evaluated the effect of the well-known ALS Asp-376-Glu target site mutation on different imidazolinone herbicides, including imazamox and imazethapyr. Greenhouse dose response experiments indicate that the Amaranthus retroflexus biotype carrying Asp-376-Glu was fully controlled by applying the field recommended dose of imazamox, whereas it displayed high level of resistance to imazethapyr. Likewise, Sorghum halepense, carrying Asp-376-Glu showed resistance to field recommended doses of imazethapyr but not of imazamox. Biochemical inhibition and kinetic characterization of the Asp-376-Glu mutant enzyme heterologously expressed using different plant sequence backbones, indicate that the Asp-376-Glu shows high level of insensitivity to imazethapyr but not to imazamox, corroborating the greenhouse results. Docking simulations revealed that imazamox can still inhibit the Asp-376-Glu mutant enzyme through a chalcogen interaction between the oxygen of the ligand and the sulfur atom of the ALS Met200, while imazethapyr does not create such interaction. These results explain the different sensitivity of the Asp-376-Glu mutation towards imidazolinone herbicides, thus providing novel information that can be exploited for defining stewardship guidelines to manage fields infested by weeds harboring the Asp-376-Glu mutation.}, } @article {pmid39277366, year = {2024}, author = {Weng, WF and Yao, X and Zhao, M and Fang, Z and Yang, S and Ruan, JJ}, title = {Novel mutations in acetolactate synthase confer high levels of resistance to tribenuron-methyl in Fagopyrum tataricum.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106039}, doi = {10.1016/j.pestbp.2024.106039}, pmid = {39277366}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Fagopyrum/genetics/drug effects ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; }, abstract = {Tartary buckwheat (Fagopyrum tataricum) field weeds are rich in species, with many weeds causing reduced quality, yield, and crop failure. The selection of herbicide-resistant Tartary buckwheat varieties, while applying low-toxicity and efficient herbicides as a complementary weed control system, is one way to improve Tartary buckwheat yield and quality. Therefore, the development of herbicide-resistant varieties is important for the breeding of Tartary buckwheat. In this experiment, 50 mM ethyl methyl sulfonate solution was used to treat Tartary buckwheat seeds (M1) and then planted in the field. Harvested seeds (M2) were planted in the experiment field of Guizhou University, and when seedlings had 5-7 leaves, the seedlings were sprayed with 166 mg/L tribenuron-methyl (TBM). A total of 15 resistant plants were obtained, of which three were highly resistant. Using the homologous cloning method, an acetolactate synthase (ALS) gene encoding 547 amino acids was identified in Tartary buckwheat. A GTG (valine) to GGA (glycine) mutation (V409G) occurred at position 409 of the ALS gene in the high tribenuron-methyl resistant mutant sm113. The dm36 mutant harbored a double mutation, a deletion mutation at position 405, and a GTG (valine) to GGA (glycine) mutation (V411G) at position 411. The dm110 mutant underwent a double mutation: an ATG (methionine) to AGG (arginine) mutation (M333R) at position 333 and an insertion mutation at position 372. The synthesis of Chl a, Chl b, total Chl, and Car was significantly inhibited by TBM treatment. TBM was more efficient at suppressing the growth of wild-type plants than that of mutant plants. Antioxidant enzyme activities such as ascorbate peroxidase, peroxidase, and superoxide dismutase were significantly higher in resistant plants than in wild-type after spraying with TBM; malondialdehyde content was significantly lower than in wild-type plants after spraying with TBM. Plants with a single-site mutation in the ALS gene could survive, but their growth was affected by herbicide application. In contrast, plants with dual-site mutations in the ALS gene were not affected, indicating that plants with dual-site mutations in the ALS gene showed higher levels of resistance than plants with a single-site mutation in the ALS gene.}, } @article {pmid39277365, year = {2024}, author = {Guan, Y and Liu, L and Zou, Y and Yang, C and Ji, M}, title = {Involvement of P450s in the metabolic resistance of Digitaria sanguinalis (L.) Scop. To ALS-inhibiting herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106038}, doi = {10.1016/j.pestbp.2024.106038}, pmid = {39277365}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology/toxicity ; *Acetolactate Synthase/metabolism/genetics/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Digitaria/drug effects ; Sulfonylurea Compounds/pharmacology ; Plant Weeds/drug effects/metabolism ; Plant Proteins/genetics/metabolism ; Pyridines ; }, abstract = {Weed resistance to a range of herbicides has rapidly evolved, often with different mechanisms of action. The resulting uninhibited growth of weeds poses demonstrable threats to crop production and sustainable agriculture. Digitaria sanguinalis (L.) Scop., a troublesome weed in corn and other agricultural fields, has developed resistance to herbicides that inhibiting ALS (Acetolactate Synthase), such as nicosulfuron. Understanding the weed's resistance patterns and mechanisms is crucial. However, little is known of the non-target site resistance (NTSR) mechanisms of D. sanguinalis owing to a lack of relevant genome sequences and other materials. Therefore, in this study, a population of D.sanguinalis presenting multiple resistance was tested and found that its high level of resistance to ALS-inhibiting herbicides was not associated with target-related alterations.Administration of P450 inhibitors reversed the resistance to ALS-inhibiting herbicides. Following the application of ALS-inhibiting herbicides, the activities of NADPH-P450 reductase and p-nitroanisole O-demethylase (PNOD) were notably greater in the resistant population of D. sanguinalis than those in the susceptible population. The results suggested P450 enzyme familyplays a major role in the metabolic resistance mechanism, that increased P450 enzyme activity promote cross-resistance in D. sanguinalis to ALS-inhibiting herbicides. RNA-seq analysis showed that five genes from the P450 family (CYP709B2, CYP714C2, CYP71A1, CYP76C2, and CYP81E8) were upregulated in resistant D. sanguinalis. In conclusion, the upregulation of several P450 genes is responsible for establishing resistance to ALS-inhibiting herbicides in D. sanguinalis.}, } @article {pmid39277361, year = {2024}, author = {Liu, L and Zou, Y and Guan, Y and Yang, C and Ji, M}, title = {Diverse mechanisms confer bensulfuron-methyl resistance in Schoenoplectiella juncoides (Roxb.) lye.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106034}, doi = {10.1016/j.pestbp.2024.106034}, pmid = {39277361}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Mutation ; Glutathione Transferase/metabolism/genetics ; }, abstract = {The effectiveness of bensulfuron-methyl in controlling Schoenoplectiella juncoides (Roxb.) Lye has significantly decreased in rice fields in China. Hence, a bensulfuron-methyl-resistant S. juncoides population (W15) was collected from Dandong City, Liaoning Province, China, to investigate the underlying resistance mechanisms. Whole-plant dose-response experiments and ALS activity assay confirmed that W15 has evolved high-level resistance to bensulfuron-methyl compared with the susceptible S. juncoides population (W4). Molecular analysis revealed a Pro-197-Ser mutation in ALS1, while there was no significant difference in the relative ALS gene expression between W15 and W4. LC-MS/MS analysis showed W15 metabolized bensulfuron-methyl more rapidly than W4. Furthermore, bensulfuron-methyl resistance in W15 was significantly alleviated by malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl). Glutathione S-transferase activity was higher in W15 than in W4. Meanwhile, W15 displayed cross-resistance to halosulfuron-methyl and multi-resistance to MCPA-Na. In summary, these findings demonstrated for the first time that both target- and non-target-site resistance are relevant in the resistance of S. juncoides to bensulfuron-methyl.}, } @article {pmid39268612, year = {2024}, author = {Meyer, T and Schumann, P and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Grosskreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Vidovic, M and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Schmitt, P and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P}, title = {SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2401131}, pmid = {39268612}, issn = {2167-9223}, abstract = {Objective: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment. Methods: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed. Results: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n = 34), variants of unknown significance (class 3) 0.8% (n = 16), FUS (class 4/5) 0.9% (n = 17), TARDBP (class 4/5) 1.3% (n = 25), C9orf72 hexanucleotide repeat expansion 7.0% (n = 135). In SOD1-ALS (encompassing class 3-5 variants, n = 50), 68.0% (n = 34) reported a negative family history. 74.0% (n = 37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy. Conclusion: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.}, } @article {pmid39276073, year = {2024}, author = {Raymond, J and Berry, JD and Larson, T and Horton, DK and Mehta, P}, title = {Effects of COVID-19 on motor neuron disease mortality in the United States: a population-based cross-sectional study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2024.2401621}, pmid = {39276073}, issn = {2167-9223}, abstract = {BACKGROUND: In March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) to be a pandemic, stating that those with underlying health conditions are most susceptible, including motor neuron disease (MND).

OBJECTIVE: To examine the effect the COVID-19 pandemic had on deaths from MND in the United States.

METHODS: Death certificate data for all MND deaths aged 20 years and older were analyzed from 2017 to 2019 (pre-COVID), then expanded to include 2020 and 2021 (COVID) deaths to evaluate if COVID-19 impacted MND deaths.

RESULTS: The average number of MND deaths documented during the COVID-19 years was 8009, up from 7485 MND deaths pre-COVID. The age-adjusted mortality rate among the non-Hispanic population increased during COVID to 2.78 per 100,000 persons (95% CI = 2.73-2.82) from 1.81 (95% CI = 1.78-1.84). The Hispanic population also saw an increase in mortality rate during COVID (1.61, 95% CI = 1.51-1.71) compared with pre-COVID (1.10, 95% CI = 1.03-1.17). Decedent's home as a place of death also saw a mortality rate increase during COVID (1.51, 95% CI = 1.48-1.54) compared with pre-COVID (1.30, 95% CI = 1.27-1.32). For the Hispanic population, the rate peaked at 80-84 years pre-COVID, but for the COVID years, the rate peaked earlier, at 75-79 years.

CONCLUSION: The total number of MND deaths was greater during COVID than in the preceding years. The analysis suggests there might have been a consequence of circumstances surrounding the global pandemic and the associated restrictions.}, } @article {pmid39275316, year = {2024}, author = {Hamm, JD and Laferrère, B and Albu, JB and Kini, S and Pi-Sunyer, X and Kissileff, HR}, title = {Responsiveness and Reliability of a Sipping Device to Measure Motivation in Normal-Weight Individuals and Bariatric Surgery Patients.}, journal = {Nutrients}, volume = {16}, number = {17}, pages = {}, pmid = {39275316}, issn = {2072-6643}, support = {R01 DK108643/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Motivation ; *Bariatric Surgery ; Female ; Male ; Adult ; Reproducibility of Results ; Middle Aged ; Obesity/surgery/psychology ; Taste ; Beverages ; Sweetening Agents ; Feeding Behavior/psychology ; }, abstract = {There is an urgent need to measure the motivation to taste a sweet fluid in order to determine the influence of sweet tastes on the potential choices and consumption of beverages in patients with obesity. Current methods utilize either survey instruments or arbitrary operant tasks. The sipometer enables the participant to utilize an actual ingestive behavioral response to measure motivation during access to beverages on either ad libitum (AL) or progressive time ratio (PR) schedules. We determined the sipometer's responsiveness and reliability as a test of change in motivation for sweet tastes after bariatric surgery. Participants (58 patients and 28 controls, BMI: 18.5-24.9 kg/m[2]) sham-consumed an aspartame-sweetened (S) and non-sweetened (N) beverage under AL and PR schedules at a pre-surgery/baseline and a 3-month and 24-month visit (patients only). Cumulative pressure (CumPres), a measure of effort, was the sum of the pressures exerted during sipping under each condition. Baseline CumPres for PRS was higher than ALS and ALN in patients (p < 0.03) and higher than PRN in controls (p = 0.009). At 3 months, CumPres did not differ amongst conditions in patients, but CumPres for PRS was higher than all other conditions in controls (p < 0.0005). There were no baseline group differences; however, patients' CumPres for PRS was lower than controls' at 3 months (p = 0.002). Patients' CumPres for PRS decreased non-significantly between the baseline and 3 months but increased at 24 months compared to 3 months (p = 0.025) and was no different from baseline. Controls' CumPres for PRS increased at 3 months (p = 0.0359), but CumPres for all conditions was correlated between visits (p's < 0.038). The sipometer is a reliable and sensitive measure of motivation to consume sweet beverages and may reflect changes in post-operative energy intake.}, } @article {pmid39273978, year = {2024}, author = {Wu, Z and Liu, S and Zhang, X and Qian, X and Chen, Z and Zhao, H and Wan, H and Yin, N and Li, J and Qu, C and Du, H}, title = {Genome-Wide Characterization of Alfin-like Genes in Brassica napus and Functional Analyses of BnaAL02 and BnaAL28 in Response to Nitrogen and Phosphorus Deficiency.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {17}, pages = {}, pmid = {39273978}, issn = {2223-7747}, support = {32072094//National Key Research and Development Program of China/ ; 2023NSCQ-MSX3166//Natural Science Foundation of Chongqing/ ; }, abstract = {Alfin-like proteins (ALs) form a plant-specific transcription factor (TF) gene family involved in the regulation of plant growth and development, and abiotic stress response. In this study, 30 ALs were identified in Brassica napus ecotype 'Zhongshuang 11' genome (BnaALs), and unevenly distributed on 15 chromosomes. Structural characteristic analysis showed that all of the BnaALs contained two highly conserved domains: the N terminal DUF3594 domain and the C-terminal PHD-finger domain. The BnaALs were classified into four groups (Group I-IV), supported by conserved intron-exon and protein motif structures in each group. The allopolyploid event between B. oleracea and B. rapa ancestors and the small-scale duplication events in B. napus both contributed to the large BnaALs expansion. The promoter regions of BnaALs contained multiple abiotic stress cis-elements. The BnaALs in I-IV groups were mainly expressed in cotyledon, petal, root, silique, and seed tissues, and the duplicated gene pairs shared highly similar expression patterns. RNA-seq and RT-qPCR analysis showed that BnaALs were obviously induced by low nitrogen (LN) and low phosphorus (LP) treatments in roots. Overexpressing BnaAL02 and BnaAL28 in Arabidopsis demonstrated their functions in response to LN and LP stresses. BnaAL28 enhanced primary roots' (PRs) length and lateral roots' (LRs) number under LP and LN conditions, where BnaAL02 can inhibit LR numbers under the two conditions. They can promote root hair (RH) elongation under LP conditions; however, they suppressed RH elongation under LN conditions. Our result provides new insight into the functional dissection of this family in response to nutrient stresses in plants.}, } @article {pmid39273694, year = {2024}, author = {Evangelisti, C and Ramadan, S and Orlacchio, A and Panza, E}, title = {Experimental Cell Models for Investigating Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273694}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/metabolism ; Animals ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Organoids/pathology ; Models, Biological ; }, abstract = {Experimental models play a pivotal role in biomedical research, facilitating the understanding of disease mechanisms and the development of novel therapeutics. This is particularly true for neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and motor neuron disease, which present complex challenges for research and therapy development. In this work, we review the recent literature about experimental models and motor neuron disease. We identified three main categories of models that are highly studied by scientists. In fact, experimental models for investigating these diseases encompass a variety of approaches, including modeling the patient's cell culture, patient-derived induced pluripotent stem cells, and organoids. Each model offers unique advantages and limitations, providing researchers with a range of tools to address complex biological questions. Here, we discuss the characteristics, applications, and recent advancements in terms of each model system, highlighting their contributions to advancing biomedical knowledge and translational research.}, } @article {pmid39273435, year = {2024}, author = {Di Chiano, M and Sallustio, F and Fiocco, D and Rocchetti, MT and Spano, G and Pontrelli, P and Moschetta, A and Gesualdo, L and Gadaleta, RM and Gallone, A}, title = {Psychobiotic Properties of Lactiplantibacillus plantarum in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273435}, issn = {1422-0067}, support = {1062//PON "RICERCA E INNOVAZIONE" 2014-2020-Innovazione/ ; Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - Next Generation EU//National Recovery and Resilience Plan (NRRP)/ ; Concession Decree No. 1550 of 11 October 2022 adopted by the Italian Ministry of University and Research, CUP D93C22000890001//Italian Ministry of University and Research, CUP D93C22000890001/ ; Codice progetto n. 2022H9MPZ5//MIUR- PRIN Progetti di Ricerca di Rilevante Interesse Nazionale 2022/ ; Id. 23239//AIRC IG 2019/ ; Call for tender No. 3138 of 16/12/2021 of Italian Ministry of University and Research funded by the European Union//National Recovery and Resilience Plan (NRRP)/ ; Project code: CN00000041, CUP H93C22000430007//NextGenerationEU/ ; PNRR-MR1-2022-12376395//European Union - Next Generation EU - PNRR M6C2/ ; "POFACS" - ARS01_00640 -", D.D. 1211/2020 and 1104/2021//Italian Ministry of University and Research (MIUR)/ ; PRA-HE 2021//University of Foggia/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Probiotics/therapeutic use ; Dysbiosis/microbiology ; Brain-Gut Axis ; Animals ; }, abstract = {Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut-brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut-brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.}, } @article {pmid39273079, year = {2024}, author = {Lundt, S and Ding, S}, title = {Potential Therapeutic Interventions Targeting NAD[+] Metabolism for ALS.}, journal = {Cells}, volume = {13}, number = {17}, pages = {}, pmid = {39273079}, issn = {2073-4409}, support = {R01NS069726/NS/NINDS NIH HHS/United States ; R01 NS123023/NS/NINDS NIH HHS/United States ; R21 AG080715/AG/NIA NIH HHS/United States ; R01 NS069726/NS/NINDS NIH HHS/United States ; R21AG080715/AG/NIA NIH HHS/United States ; R01NS123023/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *NAD/metabolism ; Humans ; Animals ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD[+]) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD[+] can be synthesized from three different intracellular pathways, but it is the NAD[+] salvage pathway that generates the largest proportion of NAD[+]. Impaired NAD[+] homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD[+] homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD[+] metabolism, either by administering NAD[+] precursor metabolites or small molecules that alter NAD[+]-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD[+] metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models.}, } @article {pmid39271939, year = {2024}, author = {Yu, Y and Pang, D and Huang, J and Li, C and Cui, Y and Shang, H}, title = {Downregulation of Lnc-ABCA12-3 modulates UBQLN1 expression and protein homeostasis pathways in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21383}, pmid = {39271939}, issn = {2045-2322}, support = {2022NSFSC0750//The Sichuan Science and Technology Program/ ; 81871000//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *RNA, Long Noncoding/genetics/metabolism ; *Autophagy-Related Proteins/genetics/metabolism ; *Down-Regulation ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Apoptosis/genetics ; Female ; Proteostasis ; Male ; Middle Aged ; Autophagy/genetics ; Oxidative Stress ; Gene Expression Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in ALS pathogenesis but their roles remain unclear. Previous studies found lnc-ABCA12-3 was downregulated in ALS patients. We aim to characterize the expression and function of lnc-ABCA12-3 in ALS and explore its mechanisms of action. Lnc-ABCA12-3 expression was analyzed in PBMCs from ALS patients and correlated with clinical outcomes. Effect of modulating lnc-ABCA12-3 expression was assessed in cell models using assays of apoptosis, protein homeostasis and pathway analysis. RNA pull-down and interaction studies were performed to identify lnc-ABCA12-3 binding partners. Lnc-ABCA12-3 was downregulated in ALS patients, correlating with faster progression and shorter survival. Overexpression of lnc-ABAC12-3 conferred protection against oxidative stress-induced apoptosis, while knockdown lnc-ABCA12-3 enhanced cell death. Lnc-ABCA12-3 maintained protein quality control pathways, including ubiquitination, autophagy and stress granule formation, by regulating the ubiquitin shuttle protein UBQLN1. This study identified lnc-ABCA12-3 as a novel regulatory lncRNA implicated in ALS pathogenesis by modulating cellular survival and stress responses through interactions with UBQLN1, influencing disease progression. Lnc-ABCA12-3 may influence ALS through regulating protein homeostasis pathways.}, } @article {pmid39271680, year = {2024}, author = {Shan, Y and Zhang, M and Tao, E and Wang, J and Wei, N and Lu, Y and Liu, Q and Hao, K and Zhou, F and Wang, G}, title = {Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges.}, journal = {Signal transduction and targeted therapy}, volume = {9}, number = {1}, pages = {242}, pmid = {39271680}, issn = {2059-3635}, support = {82104184//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82373949//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82073928//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/metabolism/cytology ; *Mesenchymal Stem Cell Transplantation ; Graft vs Host Disease/therapy ; Translational Research, Biomedical ; Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.}, } @article {pmid39271636, year = {2025}, author = {Wang, Y and Ju, R and Jiang, J and Mao, L and Li, X and Deng, M}, title = {Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {195-205}, pmid = {39271636}, issn = {1590-3478}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; China ; *DNA Copy Number Variations/genetics ; East Asian People/genetics ; *Frontotemporal Dementia/genetics ; Pedigree ; Profilins/genetics ; Whole Genome Sequencing ; *Phosphoproteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.}, } @article {pmid39270726, year = {2024}, author = {Roos, AK and Stenvall, E and Kockum, ES and Grönlund, KÅ and Alstermark, H and Wuolikainen, A and Andersen, PM and Nordin, A and Forsberg, KME}, title = {Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions.}, journal = {Human molecular genetics}, volume = {33}, number = {22}, pages = {1966-1974}, pmid = {39270726}, issn = {1460-2083}, support = {//Umea University/ ; Nos.FO 2022-0309//Swedish Brain Foundation/ ; 2012-3167//Swedish Research Council/ ; //Research and Development Unit/ ; JLL-980693//Region Jämtland Härjedalen/ ; 2012.0091//Knut and Alice Wallenberg Foundation/ ; //Neuroförbundet patient organization/ ; 2023.16//Ulla-Carin Lindquist Foundation/ ; RV-993493//Västerbotten County Council/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //Börje Salming ALS Foundation/ ; }, mesh = {Humans ; *Huntingtin Protein/genetics/metabolism ; *Penetrance ; Male ; Female ; *Motor Neuron Disease/genetics/pathology/metabolism ; Middle Aged ; Aged ; *C9orf72 Protein/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/metabolism/genetics/pathology ; Alleles ; Adult ; Huntington Disease/genetics/pathology/metabolism ; Cohort Studies ; Corpus Striatum/metabolism/pathology ; }, abstract = {Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington's disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36-39 CAG repeats), or alleles with intermediate penetrance, (27-35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%-6.61%) and reduced penetrance (range 0.57%-0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.}, } @article {pmid39270623, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J and , }, title = {Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105323}, pmid = {39270623}, issn = {2352-3964}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; *Biomarkers/blood ; Prognosis ; *Disease Progression ; Female ; Male ; *Clinical Trials as Topic ; Middle Aged ; Aged ; Research Design ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.

METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.

FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.

INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.

FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, } @article {pmid39270519, year = {2024}, author = {Nishiyama, M and Koreki, A and Isose, S and Takeda, T and Ishikawa, A and Kokubun, S and Saito, Y and Ito, K and Arai, K and Takahashi, N and Motoda, Y and Kuwabara, S and Honda, K}, title = {Factors associated with psychological distress in patients with amyotrophic lateral sclerosis: A retrospective medical records study.}, journal = {Journal of psychosomatic research}, volume = {187}, number = {}, pages = {111915}, doi = {10.1016/j.jpsychores.2024.111915}, pmid = {39270519}, issn = {1879-1360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; *Psychological Distress ; Aged ; Retrospective Studies ; Adult ; Depression/psychology ; Stress, Psychological/psychology ; Surveys and Questionnaires ; Risk Factors ; Sex Factors ; }, abstract = {OBJECTIVE: Although psychological distress is a prevalent issue among patients with amyotrophic lateral sclerosis (ALS) and can impact survival, the risk factors contributing to this distress remain insufficiently understood.

METHODS: Patients with ALS who completed the Profile of Mood States (POMS) between June 2017 and March 2022 were included. Participants with moderate to severe cognitive decline were excluded, resulting in the recruitment of 121 patients. The associations between POMS profiles and clinical characteristics were analyzed. Physical motor symptoms were evaluated using the Revised ALS Functional Rating Scale (ALSFRS-R) for objective measurement and the 40-item ALS Assessment Questionnaire (ALSAQ-40) for subjective assessment.

RESULTS: Our model, employing the ALSFRS-R, revealed significant factors associated with overall psychological distress, as assessed by the POMS, including upper limb symptoms, the presence of sleep apnea syndrome, older age at onset, and male sex, with an inverse association with tracheostomy. The POMS subscale scores revealed that anger and depression were significantly associated with upper limb symptoms. The second model, which employed subjective scales, yielded similar results, reinforcing the robustness of our findings. Moreover, subjective bulbar symptoms on the ALSAQ-40 were significantly associated with psychological distress, particularly in female patients.

CONCLUSION: This study identified the main clinical characteristics significantly associated with psychological distress in patients with ALS. Our findings may be useful in developing individualized psychological management strategies for these patients.}, } @article {pmid39269505, year = {2024}, author = {Denis, PA and Laranjeira, JAS and Martins, NF and Sambrano, JR}, title = {Codoped germanene with 3p and 4p elements elements.}, journal = {Journal of molecular modeling}, volume = {30}, number = {10}, pages = {331}, pmid = {39269505}, issn = {0948-5023}, abstract = {CONTEXT: The relentless need for new materials to be used in electronic devices has opened new research directions in materials science. One of them involves using two-dimensional materials, among which there is current interest in using germanene. The heteroatom doping of germanene has been proposed as a possible approach to fine-tuning its electronic properties. However, this procedure is complicated because locating the dopants with a specific arrangement is challenging, thus achieving reproducibility. To avoid this problem, we propose the codoping of germanene to understand if dopants prefer to be agglomerated as observed for graphene or if they prefer to adopt a random disposition. Herein, we employed first-principles calculations to study 21 codoped germanene systems with one 3p (Al, Si, P, and S) and one 4p (Ga, As, and Se) element. Our results indicate that in the cases of AlP, AlS, GaP, GaS, GaAs, and GaSe codoped germanene, the dopants show a tendency to be located in specific lattice positions. The ortho disposition of dopants is preferred for AlP, AlS, GaP and GaS codoped germanene and their 4p counterparts GaAs and GaSe codoped germanene, and the materials showed interesting electronic properties making them suitable to develop germanene-based electronic materials.

METHODS: We utilized the M06-L, HSE06 methods accompanied by the 6-31G* basis sets to perform periodic boundary conditions calculations as implemented in Gaussian 09. The unit cells were sampled employing 100 k-points for geometry optimizations and 2000 k-points for electronic properties The ultrafine grid was employed. Results were visualized employing Gaussview 5.0.1. In addition to this, we performed B3LYP-D3 periodic calculations as implemented in CRYSTAL17.}, } @article {pmid39268841, year = {2024}, author = {Xing, C and Luo, M and Sheng, Q and Zhu, Z and Yu, D and Huang, J and He, D and Zhang, M and Fan, W and Chen, D}, title = {Silk Fabric Functionalized by Nanosilver Enabling the Wearable Sensing for Biomechanics and Biomolecules.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {38}, pages = {51669-51678}, doi = {10.1021/acsami.4c10253}, pmid = {39268841}, issn = {1944-8252}, mesh = {*Wearable Electronic Devices ; *Silver/chemistry ; *Silk/chemistry ; Humans ; *Metal Nanoparticles/chemistry ; Biomechanical Phenomena ; Textiles ; Biosensing Techniques/instrumentation/methods ; Spectrum Analysis, Raman ; }, abstract = {Integrating biomechanical and biomolecular sensing mechanisms into wearable devices is a formidable challenge and key to acquiring personalized health management. To address this, we have developed an innovative multifunctional sensor enabled by plasma functionalized silk fabric, which possesses multimodal sensing capabilities for biomechanics and biomolecules. A seed-mediated in situ growth method was employed to coat silver nanoparticles (AgNPs) onto silk fibers, resulting in silk fibers functionalized with AgNPs (SFs@Ag) that exhibit both piezoresistive response and localized surface plasmon resonance effects. The SFs@Ag membrane enables accurate detection of mechanical pressure and specific biomolecules during wearable sensing, offering a versatile solution for comprehensive personalized health monitoring. Additionally, a machine learning algorithm has been established to specifically recognize muscle strain signals, potentially extending to the diagnosis and monitoring of neuromuscular disorders such as amyotrophic lateral sclerosis (ALS). Unlike electromyography, which detects large muscles in clinical medicine, sensing data for tiny muscles enhance our understanding of muscle coordination using the SFs@Ag sensor. This detection model provides feasibility for the early detection and prevention of neuromuscular diseases. Beyond muscle stress and strain sensing, biomolecular detection is a critical addition to achieving effective health management. In this study, we developed highly sensitive surface-enhanced Raman scattering (SERS) detection for wearable health monitoring. Finite-difference time-domain numerical simulations ware utilized to analyze the efficacy of the SFs@Ag sensor for wearable SERS sensing of biomolecules. Based on the specific SERS spectra, automatic extraction of signals of sweat molecules was also achieved. In summary, the SFs@Ag sensor bridges the gap between biomechanical and biomolecular sensing in wearable applications, providing significant value for personalized health management.}, } @article {pmid39268298, year = {2024}, author = {Contractor, RN and Shah, M and Manwell, W and Dempsey, KJ and Simhadri, P}, title = {Jean-Martin Charcot: Pioneer of Neurology.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66762}, pmid = {39268298}, issn = {2168-8184}, abstract = {Jean-Martin Charcot, born on November 29, 1825, in Paris, France, is known as the father of neurology. During a time when neurology was not yet a recognized medical specialty, Charcot's pioneering contributions significantly advanced the field. Charcot's use of the anatomo-clinical method, which correlates clinical symptoms with anatomical findings, led to the discovery and characterization of numerous neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Charcot's joint, and Charcot-Marie-Tooth (CMT) disease. His methodical approach to documenting clinical signs and conducting post-mortem examinations revolutionized neurological research and diagnosis, laying the groundwork for modern neurology. The anatomo-clinical methods continue to be a vital tool in neurological research and practice today. Charcot's work extended beyond clinical practice, influencing the study of neurology through his role as an educator and mentor to many, including Sigmund Freud. Despite some controversies and a reputation for being difficult to work with, Charcot's legacy endures, with his initial discoveries fostering greater awareness and the development of therapies for various neurological disorders.}, } @article {pmid39267142, year = {2024}, author = {Wang, YM and Yan, J and Williams, SK and Fairless, R and Bading, H}, title = {TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {149}, pmid = {39267142}, issn = {2051-5960}, support = {BA 1007/7-1//Deutsche Forschungsgemeinschaft/ ; FOR 2289//Deutsche Forschungsgemeinschaft/ ; Advanced Grant 233024//HORIZON EUROPE European Research Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Retinal Ganglion Cells/drug effects/pathology/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Electroretinography ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; }, abstract = {Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1[G93A], we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1[G93A] mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.}, } @article {pmid39266192, year = {2024}, author = {Chiappini, FA and Pinto, L and Alcaraz, MR and Omidikia, N and Goicoechea, HC and Olivieri, AC}, title = {Multivariate curve resolution-alternating least-squares and second-order advantage in first-order calibration. A systematic characterisation for three-component analytical systems.}, journal = {Analytica chimica acta}, volume = {1328}, number = {}, pages = {343159}, doi = {10.1016/j.aca.2024.343159}, pmid = {39266192}, issn = {1873-4324}, abstract = {BACKGROUND: Recent interest has been focused on the application of multivariate curve resolution-alternating least-squares (MCR-ALS) to systems involving the measurement of first-order and non-bilinear second-order data. The latter pose important challenges to bilinear decomposition models, due to the phenomenon of rotational ambiguity in the solutions, even under the application of the full set of chemical constraints that is usually employed in MCR-ALS calibration.

RESULTS: After the analysis of several simulated and experimental datasets, important conclusions regarding the role of the selectivity patterns in the constituent spectra have been drawn concerning the achievement of the second-order advantage. Theoretical considerations based on the calculation of the areas of feasible solutions helped to support the observations regarding the predictive ability of MCR- ALS in the various datasets.

SIGNIFICANCE: The understanding of the impact of rotational ambiguity in obtaining the second-order advantage with both first-order and non-bilinear second-order data is of paramount importance in the future development of analytical protocols of complex samples.}, } @article {pmid39264833, year = {2024}, author = {Su, B and He, Z and Liu, J and Li, M and Huang, X}, title = {Mangiferin activates the nuclear factor erythroid 2-related factor pathway to protect SOD1-G93A induced NSC-34 motor neurons from oxidative stress and apoptosis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {10}, pages = {e23849}, doi = {10.1002/jbt.23849}, pmid = {39264833}, issn = {1099-0461}, mesh = {*Xanthones/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Mice ; Animals ; *Motor Neurons/metabolism/drug effects/pathology ; *Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; NAD(P)H Dehydrogenase (Quinone)/metabolism/genetics ; }, abstract = {One of the main factors in the pathophysiology of amyotrophic lateral sclerosis is oxidative stress. Mangiferin (MF), a natural plant polyphenol, has anti-inflammatory and antioxidant effects. The aim of our study was to investigate the protective effects and mechanisms of MF in the hSOD1-G93A ALS cell model. Our result revealed that MF treatment reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreased oxidative damage, and reduced apoptosis. Additionally, it was observed that MF significantly increased the synthesis of the antioxidant genes hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are downstream of the Nrf2 signaling pathway, and increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 knockdown greatly promoted apoptosis, which was reversed by MF treatment. To summarize, MF promoted the Nrf2 pathway and scavenged MDA and ROS to protect the ALS cell model.}, } @article {pmid39264557, year = {2024}, author = {Grigoryev, PN and Gaptrakhmanova, GA and Plotnikova, AA and Zefirov, AL and Mukhamedyarov, MA}, title = {Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.}, journal = {Bulletin of experimental biology and medicine}, volume = {177}, number = {4}, pages = {449-453}, pmid = {39264557}, issn = {1573-8221}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/physiopathology ; Diaphragm/innervation/metabolism/physiopathology ; *Disease Models, Animal ; *Endocytosis/physiology ; Fluorescent Dyes/metabolism ; Imidazoles/pharmacology ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; Nerve Endings/metabolism ; Pyridinium Compounds/metabolism ; Quaternary Ammonium Compounds/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Synaptic Transmission/physiology/genetics ; *Synaptic Vesicles/metabolism ; }, abstract = {In experiments on the motor nerve endings of the diaphragm of transgenic FUS mice with a model of amyotrophic lateral sclerosis at the pre-symptomatic stage of the disease, the processes of transmitter release and endocytosis of synaptic vesicles were studied. In FUS mice, the intensity of transmitter release during high-frequency stimulation of the motor nerve (50 imp/sec) was lowered. At the same duration of stimulation, the loading of fluorescent dye FM1-43 was lower in FUS mice. However, at the time of stimulation, during which an equal number of quanta are released in wild-type and FUS mice, no differences in the intensity of dye loading were found. Thus, endocytosis is not the key factor in the mechanism of synaptic dysfunction in FUS mice at the pre-symptomatic stage.}, } @article {pmid39263607, year = {2024}, author = {He, D and He, X and Shen, D and Liu, L and Yang, X and Hao, M and Wang, Y and Li, Y and Liu, Q and Liu, M and Wang, J and Zhang, X and Cui, L}, title = {Loss-of-function variants in RNA binding motif protein X-linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis.}, journal = {MedComm}, volume = {5}, number = {9}, pages = {e712}, pmid = {39263607}, issn = {2688-2663}, abstract = {Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC-34 cells overexpressing mutant TDP43[Q331K] results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.}, } @article {pmid39262980, year = {2024}, author = {Joshi, R and Goswami, D and Saha, P and Hole, A and Mandhare, P and Wadke, R and Murthy, PR and Borgohain, S and C, MK and Kapoor, S}, title = {Serum Raman spectroscopy: Unearthing the snapshot of distinct metabolic profile in patients with congenital heart defects (CHDs).}, journal = {Heliyon}, volume = {10}, number = {16}, pages = {e34575}, pmid = {39262980}, issn = {2405-8440}, abstract = {In the present study, efficacy of minimally-invasive serum Raman spectroscopy (SRS) in stratification of congenital heart diseases was explored. Blood was collected from 62 subjects [42 congenital heart defect (CHD) patients (19 with atrial septal defect, 13 with ventricular septal defect and 10 with tetralogy of fallot) and 20 controls], and serum separated. Raman spectra of sera were recorded, pre-processed and subjected to spectral and multivariate analyses. Multivariate curve resolution-alternating least squares (MCR-ALS) analyses indicated alterations in lipid and protein levels between the study groups. Principal Component Analysis (PCA) and Principal Component based Linear Discriminant Analysis (PC-LDA), cross-validated with Leave-one-out cross validation (LOOCV), were employed to study stratification between the different groups. CHD could be classified from controls with 76 % efficiency. The different CHD subtypes could be distinguished with efficiencies as high as ∼90 %. To the best of our knowledge, differentiation between controls and CHDs as well as the stratification between controls and CHDs subtypes was for the first time successfully accomplished by serum-based Raman spectroscopy.}, } @article {pmid39261725, year = {2024}, author = {Abe, P and Lavalley, A and Morassut, I and Santinha, AJ and Roig-Puiggros, S and Javed, A and Klingler, E and Baumann, N and Prados, J and Platt, RJ and Jabaudon, D}, title = {Molecular programs guiding arealization of descending cortical pathways.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {644-651}, pmid = {39261725}, issn = {1476-4687}, mesh = {Animals ; Female ; Male ; Mice ; Axons/metabolism ; Gene Expression Regulation, Developmental ; Motor Cortex/cytology/metabolism ; *Neocortex/anatomy & histology/cytology/metabolism ; *Neural Pathways ; *Neurons/metabolism/cytology ; Single-Cell Gene Expression Analysis ; Transcription Factors/metabolism ; }, abstract = {Layer 5 extratelencephalic (ET) neurons are present across neocortical areas and send axons to multiple subcortical targets[1-6]. Two cardinal subtypes exist[7,8]: (1) Slco2a1-expressing neurons (ETdist), which predominate in the motor cortex and project distally to the pons, medulla and spinal cord; and (2) Nprs1- or Hpgd-expressing neurons (ETprox), which predominate in the visual cortex and project more proximally to the pons and thalamus. An understanding of how area-specific ETdist and ETprox emerge during development is important because they are critical for fine motor skills and are susceptible to spinal cord injury and amyotrophic lateral sclerosis[9-12]. Here, using cross-areal mapping of axonal projections in the mouse neocortex, we identify the subtype-specific developmental dynamics of ET neurons. Whereas subsets of ETprox emerge by pruning of ETdist axons, others emerge de novo. We outline corresponding subtype-specific developmental transcriptional programs using single-nucleus sequencing. Leveraging these findings, we use postnatal in vivo knockdown of subtype-specific transcription factors to reprogram ET neuron connectivity towards more proximal targets. Together, these results show the functional transcriptional programs driving ET neuron diversity and uncover cell subtype-specific gene regulatory networks that can be manipulated to direct target specificity in motor corticofugal pathways.}, } @article {pmid39260590, year = {2024}, author = {Petel Légaré, V and Harji, ZA and Rampal, CJ and Antonicka, H and Gurberg, TJN and Persia, O and Rodríguez, EC and Shoubridge, EA and Armstrong, GAB}, title = {CHCHD10[P80L] knock-in zebrafish display a mild ALS-like phenotype.}, journal = {Experimental neurology}, volume = {382}, number = {}, pages = {114945}, doi = {10.1016/j.expneurol.2024.114945}, pmid = {39260590}, issn = {1090-2430}, mesh = {Animals ; *Zebrafish ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Phenotype ; *Mitochondrial Proteins/genetics ; Zebrafish Proteins/genetics ; Motor Neurons/metabolism/pathology ; Gene Knock-In Techniques ; Animals, Genetically Modified ; Disease Models, Animal ; Neuromuscular Junction/pathology/genetics/metabolism ; }, abstract = {Mutations in the nuclear-encoded mitochondrial gene CHCHD10 have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10[P80L] variant (zebrafish: Chchd10[P83L]). Larval chchd10[P83L/P83L] fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (chchd10[-/-]). Adult, 11-month old chchd10[P83L/P83L] zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of chchd10[P83L/P83L] zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to chchd2[-/-] adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our chchd10[P83L/P83L] model. The findings presented here, suggest that the CHCHD10[P80L] variant confers an ALS-like phenotype when expressed in zebrafish.}, } @article {pmid39260416, year = {2024}, author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {662-668}, pmid = {39260416}, issn = {1476-4687}, support = {R01 AG077444/AG/NIA NIH HHS/United States ; RF1 AG071177/AG/NIA NIH HHS/United States ; U01 NS110437/NS/NINDS NIH HHS/United States ; R01 NS085770/NS/NINDS NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; R01 AG056258/AG/NIA NIH HHS/United States ; R01 DC008552/DC/NIDCD NIH HHS/United States ; RF1 NS110437/NS/NINDS NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R01 AG080001/AG/NIA NIH HHS/United States ; R01 AG071177/AG/NIA NIH HHS/United States ; R01 NS137469/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyloid/chemistry/metabolism/ultrastructure ; *Annexins/chemistry/metabolism/ultrastructure ; Aphasia/complications/metabolism ; *Brain/metabolism/pathology/ultrastructure ; Cryoelectron Microscopy ; *DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; *Frontotemporal Dementia/classification/complications/metabolism ; Models, Molecular ; Protein Multimerization ; }, abstract = {Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system[1]. Human genetic studies have established a causal role for protein assembly in neurodegeneration[2]. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients[1]. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B[3,4]. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11 that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.}, } @article {pmid39260140, year = {2024}, author = {Emori, S and Kume, K and Nakayama, Y and Ito, H and Kawakami, H}, title = {C9orf72 repeat expansions in Wakayama: One potential cause of amyotrophic lateral sclerosis in the Kii Peninsula, Japan.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123209}, doi = {10.1016/j.jns.2024.123209}, pmid = {39260140}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *C9orf72 Protein/genetics ; Japan/epidemiology ; Male ; Female ; *DNA Repeat Expansion/genetics ; Middle Aged ; Aged ; Proteins/genetics ; Adult ; Aged, 80 and over ; Genetic Predisposition to Disease/genetics ; Haplotypes ; }, abstract = {A cluster of cases of amyotrophic lateral sclerosis (ALS) exists in the southern part of the Kii Peninsula in Japan. Although both genetic and environmental factors are thought to be causative, the critical cause of this cluster has not been identified. C9orf72 is the most common genetic factor in both familial and sporadic C9orf72-related ALS in people of European ancestry, but it is rare among Japanese populations. However, a previous report revealed that the frequency of C9orf72-related ALS was significantly higher in the cluster area. We evaluated the proportion of C9orf72 hexanucleotide repeat expansions in 99 cases of ALS diagnosed in Wakayama Prefecture, including the cluster area, by using repeat-primed polymerase chain reaction and fluorescence fragment length analysis. We found that 2 of the 99 patients (0 % of those with familial ALS and 2.4 % of those with sporadic ALS) had hexanucleotide repeat expansions in C9orf72, and long-read sequencing revealed that these expansions were causative. No expansions were observed among 90 patients with Parkinson's disease or among 90 healthy controls. Haplotype analysis with long-read sequencing data revealed that the two patients with repeat expansions shared the common haplotype with that previously reported in Finnish patients with C9orf72-related ALS, which suggests a founder effect. C9orf72 was thought to be a rare causative gene in Japan, but this study revealed that it may be relatively common in Wakayama Prefecture.}, } @article {pmid39259763, year = {2024}, author = {Caredio, D and Koderman, M and Frontzek, KJ and Sorce, S and Nuvolone, M and Bremer, J and Mariutti, G and Schwarz, P and Madrigal, L and Mitrovic, M and Sellitto, S and Streichenberger, N and Scheckel, C and Aguzzi, A}, title = {Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle.}, journal = {PLoS pathogens}, volume = {20}, number = {9}, pages = {e1012552}, pmid = {39259763}, issn = {1553-7374}, mesh = {Animals ; *Muscle, Skeletal/metabolism/pathology ; *Glutamine/metabolism ; *Glutamic Acid/metabolism ; Mice ; *Prion Diseases/metabolism/genetics ; Humans ; Glutamate-Ammonia Ligase/metabolism ; Creutzfeldt-Jakob Syndrome/metabolism/pathology/genetics ; Female ; Mice, Inbred C57BL ; }, abstract = {In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer's disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.}, } @article {pmid39258797, year = {2024}, author = {Coppedè, F}, title = {DNA methylation in amyotrophic lateral sclerosis: where do we stand and what is next?.}, journal = {Epigenomics}, volume = {16}, number = {17}, pages = {1185-1196}, pmid = {39258797}, issn = {1750-192X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Methylation ; Epigenesis, Genetic ; }, abstract = {Genes involved in immune response, inflammation and metabolism are among those most likely affected by changes in DNA methylation (DNAm) and expression levels in amyotrophic lateral sclerosis (ALS) tissues. Unfortunately, it is still largely unclear whether any of these changes precede the onset of disease symptoms or whether most of them are the result of the muscular and metabolic changes that follow symptoms onset. In this article the author discusses the strengths and limitations of the available studies of DNAm in ALS and provides some suggestions on what, in his opinion, could be done in the near future for a better understanding of the DNAm changes occurring in ALS, their link with environmental exposures and their potential clinical utility.}, } @article {pmid39258740, year = {2024}, author = {O'Connell, C and Kavanaugh, MS and Cummings, C and Genge, A}, title = {How to break the news in amyotrophic lateral sclerosis/motor neuron disease: practical guidelines from experts.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2397517}, pmid = {39258740}, issn = {2167-9223}, abstract = {In amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), it is necessary to communicate difficult news during the initial diagnosis and throughout the disease trajectory as the condition progresses. However, delivering difficult news to people with ALS/MND is an emotionally demanding task for healthcare and allied health professionals-one for which many feel ill-prepared because of limited training in this area. Ineffective communication of difficult news damages the patient-provider relationship and negatively impacts patient quality of life (QoL). To address this issue, we developed the A-L S-PIKES protocol based on available literature and our extensive clinical experience. It provides easy-to-follow, stepwise guidelines to effectively deliver difficult news to people with ALS/MND (PALS) that includes: Advance Preparation (preparing for the discussion logistically and emotionally); Location & Setting (creating a comfortable setting that fosters rapport); Patient's Perceptions (assessing PALS' understanding and perception of their condition); Invitation (seeking PALS' permission to share information); Knowledge (sharing information in a clear, understandable manner); Emotion/Empathy (addressing emotions with empathy and providing emotional support); and Strategy & Summary (summarizing the discussion and collaboratively developing a plan of action). A-L S-PIKES provides practical guidelines on how to prepare for and conduct these challenging conversations. It emphasizes effective communication tailored to the individual needs of PALS and their families, empathy, sensitivity, and support for PALS' emotional well-being and autonomy. The aim of A-L S-PIKES is to both enhance skills and confidence in delivering difficult news and to improve the QoL of PALS and their families. Future studies should systematically evaluate the feasibility and effectiveness of A-L S-PIKES to establish its utility in clinical practice.}, } @article {pmid39258714, year = {2024}, author = {Winroth, I and Börjesson, A and Andersen, PM and Karlsson, T}, title = {Cognitive deficits in ALS patients with SOD1 mutations.}, journal = {Journal of clinical and experimental neuropsychology}, volume = {46}, number = {7}, pages = {669-682}, doi = {10.1080/13803395.2024.2393366}, pmid = {39258714}, issn = {1744-411X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Mutation ; Aged ; *Neuropsychological Tests ; Cognitive Dysfunction/physiopathology/genetics/etiology ; Adult ; Memory, Short-Term/physiology ; C9orf72 Protein/genetics ; Bayes Theorem ; }, abstract = {OBJECTIVE: Cognitive decline is common in patients with amyotrophic lateral sclerosis (ALS), especially in carriers of the mutation C9ORF72HRE. However, cognitive impairment is poorly understood in carriers of mutations in other genes causing ALS. We performed a comprehensive neuropsychological testing in patients with mutations in the SOD1 (mSOD1) gene.

METHODS: We examined 5 cognitive domains in 48 symptomatic patients with either hereditary or sporadic ALS. These were compared with 37 matched controls.

RESULTS: Carriers of SOD1-mutations and sporadic ALS had circumscribed deficits, but in a pattern different from C9ORF72HRE. All groups had deficits in working memory, although mSOD1-carriers significantly outperform sporadic ALS and C9ORF72HRE in an attention-driven visuospatial task involving copying a complex figure. Carriers of the D90A-SOD1 mutation overall performed as well as or better than carriers of other SOD1-mutations, except complex working memory. Bayesian analyses suggest (with evidence of moderate strength) that tasks involving the language domain did not differ between controls, mSOD1 and sporadic ALS.

CONCLUSION: Distinct cognitive impairments are prevalent in different ALS-syndromes and vary in patients with different pathogenic SOD1 mutations. The type and degree of impairment differed depending on genotype and was significantly least pronounced in patients homozygous for the D90A SOD1 mutation. The presence of cognitive deficits may influence optimal clinical management and intervention. We propose that cognitive assessment should be included in the routine examination of new patients suspected of ALS. Neuropsychological assessment is an under-recognized outcome parameter in clinical drug trials.}, } @article {pmid39258588, year = {2024}, author = {Walsh, S and Simmons, Z and Miyamoto, S and Geronimo, A}, title = {A nurse coaching intervention to improve support to individuals living with ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2399154}, pmid = {39258588}, issn = {2167-9223}, abstract = {OBJECTIVE: Health coaching may supplement the multidisciplinary ALS clinic model to facilitate patient-centered health behavior change. The aim of this study was to determine the effects of nurse health coaching (NHC) on the quality of life and self-efficacy of individuals living with ALS.

METHODS: Twenty-nine participants were randomized at 1:1 to the standard of care and coaching arms. All participants attended multidisciplinary ALS clinic visits quarterly, at which times they completed assessments of quality of life and self-efficacy. Those in the coaching arm participated in monthly coaching with a nurse coach over 12 months. The coaching sessions utilized motivational interviewing to identify personal goals along with barriers and solutions to achieve them. Linear mixed-effect models were used to quantify the effect of coaching on quality of life and self-efficacy outcomes. Thematic analysis was performed to summarize the participants' experiences with coaching.

RESULTS: Adherence to the coaching intervention was good. No effects of coaching were observed on the primary outcomes of quality of life and self-efficacy, although debriefed participants reported that they would recommend it to others. Patients and caregivers reflected on the impacts of coaching that extended beyond the pre-defined study outcomes and measures put in place to gauge effectiveness.

CONCLUSIONS: The elicited qualitative themes illustrating patient experience of coaching demonstrate the utility of nurse coaching as an important adjunct support to complement the multidisciplinary ALS clinic model.}, } @article {pmid39258586, year = {2024}, author = {Sommers-Spijkerman, M and Zwarts-Engelbert, A and Kruitwagen-Van Reenen, E and Van Eijk, RPA and Visser-Meily, JMA and Heijmans, E and Austin, J and Drossaert, C and Bohlmeijer, E and Beelen, A}, title = {Acceptability and potential benefit of a self-compassion intervention for people living with amyotrophic lateral sclerosis: a mixed methods pilot study.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2024.2400516}, pmid = {39258586}, issn = {2167-9223}, abstract = {Objective: This proof-of-concept study aimed to explore the acceptability and potential benefit of a self-guided online self-compassion intervention to aid resilient coping and reduce emotional distress among patients and caregivers living with ALS. Methods: A single-arm pilot study was conducted in 20 adults living with ALS either as a patient or as a caregiver. Acceptability was examined using questionnaires (n = 20) and semi-structured interviews (n = 9). Potential benefit was assessed as changes in self-compassion, self-criticism and emotional distress, determined using psychological questionnaires at 3 and 6 weeks. Questionnaires were analyzed using linear mixed-effects models and interview data using inductive thematic analysis. Results: Out of 20 participants who started the intervention, 16 completed the study (80%). The majority of study completers (12/16) were satisfied with the intervention, but the data suggest room for improvement in terms of personalization. Qualitative data revealed multiple psychological benefits of using the intervention, including self-kindness, emotional self-awareness and savoring. Although not statistically significant, quantitative data showed positive trends with increased self-compassion (mean difference: 2.07; 95% CI: -.5.76 - 1.63) and reduced self-criticism (mean difference: -2.62; 95% CI: -.1.97 - 7.23) and emotional distress (mean difference: -2.49; 95% CI: -.51 - 5.50) at week 6 compared to baseline. Conclusions: The findings suggest that a self-compassion intervention is acceptable to people living with ALS, but its beneficial effects and the mechanisms involved have yet to be established in larger and more diverse samples, using controlled designs.}, } @article {pmid39257530, year = {2024}, author = {Baird, MC and Likhite, SB and Vetter, TA and Caporale, JR and Girard, HB and Roussel, FS and Howard, AE and Schwartz, MK and Reed, AR and Kaleem, A and Zhang, X and Meyer, KC}, title = {Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.}, journal = {Molecular therapy. Methods & clinical development}, volume = {32}, number = {3}, pages = {101312}, pmid = {39257530}, issn = {2329-0501}, abstract = {Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 [G93A] microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 [G93A] mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.}, } @article {pmid39255192, year = {2024}, author = {Hwang, RD and Lu, Y and Tang, Q and Periz, G and Park, G and Li, X and Xiang, Q and Liu, Y and Zhang, T and Wang, J}, title = {DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39255192}, issn = {2050-084X}, support = {R01 NS128494/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; NS074324/NH/NIH HHS/United States ; NS089616/NH/NIH HHS/United States ; NS128494/NH/NIH HHS/United States ; NS110098/NH/NIH HHS/United States ; }, mesh = {Animals ; *Proteasome Endopeptidase Complex/metabolism ; *Proteostasis ; Humans ; Drosophila/metabolism ; Autophagy ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Neurons/metabolism ; Drosophila melanogaster/metabolism/genetics ; }, abstract = {Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.}, } @article {pmid39255062, year = {2024}, author = {Germeys, C and Vandoorne, T and Davie, K and Poovathingal, S and Heeren, K and Vermeire, W and Nami, F and Moisse, M and Quaegebeur, A and Sierksma, A and Rué, L and Sicart, A and Eykens, C and De Cock, L and De Strooper, B and Carmeliet, P and Van Damme, P and De Bock, K and Van Den Bosch, L}, title = {Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114719}, doi = {10.1016/j.celrep.2024.114719}, pmid = {39255062}, issn = {2211-1247}, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Astrocytes/metabolism ; Disease Models, Animal ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Interferons/metabolism ; *Motor Neurons/metabolism ; *Zebrafish/metabolism ; }, abstract = {Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.}, } @article {pmid39254699, year = {2024}, author = {Maccabeo, A and Pateri, MI and Pili, F and Pilotto, S and Pierri, V and Muroni, A and Ercoli, T and Montisci, R and Marchetti, MF and Martis, A and Fazzini, L and Defazio, G and Puligheddu, M and Borghero, G}, title = {Takotsubo syndrome in a Sardinian amyotrophic lateral sclerosis cohort.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7489-7493}, pmid = {39254699}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/physiopathology ; *Takotsubo Cardiomyopathy/physiopathology/epidemiology/etiology ; Female ; Italy/epidemiology ; Aged ; Middle Aged ; Retrospective Studies ; Cohort Studies ; Male ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is known to be associated with varying degrees of autonomic and cardiovascular dysfunction. Recent case reports showed that ALS may be linked to Takotsubo syndrome (TTS). We assessed the frequency of TTS in an incident ALS cohort from Sardinia, Italy, and investigated the relationship of TTS with ALS course.

METHODS: We retrospectively examined a 10-year (2010-2019) incident cohort of ALS patients of Sardinian ancestry, reported TTS frequency and patients' clinical characteristics. Following, we checked for TTS among patients with ALS onset after 2019 and focused on the same features as for the incident cohort.

RESULTS: Our incident cohort included 344 ALS patients and 5 of them (1.45%) developed TTS. All were female and their median onset age was 71.5 years (IQR 62.75-77). Two patients had spinal and three bulbar onset, though all patients had bulbar involvement and were at an advanced stage of disease (ALSFRS ≤ 25, King's ≥ 3) at TTS diagnosis. We identified a potential TTS trigger in three patients (hospitalization for PEG placement, pneumonia). Among patients who had ALS onset after 2019, we identified a further TTS case and described it.

CONCLUSION: TTS is not a rare condition in ALS. Female sex, bulbar involvement, and later age of disease onset may be important risk factors for developing this cardiac condition and a physical or psychological trigger is often observed. Despite autonomic dysfunction in ALS has been already demonstrated, the precise physiopathological mechanism underlying TTS needs to be further clarified.}, } @article {pmid39254548, year = {2025}, author = {Zhang, M and Xiang, C and Niu, R and He, X and Luo, W and Liu, W and Gu, R}, title = {Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders: drug stability, targeting efficiency, and safety.}, journal = {Neural regeneration research}, volume = {20}, number = {7}, pages = {1883-1899}, pmid = {39254548}, issn = {1673-5374}, abstract = {Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied. However, their inability to cross the blood-brain barrier hampers the clinical translation of these therapeutic strategies. Liposomes are nanoparticles composed of lipid bilayers, which can effectively encapsulate drugs and improve drug delivery across the blood-brain barrier and into brain tissue through their targeting and permeability. Therefore, they can potentially treat traumatic and nontraumatic central nervous system diseases. In this review, we outlined the common properties and preparation methods of liposomes, including thin-film hydration, reverse-phase evaporation, solvent injection techniques, detergent removal methods, and microfluidics techniques. Afterwards, we comprehensively discussed the current applications of liposomes in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and brain tumors. Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials. Additionally, their application as drug delivery systems in clinical practice faces challenges such as drug stability, targeting efficiency, and safety. Therefore, we proposed development strategies related to liposomes to further promote their development in neurological disease research.}, } @article {pmid39254482, year = {2024}, author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P}, title = {A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2400522}, pmid = {39254482}, issn = {2167-9223}, abstract = {Introduction: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS. Methods: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH). Results: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH. Conclusion: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.}, } @article {pmid39253877, year = {2024}, author = {Thornburg-Suresh, EJC and Summers, DW}, title = {Microtubules, Membranes, and Movement: New Roles for Stathmin-2 in Axon Integrity.}, journal = {Journal of neuroscience research}, volume = {102}, number = {9}, pages = {e25382}, pmid = {39253877}, issn = {1097-4547}, support = {R01 NS126191/NS/NINDS NIH HHS/United States ; R01NS126191/NH/NIH HHS/United States ; }, mesh = {*Stathmin/metabolism ; *Microtubules/metabolism ; Humans ; *Axons/metabolism/physiology ; Animals ; Cell Membrane/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Neurons establish functional connections responsible for how we perceive and react to the world around us. Communication from a neuron to its target cell occurs through a long projection called an axon. Axon distances can exceed 1 m in length in humans and require a dynamic microtubule cytoskeleton for growth during development and maintenance in adulthood. Stathmins are microtubule-associated proteins that function as relays between kinase signaling and microtubule polymerization. In this review, we describe the prolific role of Stathmins in microtubule homeostasis with an emphasis on emerging roles for Stathmin-2 (Stmn2) in axon integrity and neurodegeneration. Stmn2 levels are altered in Amyotrophic Lateral Sclerosis and loss of Stmn2 provokes motor and sensory neuropathies. There is growing potential for employing Stmn2 as a disease biomarker or even a therapeutic target. Meeting this potential requires a mechanistic understanding of emerging complexity in Stmn2 function. In particular, Stmn2 palmitoylation has a surprising contribution to axon maintenance through undefined mechanisms linking membrane association, tubulin interaction, and axon transport. Exploring these connections will reveal new insight on neuronal cell biology and novel opportunities for disease intervention.}, } @article {pmid39253499, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39253499}, issn = {2692-8205}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, } @article {pmid39252332, year = {2024}, author = {Li, LS and Tong, Y and Yuan, C and Zhang, W}, title = {Evaluation of diagnostic value and Mendelian randomization study of appendicitis hub genes obtained by WGCNA analysis.}, journal = {Medicine}, volume = {103}, number = {36}, pages = {e39307}, doi = {10.1097/MD.0000000000039307}, pmid = {39252332}, issn = {1536-5964}, mesh = {Humans ; *Appendicitis/genetics/diagnosis ; *Mendelian Randomization Analysis ; Gene Expression Profiling/methods ; ROC Curve ; Gene Regulatory Networks ; Nomograms ; Gastrointestinal Microbiome/genetics ; }, abstract = {The timely and precise diagnosis of appendicitis was deemed essential. This study sought to examine the diagnostic significance of hub genes linked to appendicitis and to delve deeper into the pathophysiology of the condition. Differential gene expression analysis revealed distinct genes in the appendicitis group compared to other abdominal pain group, while weighted gene co-expression network analysis identified appendicitis-associated modules. Further analysis of common genes was conducted using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. The diagnostic efficiency of hub genes was explored through the use of nomograms and receiver operator characteristic curves. Additionally, immunoinfiltration analysis was performed to investigate the immune cell infiltration in both groups. The causal relationship between hub genes and appendicitis, as well as gut microbiota and appendicitis, was ultimately examined through Mendelian randomization. By conducting differential expression analysis and weighted gene co-expression network analysis, a total of 757 common genes were identified. Subsequent Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses revealed that these common genes were primarily associated with positive regulation of cell adhesion, focal adhesion, protein serine kinase activity, and amyotrophic lateral sclerosis. Utilizing Cytoscape software, the top 10 genes with the highest degree of interaction were identified as RPS3A, RPSA, RPL5, RPL37A, RPS27L, FLT3LG, ARL6IP1, RPL32, MRPL3, and GSPT1. Evaluation using nomograms and receiver operator characteristic curves demonstrated the diagnostic value of these hub genes. Ultimately, a causal relationship between hub genes and appendicitis was not identified in our study. Nevertheless, our findings indicate that appendicitis is correlated with 9 gut microbiota. This study identified 5 hub genes, specifically HSP90AA1, RPL5, MYC, CD44, and RPS3A, which exhibit diagnostic significance of appendicitis. Furthermore, the elucidation of these hub genes aids in enhancing our comprehension of the molecular pathways implicated in the development of appendicitis.}, } @article {pmid39251386, year = {2024}, author = {Liddell, JR and Hilton, JBW and Wang, YJ and Billings, JL and Nikseresht, S and Kysenius, K and Fuller-Jackson, JP and Hare, DJ and Crouch, PJ}, title = {Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.}, journal = {Metallomics : integrated biometal science}, volume = {16}, number = {9}, pages = {}, doi = {10.1093/mtomcs/mfae036}, pmid = {39251386}, issn = {1756-591X}, support = {//National Health and Medical Research Council/ ; }, mesh = {Animals ; *Copper/metabolism ; *Motor Neurons/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; Mice ; *Copper Transporter 1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Central Nervous System/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord α-motor neurons compared to wild-type littermates, but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer α-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation was unchanged in spinal cords from Slc31a1+/- mice but highly upregulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.}, } @article {pmid39251159, year = {2024}, author = {Liu, Y and Chen, H and Zhang, Z and Wang, J}, title = {Development of an integrated framework for dissecting source-oriented ecological and health risks of heavy metals in soils.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143299}, doi = {10.1016/j.chemosphere.2024.143299}, pmid = {39251159}, issn = {1879-1298}, mesh = {*Metals, Heavy/analysis ; *Soil Pollutants/analysis ; Environmental Exposure/statistics & numerical data ; Risk Assessment ; Soil/chemistry ; }, abstract = {Heavy metals (HMs) in soils pose significant risks on ecosystem and human health. To design targeted regulatory measures for mitigating and controlling the risk, it is necessary to accurately identify the pollution sources and environmental risks of soil HMs, as well as to reveal the linkages between them. To date, yet systematic investigation aimed at deciphering the links between source apportionment of soil HMs and their associated environmental risks is still lacking. To fill the gap, an integrated framework has been developed in this study and applied for dissecting the source-sink relationship and source-oriented ecological and health risks of soil HMs in Shanxi, a province with rich coal resource, in which long-term coal mining activities in history has resulted in soil HMs pollution and unavoidably posed environmental risks. Two advanced receptor models, multivariate curve resolution alternating least squares based on maximum likelihood principal component analysis (MCR-ALS/MLPCA) and multilinear engine 2 (ME2), have been employed for apportioning the potential sources, and their apportionment results are jointly incorporated into a modified ecological risk index and a probabilistic health risk assessment model for identifying the source-oriented ecological and health risks posed by soil metals. The results show that the soils in study area have been polluted by HMs (i.e., Cd, Cr, Hg and As) to varying degrees. Industrial activities (35%-35.8%), agricultural activities (11.1%-20.5%), atmospheric deposition (10.5%-13%) and mix source (31.5%-42.6%) are apportioned as the main contributors of soil HMs in the area. The source-oriented ecological risk assessment suggests Hg has presented significant ecological risk and largely contributed by the sources from atmospheric deposition and industrial activities. The source-oriented health risk assessment shows the non-carcinogenic hazard level and carcinogenic risk posed by soil HMs in the study area are acceptable. Relatively, industrial activities and mix source have contributed more on the health risks.}, } @article {pmid39251025, year = {2025}, author = {Del Rosso, JQ and Zaenglein, A and Callender, V and Schlosser, B and Graber, E and Keri, J and Weiss, J}, title = {Response to Reynolds et al's "Guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {1}, pages = {e15}, doi = {10.1016/j.jaad.2024.07.1528}, pmid = {39251025}, issn = {1097-6787}, } @article {pmid39250425, year = {2025}, author = {Neuhaus, D and Rost, T and Haas, T and Wendebourg, MJ and Schulze, K and Schlaeger, R and Scheurer, E and Lenz, C}, title = {Comparative analysis of in situ and ex situ postmortem brain MRI: Evaluating volumetry, DTI, and relaxometry.}, journal = {Magnetic resonance in medicine}, volume = {93}, number = {1}, pages = {213-227}, doi = {10.1002/mrm.30264}, pmid = {39250425}, issn = {1522-2594}, support = {//Stiftung zur Foerderung der gastroenterologischen und der allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; //Neuromuscular Research Association Basel/ ; }, mesh = {Humans ; *Diffusion Tensor Imaging/methods ; *Brain/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; Amyotrophic Lateral Sclerosis/diagnostic imaging ; Gray Matter/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Anisotropy ; Autopsy ; White Matter/diagnostic imaging ; }, abstract = {PURPOSE: To compare postmortem in situ with ex situ MRI parameters, including volumetry, diffusion tensor imaging (DTI), and relaxometry for assessing methodology-induced alterations, which is a crucial prerequisite when performing MRI biomarker validation.

METHODS: MRI whole-brain scans of five deceased patients with amyotrophic lateral sclerosis were performed at 3 T. In situ scans were conducted within 32 h after death (SD 18 h), and ex situ scans after brain extraction and 3 months of formalin fixation. The imaging protocol included MP2RAGE, DTI, and multi-contrast spin-echo and multi-echo gradient-echo sequences. Volumetry, fractional anisotropy, mean diffusivity, T1, T2, and T 2 * $$ {T} _2^{\ast } $$ have been assessed for specific brain regions.

RESULTS: When comparing ex situ to in situ values, the following results were obtained. Deep gray matter as well as the thalamus and the hippocampus showed a reduced volume. Fractional anisotropy was reduced in the cortex and the whole brain. Mean diffusivity was decreased in white matter and deep gray matter. T1 and T2 were reduced in all investigated structures, whereas T 2 * $$ {T} _2^{\ast } $$ was increased in the cortex.

CONCLUSION: The results of this study show that the volumes and MRI parameters of several brain regions are potentially affected by tissue extraction and subsequent formalin fixation, suggesting that methodological alterations are present in ex situ MRI. To avoid overlap of indistinguishable methodological and disease-related changes, we recommend performing in situ postmortem MRI as an additional intermediate step for in vivo MRI biomarker validation.}, } @article {pmid39249108, year = {2024}, author = {Jin, W and Boss, J and Bakulski, KM and Goutman, SA and Feldman, EL and Fritsche, LG and Mukherjee, B}, title = {Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6923-6934}, pmid = {39249108}, issn = {1432-1459}, support = {20-IIA-532//ALS Association/ ; R01TS000344/CC/CDC HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; R01TS000344/CC/CDC HHS/United States ; R01TS000344/CC/CDC HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; Humans ; United Kingdom/epidemiology ; *Multifactorial Inheritance ; Male ; Female ; Middle Aged ; *Biological Specimen Banks ; Aged ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Adult ; Phenotype ; UK Biobank ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential.

METHODS: Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates.

RESULTS: Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range.

DISCUSSION: By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.}, } @article {pmid39249104, year = {2024}, author = {Hafsteinsdóttir, B and Farman, H and Lagerström, N and Zetterberg, H and Andersen, O and Novakova, L and Nellgård, B and Rosén, H and Malmeström, C and Rosenstein, I and Lycke, J and Axelsson, M}, title = {Neurofilament light chain as a diagnostic and prognostic biomarker in Guillain-Barré syndrome.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7282-7293}, pmid = {39249104}, issn = {1432-1459}, support = {ALFGBG-722081//Swedish State Support for Clinical Research/ ; }, mesh = {Humans ; *Guillain-Barre Syndrome/blood/diagnosis/cerebrospinal fluid ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; *Biomarkers/blood/cerebrospinal fluid ; Adult ; Prognosis ; Aged ; Amyotrophic Lateral Sclerosis/blood/diagnosis/cerebrospinal fluid ; }, abstract = {BACKGROUND: Elevated neurofilament light chain (NfL) levels are associated with worse prognosis in Guillain-Barré syndrome (GBS). Our objectives were to determine the utility of serum NfL (sNfL), cerebrospinal fluid (CSF)/serum NfL ratio and NfL index as prognostic and diagnostic biomarkers for GBS.

METHODS: We measured NfL in serum and/or CSF obtained from 96 GBS patients between 1989 and 2014 in western Sweden. The sNfL Z-scores, NfL ratios and NfL indices were calculated. Outcome was determined with the GBS disability scale (GBSDS) at 3 and 12 months. NfL parameters in GBS were compared with healthy controls (HC), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

RESULTS: The sNfL Z-score was higher for GBSDS > 2 at 3 months (median [IQR], 3.5 ng/L [3.2-4.0], vs 2.6 [1.7-3.4], p = 0.008) and at 12 months (3.6 ng/L [3.5-3.8] vs 2.6 [1.8-3.5], p = 0.049). NfL ratio and index were not associated with outcome. The area under the curve (AUC) for sNfL Z-score was 0.76 (95% CI 0.58-0.93, p < 0.0001) for GBSDS > 2 at 3 months. NfL ratio and index were lower in GBS than HC, MS, and ALS. The AUC for the NfL ratio was 0.66 (95% CI 0.55-0.78, p = 0.0018) and for the NfL index 0.86 (95% CI 0.78-0.93, p < 0.0001).

DISCUSSION: Our results confirm sNfL as prognostic biomarker for GBS and the precision was improved using the age-adjusted sNfL Z score. NfL index and Qalb are potential diagnostic biomarkers for GBS.}, } @article {pmid39246739, year = {2024}, author = {Li, S and Gui, J and Passarelli, MN and Andrew, AS and Sullivan, KM and Cornell, KA and Traynor, BJ and Stark, A and Chia, R and Kuenzler, RM and Pioro, EP and Bradley, WG and Stommel, EW}, title = {Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200188}, pmid = {39246739}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an age-associated, fatal neurodegenerative disorder causing progressive paralysis and respiratory failure. The genetic architecture of ALS is still largely unknown.

METHODS: We performed a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) to understand genetic risk factors for ALS using a population-based case-control study of 435 ALS cases and 279 controls from Northern New England and Ohio. Single nucleotide polymorphism (SNP) genotyping was conducted using the Illumina NeuroChip array. Odds ratios were estimated using covariate-adjusted logistic regression. We also performed a genome-wide SNP-smoking interaction screening. TWAS analyses used PrediXcan to estimate associations between predicted gene expression levels across 15 tissues (13 brain tissues, skeletal muscle, and whole blood) and ALS risk.

RESULTS: GWAS analyses identified the p.A382T missense variant (rs367543041, p = 3.95E-6) in the TARDBP gene, which has previously been reported in association with increased ALS risk and was found to share a close affinity with the Sardinian haplotype. Both GWAS and TWAS analyses suggested that ZNF235 is associated with decreased ALS risk.

DISCUSSION: Our results support the need for future evaluation to clarify the role of these potential genetic risk factors for ALS and to understand genetic susceptibility to environmental risk factors.}, } @article {pmid39246712, year = {2024}, author = {Calderón-Garcidueñas, L and Cejudo-Ruiz, FR and Stommel, EW and González-Maciel, A and Reynoso-Robles, R and Torres-Jardón, R and Tehuacanero-Cuapa, S and Rodríguez-Gómez, A and Bautista, F and Goguitchaichvili, A and Pérez-Guille, BE and Soriano-Rosales, RE and Koseoglu, E and Mukherjee, PS}, title = {Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1411849}, pmid = {39246712}, issn = {1662-5161}, abstract = {Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC ≤ 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 μT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves.}, } @article {pmid39246264, year = {2024}, author = {Iseli, LM and Poppe, C and Wangmo, T}, title = {Receiving and adjusting to a diagnosis of ALS: A qualitative study with informal caregivers.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/S1478951524001044}, pmid = {39246264}, issn = {1478-9523}, abstract = {OBJECTIVES: Diagnosis of amyotrophic lateral sclerosis (ALS) takes more than 1year from detection of first symptoms. The paper seeks to understand the ALS diagnostic process and adjustment from the perspective of informal caregivers.

METHODS: The data stems from an interview study with 9 current and 13 bereaved informal caregivers of people with ALS in Switzerland. The interviews were analyzed using thematic analysis.

RESULTS: We identified 3 key themes pertaining to ALS diagnosis. In the first theme, we present the close involvement of informal caregivers in the "diagnosis journey." Highlighted within this theme is the important role they play, which ultimately leads to diagnosis of ALS avoiding further delays. Second, we relay their perceptions on "diagnosis communication pitfalls" where they underlined empathy and planning from the part of medical professional, while communicating the terminal diagnosis of ALS. Participants' reactions and adjustments post-ALS diagnosis are described in "the aftermath of diagnosis." In this third theme, we highlight participants' shock and their need to rethink overall life plans and roles in their family.

SIGNIFICANCE OF THE RESULTS: Diagnosis communication that is clear, empathetic, and adjusted to the needs of the patients as well as their caregivers is critical. More work is needed to improve diagnosis communication for ALS patients. Receiving the diagnosis of ALS leads to complete changes in life of caregivers. It is therefore necessary that medical professionals provide adequate support that allows them to plan for their future.}, } @article {pmid39244645, year = {2024}, author = {Tang, IW and Hansen, J and Dickerson, AS and Weisskopf, MG}, title = {Occupational lead exposure and amyotrophic lateral sclerosis survival in the Danish National Patient Registry.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2024.2399155}, pmid = {39244645}, issn = {2167-9223}, abstract = {OBJECTIVES: We investigated the relationship between occupational lead exposure and amyotrophic lateral sclerosis (ALS) survival in Denmark.

METHODS: We identified 2,161 ALS cases diagnosed from 1982 to 2013 with at least 5 years of employment history before ALS diagnosis, via the Danish National Patient Registry. Cases were followed until March 2017. We defined lead exposure as never employed in a lead job, ever employed in a lead job, and ever employed in a lead job by exposure probability (<50% vs. ≥50%), excluding jobs held in the 5 years before diagnosis in main analyses. Survival was evaluated using Cox proportional hazards models and stratified by sex and age of diagnosis.

RESULTS: Median age of diagnosis was 63.5 years, and individuals in lead-exposed jobs were diagnosed at a younger age. Adjusted hazard ratios (aHR) were slightly decreased for men ever lead-exposed (aHR:0.92, 95%CI: 0.80, 1.05) and more so among those diagnosed at age 60-69 (lead ≥ 50% aHR: 0.66, 95%CI: 0.45, 0.98), but reversed for men diagnosed at age 70 and later (aHR: 2.03, 95%CI: 1.13, 3.64). No apparent pattern was observed among women.

CONCLUSIONS: Occupational lead exposure contributed to shorter survival among men diagnosed at older ages. The inverse associations observed for men diagnosed earlier could relate to possible healthy worker hire effect or health advantages of working in lead-exposed jobs. Our results are consistent with an adverse impact of lead exposure on ALS survival at older ages, with the age at which lead's effects on survival worsen later on among those in lead-exposed jobs.}, } @article {pmid39243983, year = {2025}, author = {Mohan, M and Mannan, A and Nauriyal, A and Singh, TG}, title = {Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115242}, doi = {10.1016/j.bbr.2024.115242}, pmid = {39243983}, issn = {1872-7549}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Animals ; *ATP-Binding Cassette Transporters/metabolism ; Signal Transduction/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.}, } @article {pmid39243146, year = {2024}, author = {Jimenez, JV and Tang, MJ and Wilson, MW and Morrison, AH and Ackrivo, J and Choi, PJ}, title = {Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {1099-1103}, doi = {10.1002/mus.28250}, pmid = {39243146}, issn = {1097-4598}, support = {NIH NHLBI K23 HL-151879//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/complications ; *Noninvasive Ventilation/methods ; Female ; Male ; Middle Aged ; Aged ; Retrospective Studies ; *Respiratory Insufficiency/therapy/etiology/physiopathology ; Vital Capacity/physiology ; Hypercapnia/therapy/etiology/physiopathology ; Cohort Studies ; }, abstract = {INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure.

METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45 mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60 cmH2O or forced vital capacity (FVC) <50% predicted normal.

RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64 years ±11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64% ± 19%, the mean MIP; 41 cmH2O ± 17, and diurnal TcCO2; 40 ± 6 mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1 year of NIV initiation, 126 (37%) patients were deceased.

DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.}, } @article {pmid39242803, year = {2024}, author = {Monselise, EB and Vyazmensky, M and Scherf, T and Batushansky, A and Fishov, I}, title = {Author Correction: D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20873}, doi = {10.1038/s41598-024-71813-5}, pmid = {39242803}, issn = {2045-2322}, } @article {pmid39242576, year = {2024}, author = {Phillips, MCL and Picard, M}, title = {Neurodegenerative disorders, metabolic icebergs, and mitohormesis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {46}, pmid = {39242576}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitochondria/metabolism ; Hormesis/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.}, } @article {pmid39242281, year = {2025}, author = {Amalia, R and Prasetya Wibawa, A and Surya Aditya, R and Andana Pohan, R and Tetteng, B and Zuhroh, L and Ainy Sadijah, N}, title = {Enhancing caregiver well being by integrating mindfulness and technology in amyotrophic lateral sclerosis care.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {131}, number = {}, pages = {110819}, doi = {10.1016/j.jocn.2024.110819}, pmid = {39242281}, issn = {1532-2653}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; *Mindfulness/methods ; *Caregivers/psychology ; *Quality of Life ; Mobile Applications ; Stress, Psychological/therapy/psychology ; }, abstract = {This letter discusses the pressing issue of caregiver burden in Amyotrophic Lateral Sclerosis (ALS) care, emphasizing the potential of mindfulness practices to alleviate stress and improve quality of life for caregivers. The integration of digital platforms, such as mindfulness apps, offers an accessible and effective solution, particularly in resource-limited settings. By adopting these strategies, we can enhance caregiver well-being and overall patient care, making it a crucial consideration for global health interventions.}, } @article {pmid39242252, year = {2024}, author = {Benmoussa, A and Assernannas, I and Maatoui-Belabbes, H and Dahmaoui, N and Qachouh, M and Cherkaoui, S and Lamchaheb, M and Rachid, M and Madani, A and Khoubila, N}, title = {[Acquired bone marrow aplasia in children and young adults under the age of 30: Experience of the Pediatric Hematology and Oncology Department of the 20 August Hospital, Casablanca].}, journal = {Bulletin du cancer}, volume = {111}, number = {10}, pages = {944-954}, doi = {10.1016/j.bulcan.2024.06.010}, pmid = {39242252}, issn = {1769-6917}, mesh = {Humans ; Male ; Female ; Infant ; Child, Preschool ; Child ; Adolescent ; Adult ; *Anemia, Aplastic/mortality/therapy ; Morocco/epidemiology ; Retrospective Studies ; Prognosis ; Time-to-Treatment ; *Cyclosporine/therapeutic use ; *Antilymphocyte Serum/therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Treatment Outcome ; Delayed Diagnosis ; }, abstract = {Bone marrow aplasia is a rare and serious hematologic disorder. Although benign, it is a hematologic disorder whose prognosis can be poor and whose spontaneous development can be fatal. Treatment is long, difficult and costly. In developing countries, the mortality rate is high due to the difficulties of therapeutic management, both supportive and specific. We conducted a retrospective study of 92 cases of AM identified in the Pediatric Hematology and Oncology Department of the 20 Août University Hospital in Casablanca over a 10-year period (January 2010-January 2020). In this work, we present an overview of the situation and highlight the difficulties encountered in the management of AM in the Pediatric Hematology and Oncology Department of the University Hospital of Casablanca. In our study, the mean age was 19 years, ranging from 3 months to 29 years, with a peak in the 15-20 age group. The sex ratio (M/F) was 2.06, with a male predominance of 67%. In our series, only 35% of patients had complete bone marrow failure. An anemic syndrome was present in 92% of patients, and hemorrhagic and infectious syndromes were present in 70% and 41% of patients, respectively. The median time from diagnosis to treatment was 82 days. According to the Camitta score, 31% of our patients had mild AM, 41% had severe AM, and 28% had very severe AM. After etiologic evaluation, we concluded that 90% of the patients had idiopathic bone marrow aplasia, 2% had constitutional bone marrow aplasia, and 8% of the patients were suspected to have secondary bone marrow aplasia: post-hepatitis (3 cases), toxic (2 cases), drug-induced (1 case), and aplastic PNH (1 case). Mortality in the first three months after diagnosis was 21%. Sixty-nine percent of our patients received specific treatment: 28 were treated with cyclosporin (CIS) alone as first-line therapy, 20 received a combination of antilymphocyte serum (ALS) and cyclosporin, 2 received hematopoietic stem cell transplantation (HSCT), while 3 were treated with androgens alone. The overall response rate was 30% with CIS, 42% with ALS+CIS and 100% with HSCT. In our study, the overall death rate was 44%, while the one-year survival rate was 40%. It is important to note that septic shock was the leading cause of death (53% of deaths), followed by hemorrhagic shock (24%). This highlights the lack of hemodynamic resuscitation and symptomatic treatment. Our multivariate study defined the following risk factors as predictive of worse survival: age greater than 16 years (RR: 3.28; CI: 1.29-8.33; P=0.012), PNN less than 200 or very severe bone marrow aplasia (RR: 3.01; 1.1-8.08; P=0.028), and failure to receive any specific treatment (RR: 4.07; 1.77-9.35; P=0.0003). The high overall mortality in our series was due to several factors: inaccessibility to effective therapies, delayed diagnosis, failure to initiate specific treatment, inadequate symptomatic treatment, and geographical and financial inaccessibility.}, } @article {pmid39242198, year = {2024}, author = {Grassano, M and Canosa, A and D'Alfonso, S and Corrado, L and Brodini, G and Koumantakis, E and Cugnasco, P and Manera, U and Vasta, R and Palumbo, F and Mazzini, L and Gallone, S and Moglia, C and Dewan, R and Chia, R and Ding, J and Dalgard, C and Gibbs, RJ and Scholz, S and Calvo, A and Traynor, B and Chio, A}, title = {Intermediate HTT CAG repeats worsen disease severity in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {1}, pages = {100-102}, pmid = {39242198}, issn = {1468-330X}, } @article {pmid39241508, year = {2024}, author = {Zheng, X and Liu, J and Wang, S and Xiao, Y and Jiang, Q and Li, C and Shang, H}, title = {Total physical activity, plant-based diet and neurodegenerative diseases: A prospective cohort study of the UK biobank.}, journal = {Parkinsonism & related disorders}, volume = {128}, number = {}, pages = {107125}, doi = {10.1016/j.parkreldis.2024.107125}, pmid = {39241508}, issn = {1873-5126}, mesh = {Humans ; Male ; Female ; *Exercise/physiology ; Middle Aged ; United Kingdom/epidemiology ; Aged ; *Diet, Vegetarian ; *Neurodegenerative Diseases/epidemiology ; *Biological Specimen Banks ; Prospective Studies ; Alzheimer Disease/epidemiology ; Parkinson Disease/epidemiology ; Amyotrophic Lateral Sclerosis/epidemiology ; Adult ; Cohort Studies ; Diet, Plant-Based ; UK Biobank ; }, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) result from a complex interplay of genetic, environmental and aging factors. A balanced diet and adequate physical activity (PA) are recognized as pivotal components among modifiable environmental factors. The independent impact on NDD incidence has been previously debated. This investigation seeks to delineate the association between PA and NDDs across various levels of adherence to a plant-based diet.

METHODS: In this study, a cohort of 368,934 participants from the UK Biobank was analyzed. Total physical activity (TPA) levels and healthful plant-based diet index (hPDI) were calculated and categorized. A multiple adjusted Cox model was utilized to evaluate the influence of TPA and hPDI on common NDDs, respectively.

RESULTS: Finally, 4602 identified cases diagnosed as Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). We found that higher TPA was significantly associated with a reduced risk of developing AD (Q3: HR 0.87; Q4: HR 0.78) and PD (Q3: HR 0.86; Q4: HR 0.81). The protective effect was further accentuated with adherence to a plant-based diet. However, these connections were not observed in the analysis of ALS regardless of dietary patterns.

CONCLUSION: Our findings underscore a significant association between higher TPA and reduced risks of AD and PD, with an enhanced effect observed in conjunction with a plant-based diet. This study contributes to addressing the knowledge gap regarding the combined impact of TPA and a plant-based diet on NDDs occurrence, providing insights into potential underlying mechanisms.}, } @article {pmid39241471, year = {2024}, author = {Casiraghi, V and Milone, I and Brusati, A and Peverelli, S and Doretti, A and Poletti, B and Maderna, L and Morelli, C and Ticozzi, N and Silani, V and Verde, F and Ratti, A}, title = {Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123210}, doi = {10.1016/j.jns.2024.123210}, pmid = {39241471}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis ; Female ; Male ; *Neurofilament Proteins/blood/genetics ; Middle Aged ; Aged ; *Polymorphism, Single Nucleotide ; *DNA-Binding Proteins/genetics/blood ; *Genotype ; Biomarkers/blood ; Cohort Studies ; Adult ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition affecting upper and/or lower motor neurons and characterized neuropathologically by TDP-43 proteinopathy. Given its role in ALS pathobiology, it is currently under debate whether TDP-43 might represent a suitable ALS biomarker to be measured in patients' biofluids. The rs12608932 A > C single nucleotide polymorphism in the UNC13A gene is a risk factor for ALS and patients homozygous for the high-risk C allele display a higher burden of TDP-43 neuropathology than homozygotes for the low-risk A allele, although the association with TDP-43 levels in biofluids has never been evaluated. In this study, we measured serum levels of TDP-43 and neurofilament light chain (NFL) by Simoa technology in a cohort of 69 ALS patients stratified according to the UNC13A rs12608932 genotype compared to 43 neurologically healthy controls. By multiple linear regression analysis, serum TDP-43 was significantly elevated in ALS patients compared to controls, with UNC13A AA and AC, but not CC, ALS patients showing higher serum TDP-43 levels than controls. We also confirmed that serum NFL concentration was increased in ALS patients, without any correlation with the UNC13A genotype. Our results indicate that serum TDP-43 is higher in ALS patients compared to controls and that, in contrast to NFL, this increase is specifically associated with the UNC13A rs12608932 AA and AC genotypes, but not with the high-risk CC genotype. Studies in larger cohorts will be needed to confirm these findings and to elucidate the biological link between serum TDP-43 levels and UNC13A genotype.}, } @article {pmid39241118, year = {2024}, author = {Sharkey, RJ and Cortese, F and Goodyear, BG and Korngut, LW and Jacob, SM and Sharkey, KA and Kalra, S and Nguyen, MD and Frayne, R and Pfeffer, G}, title = {Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4026-4032}, pmid = {39241118}, issn = {1460-2156}, support = {//ALS Society of Canada/ ; //Barry Barrett Foundation/ ; //Rose Family Foundation/ ; //Hotchkiss Brain Institute/ ; /CAPMC/CIHR/Canada ; //Brain Canada Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Glymphatic System/diagnostic imaging ; *Diffusion Tensor Imaging ; Disease Progression ; White Matter/diagnostic imaging/pathology ; Adult ; Motor Neuron Disease/physiopathology/diagnostic imaging/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central to the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we performed a longitudinal analysis of glymphatic function in ALS and compared it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analysed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate) and white matter hyperintensity burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared with PLS and control participants across all three time points. There was no association with clinical factors; however, the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.}, } @article {pmid39240038, year = {2024}, author = {García-Casanova, PH and Pérez-Martínez, P and Sevilla, T and Doménech, R and León, M and Vázquez-Costa, JF}, title = {Impact of SARS-CoV-2 infection and COVID-19 pandemic on the morbidity and mortality of amyotrophic lateral sclerosis patients in Valencia, Spain.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16465}, pmid = {39240038}, issn = {1468-1331}, support = {JR19/00030//Instituto de Salud Carlos III/ ; PI 21/00737//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *COVID-19/mortality/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Female ; Male ; Middle Aged ; Aged ; *Hospitalization/statistics & numerical data ; Risk Factors ; Noninvasive Ventilation/statistics & numerical data ; Pandemics ; SARS-CoV-2 ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization for coronavirus disease 2019 (COVID-19) and related death and to assess the impact of the pandemic in the survival of amyotrophic lateral sclerosis (ALS) patients.

METHODS: The risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death was assessed in ALS patients alive between March 2020 and July 2022. To evaluate its impact in the overall survival of ALS patients, the survival of patients who died before and during the pandemic was compared.

RESULTS: Amongst 263 ALS patients alive during the pandemic, 62 got infected during the study period (infection rate 14.34 per 100 person-years). Most infections (68%) occurred during the sixth wave (November 2021 to January 2022) and most patients (67%) were vaccinated at the time of infection. The hospitalization rate due to COVID-19 was 4.16 per 100 person-years. The multivariable model confirmed non-invasive ventilation (NIV) use prior to infection as a risk factor for hospitalization (odds ratio [OR] = 7.96, p = 0.003) and COVID-19 vaccination as a protective factor (OR = 0.093, p = 0.025) independent of age, sex and gastrostomy. Within 30 days after infection, 7% of non-ventilated patients started NIV and five patients (8.06%) died, of whom four were previously ventilated. The median survival of ALS patients was similar before and during the pandemic and no effect was found in the Cox regression model (hazard ratio 1.02, p = 0.89).

CONCLUSIONS: This study shows a high risk of severe COVID-19 amongst ALS patients requiring NIV. Nevertheless, the pandemic showed no impact in the overall survival of ALS patients, probably due to a high vaccination rate and an adequate access to healthcare resources.}, } @article {pmid39239358, year = {2024}, author = {Segerstrom, SC and Kasarskis, EJ}, title = {The Seattle Amyotrophic Lateral Sclerosis (ALS) Patient Project Database: observational, longitudinal, dyadic characterization of people with ALS and their partners.}, journal = {Health psychology and behavioral medicine}, volume = {12}, number = {1}, pages = {2396137}, pmid = {39239358}, issn = {2164-2850}, support = {R16 NS129748/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: The median survival time in ALS is approximately 3 years, but survival times range from less than a year to more than 10 years and much variance in disease course remains to be explained. As is true for physical outcomes, there is considerable variance in QOL, which is influenced by psychological health, coping, and social support, among other psychosocial factors. The Seattle ALS Patient Project Database (SALSPPD) provides a unique opportunity for researchers to address established and novel hypotheses about disease progression and QOL in ALS.

METHODS: The SALSPPD is a longitudinal dataset of people with ALS (n = 143) and their partners (spouses, significant others, or caregivers; n = 123) from clinics and community-based ALS support groups. Participants were interviewed in their homes every 3 months for up to 18 months between March 1987 and August 1989. Follow-up phone calls were completed in 1990, 1994, and 2008, primarily to ascertain disease outcomes.

RESULTS: The provided data dictionary includes details of the over 500 variables measured in the study, which have been subsetted into domain datasets. Domains address physical, psychological, social, and behavioral status on the person with ALS and their partners. Missing data were coded according to their mechanism. Data are available in two formats: The person-level (wide) databases and the time-level (long) databases.

DISCUSSION: The SALSPPD will provide a rich resource to scientists interested in the natural history of ALS, psychosocial effects on ALS outcomes and vice versa, and psychosocial and disease outcomes of treatments.}, } @article {pmid39239150, year = {2024}, author = {Vidovic, M and Lapp, HS and Weber, C and Plitzko, L and Seifert, M and Steinacker, P and Otto, M and Hermann, A and Günther, R}, title = {Comparative analysis of neurofilaments and biomarkers of muscular damage in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae288}, pmid = {39239150}, issn = {2632-1297}, abstract = {Diagnosis of the fatal neurodegenerative disease amyotrophic lateral sclerosis is challenging. Neurofilaments, indicative of neuronal damage, along with creatine kinase, creatinine, myoglobin, and troponin T, representing muscular damage, have been identified as promising fluid biomarkers. This study aims to comprehensively assess and compare their diagnostic and prognostic potential in a 'real-world' cohort of patients with amyotrophic lateral sclerosis. About 77 patients with amyotrophic lateral sclerosis and its clinical variants, and 26 age- and sex-matched controls with various neuromuscular and neurodegenerative diseases, were retrospectively included in this monocentric, cross-sectional study. Neurofilaments in cerebrospinal fluid and biomarkers of muscular damage in serum were measured and correlated with demographic features, motor function, survival time, clinical phenotypes, and the extent of upper and lower motor neuron involvement. Neurofilament, myoglobin, and troponin T concentrations were higher in patients with amyotrophic lateral sclerosis compared to disease controls. Higher neurofilament levels correlated with lower motor function and faster disease progression rate, while higher creatine kinase and creatinine concentrations were linked to preserved motor function. In contrast, troponin T elevation indicated poorer fine and gross motor functions. Increased neurofilament levels were associated with shorter survival, whereas biomarkers of muscular damage lacked survival correlation. Neurofilament concentrations were higher in classical amyotrophic lateral sclerosis than in progressive muscular atrophy, while myoglobin and troponin T levels were elevated in progressive muscular atrophy compared to primary lateral sclerosis. Neurofilaments were predominantly linked to upper motor neuron involvement. Our findings confirmed the robust diagnostic and prognostic value of neurofilaments in amyotrophic lateral sclerosis. Elevated neurofilament concentrations were associated with higher disease severity, faster disease progression, shorter survival, and predominant upper motor neuron degeneration. Biomarkers of muscular damage were inferior in distinguishing amyotrophic lateral sclerosis from other neuromuscular and neurodegenerative diseases. However, they may serve as complementary biomarkers and support in discriminating clinical variants of amyotrophic lateral sclerosis.}, } @article {pmid39239063, year = {2024}, author = {Pezeshgi, S and Ghaderi, S and Mohammadi, S and Karimi, N and Ziaadini, B and Mohammadi, M and Fatehi, F}, title = {Diffusion tensor imaging biomarkers and clinical assessments in amyotrophic lateral sclerosis (ALS) patients: an exploratory study.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {9}, pages = {5080-5090}, pmid = {39239063}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Biomarkers are needed to improve diagnosis, gauge progression, and evaluate treatment. Diffusion tensor imaging (DTI) is a promising biomarker for detecting microstructural alterations in the white matter tracts. This study aimed to assess DTI metrics as biomarkers and to examine their relationship with clinical assessments in patients with ALS. Eleven patients with ALS and 21 healthy controls (HCs) underwent 3T MRI with DTI. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were compared between key motor and extra-motor tract groups. Group comparisons and correlations between DTI metrics also correlated with clinical scores of disability (ALSFRS-R), muscle strength (dynamometry), and motor unit loss (MUNIX). Widespread differences were found between patients with ALS and HCs in DTI metrics, including decreased FA and increased diffusivity metrics. However, MD and RD are more sensitive metrics for detecting white matter changes in patients with ALS. Significant interhemispheric correlations between the tract DTI metrics were also observed. DTI metrics showed symmetry between the hemispheres and correlated with the clinical assessments. MD, RD, and AD increases significantly correlated with lower ALSFRS-R and MUNIX scores and weaker dynamometry results. DTI reveals microstructural damage along the motor and extra-motor regions in ALS patients. DTI metrics can serve as quantitative neuroimaging biomarkers for diagnosis, prognosis, monitoring of progression, and treatment. Combined analysis of imaging, electrodiagnostic, and functional biomarkers shows potential for characterizing disease pathophysiology and progression.}, } @article {pmid39236857, year = {2024}, author = {Reiter, RJ and Sharma, RN and Manucha, W and Rosales-Corral, S and Almieda Chuffa, LG and Loh, D and Luchetti, F and Balduini, W and Govitrapong, P}, title = {Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102480}, doi = {10.1016/j.arr.2024.102480}, pmid = {39236857}, issn = {1872-9649}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use ; *Mitochondria/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.}, } @article {pmid39236792, year = {2024}, author = {Hattori, H and Osumi, K and Tanaka, M and Arai, T and Nishimura, K and Yamamoto, N and Sakamoto, K and Goto, Y and Sugawara, Y}, title = {Discovery of 5-phenyl-3-ureidothiophene-2-carboxamides as protective agents for ALS patient iPSC-derived motor neurons.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {113}, number = {}, pages = {129935}, doi = {10.1016/j.bmcl.2024.129935}, pmid = {39236792}, issn = {1464-3405}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Drug Discovery ; Structure-Activity Relationship ; Molecular Structure ; Thiophenes/chemistry/pharmacology/chemical synthesis ; Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Superoxide Dismutase-1/metabolism/genetics ; Intracellular Signaling Peptides and Proteins ; }, abstract = {We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds.}, } @article {pmid39236307, year = {2024}, author = {Doneddu, PE and Gallo, C and Gentile, L and Cocito, D and Falzone, Y and Di Stefano, V and Inghilleri, M and Cosentino, G and Matà, S and Mazzeo, A and Filosto, M and Peci, E and Sorrenti, B and Brighina, F and Moret, F and Vegezzi, E and Sperti, M and Risi, B and Nobile-Orazio, E and , }, title = {Comparison of the diagnostic accuracy of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society and American Association of Electrodiagnostic Medicine diagnostic criteria for multifocal motor neuropathy.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16444}, pmid = {39236307}, issn = {1468-1331}, support = {IIR-ITA-BXLT-001955/ IISR-2017-104226//Takeda Italia SPA/ ; //Fondazione Humanitas per la Ricerca/ ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Electrodiagnosis/standards/methods ; *Sensitivity and Specificity ; Retrospective Studies ; Aged ; *Neural Conduction/physiology ; *Societies, Medical/standards ; *Polyneuropathies/diagnosis/physiopathology ; Adult ; Europe ; Motor Neuron Disease/diagnosis/physiopathology ; United States ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: This study was undertaken to compare the sensitivity and specificity of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for multifocal motor neuropathy (MMN) with those of the American Association of Electrodiagnostic Medicine (AAEM).

METHODS: Sensitivity and specificity of the two sets of criteria were retrospectively evaluated in 53 patients with MMN and 280 controls with axonal peripheral neuropathy, inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis. Comparison of the utility of nerve conduction studies with different numbers of nerves examined was also assessed.

RESULTS: The 2010 EFNS/PNS criteria had a sensitivity of 47% for definite MMN and 57% for probable/definite MMN, whereas the AAEM criteria had a sensitivity of 28% for definite MMN and 53% for probable/definite MMN. The sensitivity of the AAEM criteria was higher when utilizing area compared to amplitude reduction to define conduction block. Using supportive criteria, the sensitivity of the 2010 EFNS/PNS criteria for probable/definite MMN increased to 64%, and an additional 36% patients fulfilled the criteria (possible MMN). Specificity values for definite and probable/definite MMN were slightly higher with the AAEM criteria (100%) compared to the EFNS/PNS criteria (98.5% and 97%). Extended nerve conduction studies yielded slightly increased diagnostic sensitivity for both sets of criteria without significantly affecting specificity.

CONCLUSIONS: In our patient populations, the 2010 EFNS/PNS criteria demonstrated higher sensitivity but slightly lower specificity compared to the AAEM criteria. Extended nerve conduction studies are advised to achieve slightly higher sensitivity while maintaining very high specificity.}, } @article {pmid39235524, year = {2024}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Solca, F and Faltracco, V and Telesca, A and Palumbo, F and Dalla Bella, E and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6944-6955}, pmid = {39235524}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; Prevalence ; Frontotemporal Dementia/physiopathology/epidemiology ; Cohort Studies ; Neuropsychological Tests ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates.

METHODS: N = 808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi).

RESULTS: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15-17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤ .008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤ .031).

CONCLUSIONS: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.}, } @article {pmid39234934, year = {2024}, author = {Mao, M and Zeng, W and Zheng, Y and Fan, W and Yao, Y}, title = {Fasudil attenuates syncytin-1-mediated activation of microglia and impairments of motor neurons and motor function in mice.}, journal = {Drug development research}, volume = {85}, number = {6}, pages = {e22254}, doi = {10.1002/ddr.22254}, pmid = {39234934}, issn = {1098-2299}, support = {81860245//National Natural Science Foundation of China/ ; [2019]5664//Department of Science and Technology of Guizhou Province/ ; GZSYBS[2017]01//Doctor Fund of Guizhou Provincial People's Hospital/ ; GZSYQN[2018]09//Youth Fund of Guizhou Provincial People's Hospital/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; Mice ; *Mice, Inbred C57BL ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/pharmacology ; Gene Products, env ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Pregnancy Proteins/metabolism ; Male ; Cytokines/metabolism ; Disease Models, Animal ; Motor Activity/drug effects ; Spinal Cord/metabolism/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin-1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus-W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered. In this study, C57BL/6 mice were injected with adeno-associated virus-overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin-eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial- and motor neurons-related proteins. Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule-associated protein 2, HB9, neuronal nuclei and neuron-specific enolase in Syn-induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration. This study provides evidence that Syn-activated microglia plays a pivotal role during the progression of ALS.}, } @article {pmid39233852, year = {2024}, author = {Gilbert, JW and Kennedy, Z and Godinho, BMDC and Summers, A and Weiss, A and Echeverria, D and Bramato, B and McHugh, N and Cooper, D and Yamada, K and Hassler, M and Tran, H and Gao, FB and Brown, RH and Khvorova, A}, title = {Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102291}, pmid = {39233852}, issn = {2162-2531}, abstract = {A hexanucleotide (G4C2) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different C9ORF72 transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing C9ORF72 mRNA variants are found to preferentially localize to the nucleus, and thus C9ORF72 mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting C9ORF72 mRNA variants specifically or non-selectively reduce the expression of C9ORF72 mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all C9ORF72 mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing C9ORF72 mRNA transcripts. Combined, these data support RNAi-based degradation of C9ORF72 as a potential therapeutic paradigm.}, } @article {pmid39233624, year = {2024}, author = {Garnier, M and Camdessanché, JP and Cassereau, J and Codron, P}, title = {From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2398199}, pmid = {39233624}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Diagnosis, Differential ; Electromyography/methods ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.}, } @article {pmid39233146, year = {2024}, author = {Wang, H and Liu, S and Sun, Y and Chen, C and Hu, Z and Li, Q and Long, J and Yan, Q and Liang, J and Lin, Y and Yang, S and Lin, M and Liu, X and Wang, H and Yu, J and Yi, F and Tan, Y and Yang, Y and Chen, N and Ai, Q}, title = {Target modulation of glycolytic pathways as a new strategy for the treatment of neuroinflammatory diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102472}, doi = {10.1016/j.arr.2024.102472}, pmid = {39233146}, issn = {1872-9649}, mesh = {Humans ; *Glycolysis/physiology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Aging/metabolism ; }, abstract = {Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5'-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases-stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression-and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells-neurons, microglia, and astrocytes-within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.}, } @article {pmid39232594, year = {2024}, author = {Martínez-Payá, JJ and Ríos-Díaz, J and Del Baño-Aledo, ME and Hervás, D and Tembl-Ferrairó, JI and Sevilla-Mantecón, T and Vázquez-Costa, JF}, title = {The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis.}, journal = {Neurologia}, volume = {39}, number = {7}, pages = {564-572}, doi = {10.1016/j.nrleng.2024.07.003}, pmid = {39232594}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Male ; Middle Aged ; Female ; *Median Nerve/diagnostic imaging ; Prognosis ; *Biomarkers ; Aged ; *Ultrasonography ; Disease Progression ; Cohort Studies ; }, abstract = {INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS).

METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed.

RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay.

CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.}, } @article {pmid39232248, year = {2024}, author = {Borchert, GA and Shanks, ME and Whitfield, J and Clouston, P and Raji, S and Sperring, S and Thompson, JA and Xue, K and De Silva, SR and Downes, SM and MacLaren, RE and Cehajic-Kapetanovic, J}, title = {Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.}, journal = {Ophthalmic genetics}, volume = {45}, number = {6}, pages = {633-639}, pmid = {39232248}, issn = {1744-5094}, mesh = {Humans ; Female ; Adult ; *Ciliopathies/genetics ; *Pedigree ; *Phenotype ; Retrospective Studies ; Genotype ; Cone Dystrophy/genetics/diagnosis ; Consanguinity ; Visual Acuity/physiology ; Tomography, Optical Coherence ; Mutation ; Homozygote ; }, abstract = {BACKGROUND: CFAP410 (Cilia and Flagella Associated Protein 410) encodes a protein that has an important role in the development and function of cilia. In ophthalmology, pathogenic variants in CFAP410 have been described in association with cone rod dystrophy, retinitis pigmentosa, with or without macular staphyloma, or with systemic abnormalities such as skeletal dysplasia and amyotrophic lateral sclerosis. Herein, we report a consanguineous family with a novel homozygous CFAP410 c.335_346del variant with cone only degeneration and no systemic features.

METHODS: A retrospective analysis of ophthalmic history, examination, retinal imaging, electrophysiology and microperimetry was performed as well as genetic testing with in silico pathogenicity predictions and a literature review.

RESULTS: A systemically well 28-year-old female of Pakistani ethnicity with parental consanguinity and no relevant family history, presented with childhood-onset poor central vision and photophobia. Best-corrected visual acuity and colour vision were reduced (0.5 LogMAR, 6/17 Ishihara plates (right) and 0.6 LogMAR, 3/17 Ishihara plates (left). Fundus examination showed no pigmentary retinopathy, no macular staphyloma and autofluorescence was unremarkable. Optical coherence tomography showed subtle signs of intermittent disruption of the ellipsoid zone. Microperimetry demonstrated a reduction in central retinal sensitivity. Electrodiagnostic testing confirmed a reduction in cone-driven responses. Whole-genome sequencing identified an in-frame homozygous deletion of 12 base pairs at c.335_346del in CFAP410.

CONCLUSIONS: The non-syndromic cone dystrophy phenotype reported herein expands the genotypic and phenotypic spectra of CFAP410-associated ciliopathies and highlights the need for light of potential future genetic therapies.}, } @article {pmid39231585, year = {2024}, author = {Kato, C and Morimoto, S and Takahashi, S and Namba, S and Wang, QS and Okada, Y and Okano, H}, title = {Spinal cord motor neuron phenotypes and polygenic risk scores in sporadic amyotrophic lateral sclerosis: deciphering the disease pathology and therapeutic potential of ropinirole hydrochloride.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-333690}, pmid = {39231585}, issn = {1468-330X}, } @article {pmid39231554, year = {2024}, author = {Gong, Z and Deng, W and Li, Z and Tang, J and Zhang, M}, title = {Association between apathy and caregiver burden in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e080803}, pmid = {39231554}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Cross-Sectional Studies ; *Apathy ; Middle Aged ; *Anxiety/psychology/etiology ; *Depression/psychology/etiology ; China/epidemiology ; *Caregiver Burden/psychology ; Aged ; Caregivers/psychology ; Adult ; Cognitive Dysfunction/etiology/psychology ; Psychiatric Status Rating Scales ; Logistic Models ; Cost of Illness ; }, abstract = {OBJECTIVES: To investigate the relationship among patients' apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS).

DESIGN: A cross-sectional study design was used.

SETTING: The study was conducted at a tertiary hospital in Wuhan, Hubei, China.

PARTICIPANTS: A total of 109 patients with ALS and their caregivers were included.

OUTCOME MEASURES: Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients' apathy on the relationship between depression/anxiety and caregiver burden.

RESULTS: Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p<0.05). There was a positive association observed between caregiver burden and disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). There was a negative association between caregiver burden and the Revised ALS Functional Rating Scale (rs=-0.275, p<0.05). Apathy was an independent risk factor for higher caregiver burden (OR 1.121, 95% CI 1.041 to 1.206, p<0.05). Apathy fully mediated the relationship between depression and caregiver burden (β=0.35, 95% CI 0.16 to 0.54, p<0.05) while partially mediating the relationship between anxiety and caregiver burden (β=0.34, 95% CI 0.16 to 0.52, p<0.05).

CONCLUSIONS: Apathy, depression and anxiety exerted a detrimental impact on caregiver burden in individuals with ALS. Apathy played a mediating role in the relationship between depression and caregiver burden and between anxiety and caregiver burden. These findings underscore the importance of identifying apathy and developing interventions for its management within the context of ALS.}, } @article {pmid39231437, year = {2024}, author = {Chu, HS and Oh, J}, title = {Family Caregivers' Experiences of People With Amyotrophic Lateral Sclerosis Undergoing Gastrostomy Tube Feeding.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {56}, number = {6}, pages = {224-228}, pmid = {39231437}, issn = {1945-2810}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; *Caregivers/psychology ; *Enteral Nutrition ; *Gastrostomy ; Female ; Male ; Middle Aged ; Republic of Korea ; *Qualitative Research ; Adult ; Aged ; Stress, Psychological ; Interviews as Topic ; }, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS) patients with impaired swallowing function, gastrostomy tube (G-tube) placement is recommended, but significantly increases the caregiving burden on families. This study aimed to describe the experiences of family caregivers of patients with ALS receiving home enteral nutrition through a G-tube. METHOD: Using purposive sampling, 8 family caregivers participated in the study. Data collection was conducted between February 2021 and October 2022 at a university hospital in Seoul, Korea. Semistructured face-to-face interviews were used to collect data until saturation. Data were analyzed using Krippendorff's content analysis approach. RESULTS: Qualitative analysis of the data revealed 3 main themes regarding caregiving. The emerging themes included psychological distress, unmet practical needs, and the struggle to provide care. CONCLUSION: After a G-tube placement, family caregivers experience various emotional stresses and have numerous unmet practical needs. Healthcare professionals caring for people with ALS receiving enteral nutrition should provide a tailored support program that addresses the specific needs of these family caregivers.}, } @article {pmid39231048, year = {2024}, author = {Trescato, I and Tavazzi, E and Vettoretti, M and Gatta, R and Vasta, R and Chio, A and Camillo, BD}, title = {DYNAMITE: Integrating Archetypal Analysis and Process Mining for Interpretable Disease Progression Modelling.}, journal = {IEEE journal of biomedical and health informatics}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/JBHI.2024.3453602}, pmid = {39231048}, issn = {2168-2208}, abstract = {DYNAMITE, an acronym for DYNamic Archetypal analysis for MIning disease TrajEctories, is a new methodology developed specifically to model disease progression by exploiting information available in longitudinal clinical datasets. First, archetypal analysis is applied to data organised in matrix form, with the aim of finding extreme and representative disease states (archetypes) linked to the original data through convex coefficients. Then, each original observation is associated with a single archetype based on their similarity; finally, an event log is created encoding the progression of disease states for each patient in terms of archetype states. In the last stage of the procedure, archetypal analysis is coupled with process mining, which allows the event log archetypes to be visualised graphically as sequences of disease states, allowing the clinical trajectories of patients to be extracted and examined. As a proof of concept, we applied the proposed method to data from a cohort of amyotrophic lateral sclerosis patients whose progression was monitored using the 12-item ALSFRS-R questionnaire. Without any a priori knowledge, DYNAMITE identified six archetypes clearly describing different types and severity of impairment and provided reliable clinical trajectories consistent with the prognosis of amyotrophic lateral sclerosis patients. DYNAMITE offers high interpretability at every stage of the analysis, which makes it particularly suitable for use in healthcare where explainability is paramount, and enables analysis of clinical trajectories at both individual and population levels.}, } @article {pmid39230722, year = {2024}, author = {Chalitsios, CV and Ley, H and Gao, J and Turner, MR and Thompson, AG}, title = {Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6956-6969}, pmid = {39230722}, issn = {1432-1459}, support = {Thompson/Apr23/896-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology ; *Apolipoproteins/antagonists & inhibitors/blood/genetics ; *Frontotemporal Dementia/blood/genetics/epidemiology ; Hypolipidemic Agents/pharmacology/therapeutic use ; Lipids/blood ; Mendelian Randomization Analysis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS.

METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications.

RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362).

CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.}, } @article {pmid39229489, year = {2024}, author = {Feng, F and Feng, G and Liu, J and Hao, W and Huang, W and Bi, X and Li, M and Wang, H and Yang, F and He, Z and Bai, J and Wang, H and Ma, G and Xu, B and Shu, N and Huang, X}, title = {Different patterns of structural network impairments in two amyotrophic lateral sclerosis subtypes driven by [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae222}, pmid = {39229489}, issn = {2632-1297}, abstract = {The structural network damages in amyotrophic lateral sclerosis patients are evident but contradictory due to the high heterogeneity of the disease. We hypothesized that patterns of structural network impairments would be different in amyotrophic lateral sclerosis subtypes by a data-driven method using [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging. The data of positron emission tomography, structural MRI and diffusion tensor imaging in fifty patients with amyotrophic lateral sclerosis and 23 healthy controls were collected by a [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid. Two amyotrophic lateral sclerosis subtypes were identified as the optimal cluster based on grey matter volume and standardized uptake value ratio. Network metrics at the global, local and connection levels were compared to explore the impaired patterns of structural networks in the identified subtypes. Compared with healthy controls, the two amyotrophic lateral sclerosis subtypes displayed a pattern of a locally impaired structural network centralized in the sensorimotor network and a pattern of an extensively impaired structural network in the whole brain. When comparing the two amyotrophic lateral sclerosis subgroups by a support vector machine classifier based on the decreases in nodal efficiency of structural network, the individualized network scores were obtained in every amyotrophic lateral sclerosis patient and demonstrated a positive correlation with disease severity. We clustered two amyotrophic lateral sclerosis subtypes by a data-driven method, which encompassed different patterns of structural network impairments. Our results imply that amyotrophic lateral sclerosis may possess the intrinsic damaged pattern of white matter network and thus provide a latent direction for stratification in clinical research.}, } @article {pmid39229486, year = {2024}, author = {Rivers-Auty, J and Hoyle, C and Pointer, A and Lawrence, C and Pickering-Brown, S and Brough, D and Ryan, S}, title = {C9orf72 dipeptides activate the NLRP3 inflammasome.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae282}, pmid = {39229486}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases with considerable clinical, genetic and pathological overlap. The most common cause of both diseases is a hexanucleotide repeat expansion in C9orf72. The expansion is translated to produce five toxic dipeptides, which aggregate in patient brain. Neuroinflammation is a feature of frontotemporal dementia and amyotrophic lateral sclerosis; however, its causes are unknown. The nod-like receptor family, pyrin domain-containing 3 inflammasome is implicated in several other neurodegenerative diseases as a driver of damaging inflammation. The inflammasome is a multi-protein complex which forms in immune cells in response to tissue damage, pathogens or aggregating proteins. Inflammasome activation is observed in models of other neurodegenerative diseases such as Alzheimer's disease, and inflammasome inhibition rescues cognitive decline in rodent models of Alzheimer's disease. Here, we show that a dipeptide arising from the C9orf72 expansion, poly-glycine-arginine, activated the inflammasome in microglia and macrophages, leading to secretion of the pro-inflammatory cytokine, interleukin-1β. Poly-glycine-arginine also activated the inflammasome in organotypic hippocampal slice cultures, and immunofluorescence imaging demonstrated formation of inflammasome specks in response to poly-glycine-arginine. Several clinically available anti-inflammatory drugs rescued poly-glycine-arginine-induced inflammasome activation. These data suggest that C9orf72 dipeptides contribute to the neuroinflammation observed in patients, and highlight the inflammasome as a potential therapeutic target for frontotemporal dementia and amyotrophic lateral sclerosis.}, } @article {pmid39229047, year = {2024}, author = {Wairagkar, M and Card, NS and Singer-Clark, T and Hou, X and Iacobacci, C and Hochberg, LR and Brandman, DM and Stavisky, SD}, title = {An instantaneous voice synthesis neuroprosthesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229047}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Brain computer interfaces (BCIs) have the potential to restore communication to people who have lost the ability to speak due to neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text[1-3]. However, text communication fails to capture the nuances of human speech such as prosody, intonation and immediately hearing one's own voice. Here, we demonstrate a "brain-to-voice" neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real-time to change intonation, emphasize words, and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.}, } @article {pmid39229019, year = {2024}, author = {Erwin, AL and Chang, ML and Fernandez, MG and Attili, D and Russ, JE and Sutanto, R and Pinarbasi, ES and Bekier, M and Brant, TS and Hahn, T and Dykstra, M and Thomas, D and Li, X and Baldridge, RD and Tank, EMH and Barmada, SJ and Mosalaganti, S}, title = {Molecular Visualization of Neuronal TDP43 Pathology In Situ.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229019}, issn = {2692-8205}, support = {DP2 GM150019/GM/NIGMS NIH HHS/United States ; S10 OD030275/OD/NIH HHS/United States ; T32 GM007544/GM/NIGMS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R35 GM128592/GM/NIGMS NIH HHS/United States ; }, abstract = {Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, enhancing RNA misprocessing due to loss of nuclear TDP43 and engendering a cycle that ends in cell death. Here, we show that adding small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation in iPSC-derived neurons (iNeurons). By employing a multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine how RNA influences the localization and aggregation of TDP43 in near-native conditions. We find that mislocalized TDP43 forms ordered fibrils within lysosomes and autophagosomes in iNeurons as well as in patient tissue, and provide the first high-resolution snapshots of TDP43 aggregates in situ. In so doing, we provide a cellular model for studying initial pathogenic events underlying ALS, FTLD, and related TDP43-proteinopathies.}, } @article {pmid39227882, year = {2024}, author = {Zelina, P and de Ruiter, AA and Kolsteeg, C and van Ginneken, I and Vos, HR and Supiot, LF and Burgering, BMT and Meye, FJ and Veldink, JH and van den Berg, LH and Pasterkamp, RJ}, title = {ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {144}, pmid = {39227882}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; MAXOMOD//E-Rare/ ; TRIAGE//JPND/ ; X-omics initiative//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; EScORIAL//H2020 European Research Council/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA Damage ; DNA Repair/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Mitochondria/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; Mutation ; *NIMA-Related Kinase 1/genetics/metabolism ; *Zebrafish ; Cytoskeletal Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS.}, } @article {pmid39227337, year = {2024}, author = {Choi, SJ and Yoo, SH and Lee, SY and Sung, JJ}, title = {Withdrawal of Life-Sustaining Mechanical Ventilation for a Patient With Amyotrophic Lateral Sclerosis in Locked-In Syndrome.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {5}, pages = {537-538}, pmid = {39227337}, issn = {1738-6586}, support = {NRF-2018R1A5A2025964/NRF/National Research Foundation of Korea/Korea ; }, } @article {pmid39226927, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Adaptive and self-learning Bayesian filtering algorithm to statistically characterize and improve signal-to-noise ratio of heart-rate data in wearable devices.}, journal = {Journal of the Royal Society, Interface}, volume = {21}, number = {218}, pages = {20240222}, pmid = {39226927}, issn = {1742-5662}, support = {//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Bayes Theorem ; *Wearable Electronic Devices ; *Heart Rate/physiology ; *Algorithms ; *Signal-To-Noise Ratio ; Male ; Female ; Signal Processing, Computer-Assisted ; }, abstract = {The use of wearable sensors to monitor vital signs is increasingly important in assessing individual health. However, their accuracy often falls short of that of dedicated medical devices, limiting their usefulness in a clinical setting. This study introduces a new Bayesian filtering (BF) algorithm that is designed to learn the statistical characteristics of signal and noise, allowing for optimal smoothing. The algorithm is able to adapt to changes in the signal-to-noise ratio (SNR) over time, improving performance through windowed analysis and Bayesian criterion-based smoothing. By evaluating the algorithm on heart-rate (HR) data collected from Garmin Vivoactive 4 smartwatches worn by individuals with amyotrophic lateral sclerosis and multiple sclerosis, it is demonstrated that BF provides superior SNR tracking and smoothing compared with non-adaptive methods. The results show that BF accurately captures SNR variability, reducing the root mean square error from 2.84 bpm to 1.21 bpm and the mean absolute relative error from 3.46% to 1.36%. These findings highlight the potential of BF as a preprocessing tool to enhance signal quality from wearable sensors, particularly in HR data, thereby expanding their applications in clinical and research settings.}, } @article {pmid39226712, year = {2024}, author = {Santos Silva, C and Gormicho, M and Simão, S and Pronto-Laborinho, AC and Alves, I and Pinto, S and Oliveira Santos, M and de Carvalho, M}, title = {C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.}, journal = {Journal of the neurological sciences}, volume = {465}, number = {}, pages = {123208}, doi = {10.1016/j.jns.2024.123208}, pmid = {39226712}, issn = {1878-5883}, mesh = {Humans ; Male ; Portugal/epidemiology ; Female ; Middle Aged ; *C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics/epidemiology ; Aged ; *Phenotype ; *DNA Repeat Expansion/genetics ; Cohort Studies ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; }, abstract = {BACKGROUND: C9orf72 gene repeat expansion (C9RE) is the most frequent gene variant associated with amyotrophic lateral sclerosis (ALS). We aimed to study the phenotype of motor neurone disease (MND) patients with C9RE in a Portuguese cohort.

METHODS: Demographical and clinical data of MND patients with (C9RE+) and without C9RE were compared. ALS al Rating Scale-Revised (ALSFRS-R) and Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were used to evaluate functional and cognitive performance, respectively. Survival analysis was performed using Kaplan Meier log-rank test and Cox proportional hazards model.

RESULTS: We included 761 patients of whom 61 (8.0 %) were C9RE+. C9RE+ patients had a higher frequency of ALS (95.1 vs 78.4 %, p = 0.002), and lower frequency of progressive muscular atrophy (3.3 vs 16.7 %, p = 0.006). C9RE+ was associated with earlier age of onset (58.1 vs 62.6 years, p = 0.003) and more frequent MND family history (65.5 vs 11.4 %, p < 0.001). Gender, ethnicity, onset site, diagnostic delay, disease progression rate until diagnosis (ΔF), ALSFRS-R and time until non-invasive ventilation did not differ between groups. Cognitive/behavioural symptoms and ECAS did not differ between groups, except a worse visuospatial score in C9RE+ group (p = 0.035). Death rate was 1.8 and 1.6 times higher in C9RE+ patients with MND and ALS, respectively. Significant survival prognostic factors in C9RE+ group were diagnosis delay (HR = 0.96, 95 %CI 0.92-0.99, p = 0.008) and ΔF (HR = 1.93, 95 %CI 1.26-2.96, p = 0.002).

CONCLUSION: Our study corroborates most previous cohorts' findings, but harbours some singularities regarding onset site, phenotype, and cognitive profile, that contribute to a better understanding of C9RE epidemiology.}, } @article {pmid39226692, year = {2024}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Risk of depression in amyotrophic lateral sclerosis: A nationwide cohort study in South Korea.}, journal = {Journal of psychiatric research}, volume = {178}, number = {}, pages = {414-420}, doi = {10.1016/j.jpsychires.2024.08.030}, pmid = {39226692}, issn = {1879-1379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Republic of Korea/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Depression/epidemiology ; Adult ; Cohort Studies ; Proportional Hazards Models ; }, abstract = {Depression is frequently reported in amyotrophic lateral sclerosis (ALS) due to the disastrous prognosis of progressive motor impairment, but the risk of depression in ALS is still unclear. Therefore, we investigated the risk of depression in ALS and analyzed the effect of ALS-related physical disability on the risk of developing depression using the Korean National Health Insurance Service (KNHIS) database. A total of 2241 ALS patients, as defined by the International Classification Diseases (ICD, G12.21) and Rare Intractable Disease codes (V123), and 1:10 sex- and age-matched controls were selected from the KNHIS. After applying exclusion criteria (non-participation in national health screening, history of depression, or having missing data), 595 ALS patients and 9896 non-ALS individuals were finally selected. Primary outcome is newly diagnosed depression during follow-up duration defined by ICD code (F32 or F33). A Cox regression model was used to examine the hazard ratios (HRs) after adjustment for potential confounders. During the follow-up period, 283 cases of depression in the ALS group and 1547 in the controls were recorded. The adjusted HR for depression in ALS was 9.1 (95% confidence interval [CI] 7.87-10.60). The risk of depression was slightly higher in the disabled ALS group (aHR 10.1, 95% CI 7.98-12.67) than in the non-disabled ALS group (aHR 8.78, 95% CI 7.42-10.39). The relative risk of depression was higher in younger patients than in older patients, and in obese patients than in non-obese patients. Our study showed that ALS patients have an increased risk of depression compared to non-ALS individuals.}, } @article {pmid39225243, year = {2024}, author = {Liang, J and Zhu, Y and Liu, S and Kuang, B and Tian, Z and Zhang, L and Yang, S and Lin, M and Chen, N and Liu, X and Ai, Q and Yang, Y}, title = {Progress of Exosomal MicroRNAs and Traditional Chinese Medicine Monomers in Neurodegenerative Diseases.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {11}, pages = {5323-5349}, doi = {10.1002/ptr.8322}, pmid = {39225243}, issn = {1099-1573}, support = {//The Key Discipline of Biological Engineering of Hunan University of Chinese Medicine [2018] No. 3/ ; 22JBZ052//Hunan University of Chinese Medicine Discipline Construction Project/ ; 202329-2//Key Project of Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University/ ; 2021JJ30512//Hunan Natural Science Foundation/ ; 2022JJ40313//Hunan Natural Science Foundation/ ; 2022JJ40456//Hunan Natural Science Foundation/ ; 2023JJ60126//Hunan Natural Science Foundation/ ; 2023JJ60471//Hunan Natural Science Foundation/ ; 21B0354//Outstanding Youth Project of Hunan Education Department/ ; B2023061//Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ ; //Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica/ ; kq2014091//Changsha Natural Science Foundation/ ; kq2202269//Changsha Natural Science Foundation/ ; //The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine/ ; 212010//Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd/ ; 2019xjjj001//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; 2021XJJJ028//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; U2202214//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/drug therapy ; *Medicine, Chinese Traditional/methods ; Drugs, Chinese Herbal/pharmacology ; Animals ; }, abstract = {Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions.}, } @article {pmid39225106, year = {2024}, author = {Białobrodzka, E and Flis, DJ and Akdogan, B and Borkowska, A and Wieckowski, MR and Antosiewicz, J and Zischka, H and Dzik, KP and Kaczor, JJ and Ziolkowski, W}, title = {Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {1111-1118}, doi = {10.1002/mus.28237}, pmid = {39225106}, issn = {1097-4598}, support = {//Narodowe Centrum Nauki/ ; DEC-2013/09/NZ7/02538//National Science Centre/ ; 2020/39/B/NZ7/03366//National Science Centre/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Muscle, Skeletal/metabolism ; Mice ; *Copper/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; *Swimming ; Superoxide Dismutase/metabolism ; Copper-Transporting ATPases/metabolism/genetics ; Physical Conditioning, Animal/physiology ; Superoxide Dismutase-1/metabolism/genetics ; Adenosine Triphosphatases/metabolism ; Cation Transport Proteins/metabolism ; Male ; Copper Transporter 1/metabolism ; }, abstract = {INTRODUCTION/AIMS: Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice.

METHODS: SOD1G93A mice (n = 6 per group) were used as the ALS model, and wild-type B6SJL (WT) mice as controls (n = 6). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined.

RESULTS: ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43 ± 1.81 and 38.67 ± 11.50 μg/mg, respectively, p = .0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p = .0021) and 34% (p = .0372), while the CTR1 protein (copper importer) decreased by 45% (p = .002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles.

DISCUSSION: The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life.}, } @article {pmid39224919, year = {2024}, author = {Kiernan, MC and Kaji, R}, title = {Emerging concepts and therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {558-559}, doi = {10.1097/WCO.0000000000001308}, pmid = {39224919}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; }, } @article {pmid39224887, year = {2024}, author = {Yang, J and Tian, M and Zhang, L and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Assessment of Rab geranylgeranyltransferase subunit beta in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1447461}, pmid = {39224887}, issn = {1664-2295}, abstract = {INTRODUCTION: Geranylgeranyltransferase Subunit Beta (RABGGTB) was expressed at higher levels in patients with Amyotrophic lateral sclerosis (ALS) compared with healthy controls. This study aims to observe the expression of RABGGTB in different cells from patients with ALS and different diseases.

METHODS: In this case-control study, we collected peripheral blood from patients with ALS and healthy controls, and compared the expression of RABGGTB in natural killer cells (NK), T cells and B cells between patients with ALS and healthy controls by flow cytometry. And compared the expression of RABGGTB in monocytes and monocyte-derived macrophages from patients with ALS, Parkinson's disease (PD), acute cerebrovascular disease (ACVD), and healthy controls by flow cytometry and immunofluorescence. Then flow cytometry was used to detect the expression of RABGGTB in monocytes from SOD1G93A mice and WT mice.

RESULTS: The expression of RABGGTB was not significantly changed in NK cells, cytotoxic T cells (CTL), helper T cells (Th), regulatory T cells (Treg), and B cells from patients with ALS compared to healthy controls. And the expression of RABGGTB in monocytes and monocyte-derived macrophages was higher in the ALS group than in the PD, ACVD and control group. The expression of RABGGTB was significantly higher in monocytes of SOD1G93A mice compared to WT mice.

CONCLUSION: These findings suggest that RABGGTB expression was increased in monocytes and monocyte-derived macrophages from patients with ALS, not in NK, CTL, Th, Treg, and B cells. Future studies are needed to find the clinical implication of RABGGTB in ALS.}, } @article {pmid39223525, year = {2024}, author = {Iakovleva, V and Verde, F and Cinnante, C and Sillani, A and Conte, G and Corsini, E and Ciusani, E and Erbetta, A and Silani, V and Ticozzi, N}, title = {Duropathy as a rare motor neuron disease mimic: from bibrachial amyotrophy to infratentorial superficial siderosis.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {309}, pmid = {39223525}, issn = {1471-2377}, support = {PNC-E3-2022-23683266//Italian Ministry of Education and Research (MUR)/ ; }, mesh = {Humans ; Male ; Middle Aged ; *Motor Neuron Disease/diagnosis/complications/diagnostic imaging ; *Siderosis/complications/diagnosis/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Diagnosis, Differential ; Dura Mater/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Bibrachial amyotrophy associated with an extradural CSF collection and infratentorial superficial siderosis (SS) are rare conditions that may occasionally mimic ALS. Both disorders are assumed to be due to dural tears.

CASE PRESENTATION: A 53-year-old man presented with a 7-year history of slowly progressive asymmetric bibrachial amyotrophy. Initially, a diagnosis of atypical motor neuron disease (MND) was made. At re-evaluation 11 years later, upper limb wasting and weakness had further progressed and were accompanied by sensorineural hearing loss. MRI of the brain and spine demonstrated extensive supra- and infratentorial SS (including the surface of the whole spinal cord) as well as a ventral longitudinal intraspinal fluid collection (VLISFC) extending along almost the entire thoracic spine. Osteodegenerative changes were observed at C5-C7 level, with osteophytes protruding posteriorly. The bony spurs at C6-C7 level were hypothesized to have lesioned the dura, causing a CSF leak and thus a VLISFC. Review of the MRI acquired at first evaluation showed that the VLISFC was already present at that time (actually beginning at C7 level), whereas the SS was not. 19 years after the onset of upper limb weakness, the patient additionally developed parkinsonism. Response to levodopa, brain scintigraphy with [123]I-ioflupane and brain MRI with nigrosome 1 evaluation were consistent with idiopathic Parkinson's disease (PD). On the latest follow-up 21 years after symptom onset, the VLISFC was unchanged, as were upper arm weakness and wasting.

CONCLUSIONS: Based on the long-term follow-up, we could establish that, while the evidence of the VLISFC was concomitant with the clinical presentation of upper limb amyotrophy and weakness, the radiological signs of SS appeared later. This suggests that SS was not per se the cause of the ALS-like clinical picture, but rather a long-term sequela of a dural leak. The latter was instead the causative lesion, giving rise to a VLISFC which compressed the cervical motor roots. Dural tears can actually cause several symptoms, and further studies are needed to elucidate the pathophysiological correlates of "duropathies". Finally, as iron metabolism has been implicated in PD, the co-occurrence of PD with SS deserves further investigation.}, } @article {pmid39222049, year = {2024}, author = {Santangelo, S and Invernizzi, S and Sorce, MN and Casiraghi, V and Peverelli, S and Brusati, A and Colombrita, C and Ticozzi, N and Silani, V and Bossolasco, P and Ratti, A}, title = {NEK1 haploinsufficiency worsens DNA damage, but not defective ciliogenesis, in C9ORF72 patient-derived iPSC-motoneurons.}, journal = {Human molecular genetics}, volume = {33}, number = {21}, pages = {1900-1907}, pmid = {39222049}, issn = {1460-2083}, support = {GR-2016-02364373//BIBLIOSAN/ ; PSR 2021//Italian Ministery of Health/ ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *NIMA-Related Kinase 1/genetics ; *DNA Damage/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; *Haploinsufficiency/genetics ; *Motor Neurons/metabolism/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Cilia/genetics/pathology/metabolism ; Cell Differentiation/genetics ; DNA Repeat Expansion/genetics ; Mutation ; }, abstract = {The hexanucleotide G4C2 repeat expansion (HRE) in C9ORF72 gene is the major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to both loss- and gain-of-function pathomechanisms. The wide clinical heterogeneity among C9ORF72 patients suggests potential modifying genetic and epigenetic factors. Notably, C9ORF72 HRE often co-occurs with other rare variants in ALS/FTD-associated genes, such as NEK1, which encodes for a kinase involved in multiple cell pathways, including DNA damage response and ciliogenesis. In this study, we generated induced pluripotent stem cells (iPSCs) and differentiated motoneurons (iPSC-MNs) from an ALS patient carrying both C9ORF72 HRE and a NEK1 loss-of-function mutation to investigate the biological effect of NEK1 haploinsufficiency on C9ORF72 pathology in a condition of oligogenicity. Double mutant C9ORF72/NEK1 cells showed increased pathological C9ORF72 RNA foci in iPSCs and higher DNA damage levels in iPSC-MNs compared to single mutant C9ORF72 cells, but no effect on DNA damage response. When we analysed the primary cilium, we observed a defective ciliogenesis in C9ORF72 iPSC-MNs which was not worsened by NEK1 haploinsufficiency in the double mutant iPSC-MNs. Altogether, our study shows that NEK1 haploinsufficiency influences differently DNA damage and cilia length, potentially acting as a modifier at biological level in an in vitro ALS patient-derived disease model of C9ORF72 pathology.}, } @article {pmid39218769, year = {2024}, author = {Sun, J and Zhang, Y}, title = {Microbiome and micronutrient in ALS: From novel mechanisms to new treatments.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00441}, pmid = {39218769}, issn = {1878-7479}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/therapy ; Humans ; *Micronutrients/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; Microbiota/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.}, } @article {pmid39218293, year = {2024}, author = {Dibaj, P and Safavi-Abbasi, S and Asadollahi, E}, title = {In vivo spectrally unmixed multi-photon imaging of longitudinal axon-glia changes in injured spinal white matter.}, journal = {Neuroscience letters}, volume = {841}, number = {}, pages = {137959}, doi = {10.1016/j.neulet.2024.137959}, pmid = {39218293}, issn = {1872-7972}, mesh = {Animals ; *White Matter/pathology/metabolism/diagnostic imaging ; *Spinal Cord Injuries/pathology/metabolism/diagnostic imaging ; *Axons/pathology/metabolism ; *Mice, Transgenic ; Neuroglia/metabolism/pathology ; Mice ; Microscopy, Fluorescence, Multiphoton/methods ; Spinal Cord/pathology/metabolism ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; }, abstract = {Understanding the sequence of cellular responses and their contributions to pathomorphogical changes in spinal white matter injuries is a prerequisite for developing efficient therapeutic strategies for spinal cord injury (SCI) as well as neurodegenerative and inflammatory diseases of the spinal cord such as amyotrophic lateral sclerosis and multiple sclerosis. We have developed several types of surgical procedures suitable for acute one-time and chronic recurrent in vivo multiphoton microscopy of spinal white matter [1]. Sophisticated surgical procedures were combined with transgenic mouse technology to image spinal tissue labeled with up to four fluorescent proteins (FPs) in axons, astrocytes, microglia, and blood vessels. To clearly separate the simultaneously excited FPs, spectral unmixing including iterative procedures was performed after imaging the diversely labeled spinal white matter with a custom-made 4-channel two-photon laser-scanning microscope. In our longitudinal multicellular studies of injured spinal white matter, we imaged axonal dynamics and invasion of microglia and astrocytes for a time course of over 200 days after SCI. Our methods offer ideal platforms for investigating acute and chronic cellular dynamics, cell-cell interactions, and metabolite fluctuations in health and disease as well as pharmacological manipulations in vivo.}, } @article {pmid39218010, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Garrahy, S and Habash-Bailey, H and Thomson, R and Opie-Martin, S and Javidnia, S and Leigh, PN and Al-Chalabi, A}, title = {Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {702-707}, pmid = {39218010}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/economics ; Male ; Female ; Middle Aged ; *Social Class ; Aged ; Adult ; Age of Onset ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.}, } @article {pmid39217855, year = {2024}, author = {Zhang, J and Chen, K and Chen, Y and Hua, L and Chen, S and Chen, X and Zou, L and Li, S and Yang, X and Shen, Y}, title = {Pathology reduction and motor behavior improvement associated with ultrasound-mediated delivery of arctiin to the motor cortex in a mutant SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Ultrasonics}, volume = {144}, number = {}, pages = {107449}, doi = {10.1016/j.ultras.2024.107449}, pmid = {39217855}, issn = {1874-9968}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis ; *Disease Models, Animal ; Drug Delivery Systems ; Furans/pharmacology/administration & dosage ; Glucosides/pharmacology/administration & dosage ; *Mice, Transgenic ; Microbubbles ; *Motor Cortex/drug effects/physiopathology ; Mutation ; Superoxide Dismutase-1/genetics ; Ultrasonic Therapy/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders.

OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model.

METHODS: The ALS mouse model with the SOD1[G93A] mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining.

RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord.

CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.}, } @article {pmid39217293, year = {2024}, author = {Aljthalin, R and Albalawi, R and Alyahya, A and Alhathlool, R and Alhashemi, M}, title = {Multiple sclerosis and amyotrophic lateral sclerosis: is there an association or a red flag? A case report and literature review.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {307}, pmid = {39217293}, issn = {1471-2377}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/pathology ; Middle Aged ; *Multiple Sclerosis/complications/diagnosis/pathology ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that causes damage to the myelin and axons and is caused by genetic or environmental factors. Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive degeneration of the motor neurons resulting in the presence of upper and lower motor-neuron signs and symptoms.

CASE PRESENTATION: A 46-year-old female patient presented with symmetrical weakness of the lower limbs and numbness that developed over weeks. Magnetic resonance imaging (MRI) of the brain exhibited typical demyelination features, high signal abnormality involving the periventricular and subcortical white matter, and an oval-shaped lesion. The patient was diagnosed with MS based on the clinical presentation and radiological examination. However, there was rapid progression of the symptoms, involvement of bulbar dysfunction, and muscle atrophy. Furthermore, the patient did not respond to acute therapy and immunotherapy, which made the diagnosis of MS less likely or suggested that it could be associated with another diagnosis. Her neurophysiological test met the criteria of ALS, and she was started on riluzole.

LITERATURE REVIEW: We reviewed all articles from 1986 to 2023, and there were 32 reported cases describing the co-occurrence of ALS and MS in different populations. Our case is the 33rd, and to our knowledge, it is the only case reported in the Middle East and specifically in Saudi Arabia. The main proposed mechanism according to postmortem examinations is a combination of degenerative and inflammatory processes with a cascade of production of reactive oxygen species and nitric oxide, which lead to cell death and apoptosis during concomitant ALS with MS.

CONCLUSION: The co-occurrence of ALS and MS is extremely rare, but it can be explained by pathogenesis related to neurodegeneration, inflammation, or genetic susceptibility. Rapid progressive motor and bulbar symptoms could be red-flag symptoms, extensive evaluation might be needed for these patients.}, } @article {pmid39216161, year = {2024}, author = {Wang, J and Qi, J and Ouyang, Y and Zhou, S and Qin, L and Zhang, B and Bai, L and Pan, L}, title = {The mutation Asp-376-Glu in the ALS gene confers resistance to mesosulfuron-methyl in Beckmannia syzigachne.}, journal = {Plant physiology and biochemistry : PPB}, volume = {215}, number = {}, pages = {109083}, doi = {10.1016/j.plaphy.2024.109083}, pmid = {39216161}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Sulfonylurea Compounds/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; Poaceae/genetics/drug effects ; Molecular Docking Simulation ; Plant Weeds/genetics/drug effects ; }, abstract = {Understanding the mechanisms by which weeds develop herbicide resistance is crucial for managing resistance effectively and optimizing herbicide use. Beckmannia syzigachne, a harmful grass weed prevalent in wheat and rice-wheat rotation areas, poses a significant threat to crop productivity. A field herbicide resistance survey identified a resistant population with a new ALS mutation (Asp-376-Glu). The Glu-376-Asp population displayed varying resistance levels to seven ALS herbicides, verified using the dCAPS method. qRT-PCR analysis showed that no significant difference existed in the ALS gene expression between the Asp-376-Glu and S populations. P450 and GST inhibitors failed to reverse resistance to mesosulfuron-methyl, suggesting no involvement of P450- and GST-based metabolic resistance. Molecular docking indicated that the Asp-376-Glu mutation reduces the binding affinity between ALS-inhibitors and BsALS. The findings provide valuable insights into herbicide resistance mechanisms for weed resistance control.}, } @article {pmid39473802, year = {2024}, author = {Lukac, M and Luben, H and Martin, AE and Simmons, Z and Geronimo, A}, title = {Spatial-Temporal Analysis of Gait in Amyotrophic Lateral Sclerosis Using Foot-Worn Inertial Sensors: An Observational Study.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {22-29}, pmid = {39473802}, issn = {2504-110X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that alters gait and increases the risk of falls. The current model of care involves in-person multidisciplinary clinic visits to, in part, assess alterations in gait, evaluate safety, and make recommendations for management. Clinic visits, however, are relatively infrequent, and multidisciplinary evaluations can be physically demanding for patients. To better understand how gait changes over time in those with ALS and enable healthcare providers to properly respond to these changes, remote monitoring of functional mobility would be advantageous.

METHODS: The objective of this study was to remotely track long-term changes in walking speed using wearable inertial measurement units (IMUs). Nine ALS patients and 6 healthy controls submitted twice-weekly home walking recordings for 24 and 4 weeks, respectively. An IMU data processing method was developed and validated against laboratory-measured walking speed.

RESULTS: For both ALS patients and healthy controls, home walking speed was less than clinic walking speed by an average of 0.19 m/s (p = 0.0024). Over 24 weeks, home walking speed significantly decreased for 5 of 9 ALS patients at an average of -0.021 m/s/months (p = 0.005). Those who eventually transitioned to using assistive device (AD) while on the study demonstrated a greater decrease in walking speed than those who did not.

CONCLUSIONS: Remote longitudinal gait monitoring of ALS patients is feasible with the use of an IMU. Decreases in walking speed were detected in the majority of patients, most strongly in those who eventually transitioned to an AD. Home walking speed may more accurately represent the walking abilities of ALS patients in their real-life environments, a finding which further supports the case for remote monitoring in ALS.}, } @article {pmid39355053, year = {2023}, author = {Cortés Mancera, EA and Sinisterra Solis, FA and Romero-Castellanos, FR and Diaz-Meneses, IE and Kerik-Rotenberg, NE}, title = {[18]F-FDG PET/CT as a molecular biomarker in the diagnosis of amyotrophic lateral sclerosis associated with prostate cancer and progressive supranuclear palsy: A case report.}, journal = {Frontiers in nuclear medicine}, volume = {3}, number = {}, pages = {1137875}, pmid = {39355053}, issn = {2673-8880}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative, multisystem disorder. Its clinical presentation typically consists of progressive focal muscle atrophy and weakness. In addition to motor disorders, the association between ALS and cancer has been researched, such as frontotemporal dementia and progressive supranuclear palsy. The diagnosis is based primarily on the clinical history, physical examination, electrodiagnostic tests (with an EMG needle), and neuroimaging, such as MRI and [18]F-FDG PET/CT.

PRESENTATION OF THE CASE: A 67-year-old male patient was diagnosed with prostate adenocarcinoma with a clinical picture of muscle weakness in the lower limbs that caused falls and was associated with fasciculations in the thighs and arms, alterations in the tone of voice, poor memory, and difficulty articulating words. In the neurological assessment, he described walking supported by a walker with decreased strength in both lower limbs and sensitivity without alterations. The diagnoses of upper and lower motor neuron disease and probable ALS were integrated. Furthermore, the probable coexistence of frontotemporal dementia/disorder (FDD) with ALS was considered. The main findings in the [18]F-FDG PET/CT study was hypometabolism in the cortex of the bilateral motor and premotor areas, the anterior cingulate, both caudate and putamen, a metabolic pattern compatible with ALS, and progressive supranuclear palsy.

CONCLUSION: Through the PET/CT studies, we demonstrated a case in which ALS, prostate cancer and progressive supranuclear palsy coexisted molecularly; it was clinically difficult to diagnose. Molecular imaging has potential in the diagnostic and prognostic evaluation of ALS. It is crucial to identify the disease early and reliably through metabolic patterns that allow us to confirm the disease or differentiate it from other pathologies.}, } @article {pmid39291146, year = {2023}, author = {Mathew, AM and Bhuvanendran, S and Nair, RS and K Radhakrishnan, A}, title = {Exploring the anti-inflammatory activities, mechanism of action and prospective drug delivery systems of tocotrienol to target neurodegenerative diseases.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {338}, pmid = {39291146}, issn = {2046-1402}, abstract = {A major cause of death in the elderly worldwide is attributed to neurodegenerative diseases, such as AD (Alzheimer's disease), PD (Parkinson's disease), ALS (Amyotrophic lateral sclerosis), FRDA (Friedreich's ataxia), VaD (Vascular dementia) etc. These can be caused due to multiple factors such as genetic, physiological problems like stroke or tumor, or even external causes like viruses, toxins, or chemicals. T3s (tocotrienols) exhibit various bioactive properties where it acts as an antioxidant, anti-inflammatory, anti-tumorigenic, and cholesterol lowering agent. Since T3 interferes with and influences several anti-inflammatory mechanisms, it aids in combating inflammatory responses that lead to disease progression. T3s are found to have a profound neuroprotective ability, however, due to their poor oral bioavailability, their full potential could not be exploited. Hence there is a need to explore other drug delivery techniques, especially focusing on aspects of nanotechnology. In this review paper we explore the anti-inflammatory mechanisms of T3 to apply it in the treatment of neurodegenerative diseases and also discusses the possibilities of nano methods of administering tocotrienols to target neurodegenerative diseases.}, } @article {pmid39281332, year = {2022}, author = {Kirikae, H and Harada, R and Hosaka, T and Misu, T and Ando, D and Warita, H and Endo, T and Sonobe, S and Niizuma, K and Aoki, M}, title = {Case Report: Vertebro-vertebral arteriovenous fistula showing symptoms mimicking ALS: Diagnostic imaging supports accurate differentiation between ALS and mimicking conditions.}, journal = {F1000Research}, volume = {11}, number = {}, pages = {546}, pmid = {39281332}, issn = {2046-1402}, abstract = {We report a rare case of a vertebro-vertebral arteriovenous fistula (VVAVF) manifesting as amyotrophic lateral sclerosis (ALS). A 76-year-old female patient presented with progressive weakness, muscle atrophy, fasciculation, and preserved deep tendon reflexes in the right upper limb. Electrophysiological testing showed lower motor neuron dysfunction. The patient was suspected to have ALS, but cervical magnetic resonance imaging (MRI) revealed enlarged blood vessels in the spinal canal, which compressed the cervical spinal cord and nerve roots. Angiography showed a shunt from the right vertebral artery to the right intervertebral vein and the vertebral venous plexus; therefore, the patient was diagnosed with VVAVF. Transarterial embolization was performed to obliterate the shunt, and weakness in the patient's right upper limb subsequently improved. It is worth considering VVAVF as a differential diagnosis of ALS-like diseases.}, } @article {pmid39484675, year = {2022}, author = {Chopra, N and Menounos, S and Choi, JP and Hansbro, PM and Diwan, AD and Das, A}, title = {Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies.}, journal = {NeuroSci}, volume = {3}, number = {1}, pages = {1-27}, pmid = {39484675}, issn = {2673-4087}, abstract = {The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause-effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it.}, } @article {pmid39216080, year = {2024}, author = {Mazurie, Z and Branchereau, P and Cattaert, D and Henkous, N and Savona-Baron, C and Vouimba, RM}, title = {Acute stress differently modulates interneurons excitability and synaptic plasticity in the primary motor cortex of wild-type and SOD1[G93A] mouse model of ALS.}, journal = {The Journal of physiology}, volume = {602}, number = {19}, pages = {4987-5015}, doi = {10.1113/JP285210}, pmid = {39216080}, issn = {1469-7793}, support = {GPR BRAIN-2030//Université de Bordeaux (University of Bordeaux)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics ; *Interneurons/physiology ; *Neuronal Plasticity ; *Motor Cortex/physiopathology ; Mice ; Male ; *Mice, Transgenic ; Disease Models, Animal ; Stress, Psychological/physiopathology ; Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; }, abstract = {Primary motor cortex (M1) network stability depends on activity of inhibitory interneurons, for which susceptibility to stress was previously demonstrated in limbic regions. Hyperexcitability in M1 following changes in the excitatory/inhibitory balance is a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Using electrophysiological approaches, we assessed the impact of acute restraint stress on inhibitory interneurons excitability and global synaptic plasticity in M1 of the SOD1[G93A] ALS mouse model at a late pre-symptomatic stage (10-12.5 weeks). Based on their firing type (continuous, discontinuous, with accommodation or not) and electrophysiological characteristics (resting potential, rheobase, firing frequency), interneurons from M1 slices were separated into four clusters, labelled from 1 to 4. Among them, only interneurons from the first cluster, presenting continuous firing with few accommodations, tended to show increased excitability in wild-type (WT) and decreased excitability in SOD1[G93A] animals following stress. In vivo analyses of evoked field potentials showed that stress suppressed the theta burst-induced plasticity of an excitatory component (N1) recorded in the superficial layers of M1 in WT, with no impact on an inhibitory complex (N2-P1) from the deeper layers. In SOD1[G93A] mice, stress did not affect N1 but suppressed the N2-P1 plasticity. These data suggest that stress can alter M1 network functioning in a different manner in WT and SOD1[G93A] mice, possibly through changes of inhibitory interneurons excitability and synaptic plasticity. This suggests that stress-induced activity changes in M1 may therefore influence ALS outcomes. KEY POINTS: Disruption of the excitatory/inhibitory balance in the primary motor cortex (M1) has been linked to cortical hyperexcitability development, a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Psychological stress was reported to influence excitatory/inhibitory balance in limbic regions, but very little is known about its influence on the M1 functioning under physiological or pathological conditions. Our study revealed that acute stress influences the excitatory/inhibitory balance within the M1, through changes in interneurons excitability along with network plasticity. Such changes were different in pathological (SOD1[G93A] ALS mouse model) vs. physiological (wild-type) conditions. The results of our study help us to better understand how stress modulates the M1 and highlight the need to further characterize stress-induced motor cortex changes because it may be of importance when evaluating ALS outcomes.}, } @article {pmid39215697, year = {2024}, author = {Burrows, DJ and McGown, A and Abduljabbar, O and Castelli, LM and Shaw, PJ and Hautbergue, GM and Ramesh, TM}, title = {RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1058-1069}, doi = {10.1002/ana.27068}, pmid = {39215697}, issn = {1531-8249}, support = {Apr17/854-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; BB/S005277/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; *Zebrafish ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Animals, Genetically Modified ; *Disease Models, Animal ; *Dipeptides ; Hypothermia, Induced/methods ; Frontotemporal Dementia/genetics/metabolism ; Humans ; Protein Biosynthesis/genetics/physiology ; }, abstract = {OBJECTIVE: Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.

METHODS: A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.

RESULTS: Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.

INTERPRETATION: The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058-1069.}, } @article {pmid39215690, year = {2024}, author = {Suwa, S and Ando, M and Nakashima, T and Horii, S and Anai, T and Takeyama, H}, title = {In Situ Raman Hyperspectral Analysis of Microbial Colonies for Secondary Metabolites Screening.}, journal = {Analytical chemistry}, volume = {96}, number = {37}, pages = {14909-14917}, pmid = {39215690}, issn = {1520-6882}, mesh = {*Spectrum Analysis, Raman/methods ; *Escherichia coli/metabolism/isolation & purification ; Anti-Bacterial Agents/analysis/metabolism ; Streptomyces/metabolism ; Least-Squares Analysis ; }, abstract = {Since the discovery of penicillin, a vast array of microbial antibiotics has been identified and applied in the medical field. Globally, the search for drug candidates via microbial screening is ongoing. Traditional screening methods, however, are time-consuming and require labor-intensive sample processing, significantly reducing throughput. This research introduces a Raman spectroscopy-based screening system tailored to the in situ analysis of microbial colonies on solid culture media. Employing multivariate curve resolution-alternating least-squares (MCR-ALS) for spectral decomposition, our approach reveals the production of secondary metabolites at the single colony level. We enhanced the microbial culture method, enabling direct, high signal-to-noise (S/N) ratio Raman spectroscopic measurements of colonies of Escherichia coli and actinomycetes species. Through semisupervised MCR analysis using the known spectra of actinorhodin and undecylprodigiosin as references, we accurately assessed the production of these compounds by Streptomyces coelicolor A3(2). Furthermore, we herein successfully detected the production of amphotericin B by Streptomyces nodosus, even in the absence of prior spectral information. This demonstrates the potential of our technique in the discovery of secondary metabolites. In addition to enabling the detection of the above-mentioned compounds, this analysis revealed the heterogeneity of the spatial distribution of their production in each colony. Our technique makes a significant contribution to the advancement of microbial screening, offering a rapid, efficient alternative to conventional methods and opening avenues for secondary metabolites discovery.}, } @article {pmid39215326, year = {2024}, author = {Carlton, J and Powell, P and Rowen, D and Williams, C and Griffiths, AW and Hobson, E and McDermott, C}, title = {Development of a novel patient reported outcome measure for health-related quality of life in amyotrophic lateral sclerosis (PROQuALS): study protocol.}, journal = {Health and quality of life outcomes}, volume = {22}, number = {1}, pages = {69}, pmid = {39215326}, issn = {1477-7525}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy ; Humans ; *Quality of Life/psychology ; *Patient Reported Outcome Measures ; Surveys and Questionnaires ; Research Design ; Psychometrics ; Cost-Benefit Analysis ; }, abstract = {BACKGROUND: Patient reported outcome measures (PROMs) can be used to assess the impact of health conditions upon an individual's health-related quality of life (HRQoL). Whilst PROMs have been used to quantify the HRQoL impact of amyotrophic lateral sclerosis (ALS), existing instruments may not fully capture what matters to people living with ALS (plwALS) or be appropriate to be used directly to inform the cost-effectiveness of new treatments. This highlights a need for a new condition-specific PROM that can both capture what's important to plwALS and be used in economic evaluation. This study has two key aims: 1) to produce a novel PROM for measuring HRQoL in plwALS (PROQuALS). 2) to value a set of items from the novel PROM to generate an associated preference-weighted measure (PWM) that will enable utility values to be generated.

METHODS: A mixed-methods study design will be conducted across three stages. Stage 1 involves concept elicitation and the generation of draft PROM content from a robust and comprehensive systematic review of HRQoL in ALS, with input from plwALS. Stage 2 consists of cognitive debriefing of the draft PROM content to ascertain its content validity (Stage 2a), followed by a psychometric survey (Stage 2b) to assess statistical performance. Evidence from Stage 2 will be used to make decisions on the final content and format of the novel PROM. Stage 3 will involve valuation and econometric modeling using health economics methods to generate preference weights, so a PWM derived from the novel PROM can be used in the cost-effectiveness analyses of treatments. Patient and clinical advisory groups will have critical, collaborative input throughout the project.

DISCUSSION: The novel PROM will be designed to comprehensively assess important aspects of HRQoL to plwALS and to quantify HRQoL in terms of subjective impact. The PROQuALS measure will be available for use in research and healthcare settings. The associated PWM component will extend and enable the use of PROQuALS in cost-effective analyses of new treatments for ALS.

TRIAL REGISTRATION: Not applicable.}, } @article {pmid39211392, year = {2024}, author = {Matsuo, K and Nagamatsu, J and Nagata, K and Umeda, R and Shiota, T and Morimoto, S and Suzuki, N and Aoki, M and Okano, H and Nakamori, M and Nishihara, H}, title = {Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP [N345K/+])-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1357204}, pmid = {39211392}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP [N345K/+] carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP [K263E/K263E] and TARDBP [G295S/G295S]) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP [N345K/+] carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP [N345K/+])-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP [N345K/+] carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.}, } @article {pmid39209824, year = {2024}, author = {Vieira de Sá, R and Sudria-Lopez, E and Cañizares Luna, M and Harschnitz, O and van den Heuvel, DMA and Kling, S and Vonk, D and Westeneng, HJ and Karst, H and Bloemenkamp, L and Varderidou-Minasian, S and Schlegel, DK and Mars, M and Broekhoven, MH and van Kronenburg, NCH and Adolfs, Y and Vangoor, VR and de Jongh, R and Ljubikj, T and Peeters, L and Seeler, S and Mocholi, E and Basak, O and Gordon, D and Giuliani, F and Verhoeff, T and Korsten, G and Calafat Pla, T and Venø, MT and Kjems, J and Talbot, K and van Es, MA and Veldink, JH and van den Berg, LH and Zelina, P and Pasterkamp, RJ}, title = {ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7484}, pmid = {39209824}, issn = {2041-1723}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Ataxin-2/genetics/metabolism ; Humans ; Animals ; *Peptides/metabolism/genetics ; Mice ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Disease Models, Animal ; *Mice, Transgenic ; DNA-Binding Proteins/genetics/metabolism ; Phenotype ; Male ; Female ; Mitochondria/metabolism ; Neurites/metabolism ; }, abstract = {Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43[Tg]-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.}, } @article {pmid39210549, year = {2024}, author = {Yeo, CJJ and Simmons, Z}, title = {Caring for people living with ALS in Korea: challenges and possible paths forward.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {881-883}, doi = {10.1002/mus.28241}, pmid = {39210549}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Republic of Korea/epidemiology ; Caregivers/psychology ; }, } @article {pmid39210467, year = {2024}, author = {Faggioli, G and Menotti, L and Marchesin, S and Chió, A and Dagliati, A and de Carvalho, M and Gromicho, M and Manera, U and Tavazzi, E and Di Nunzio, GM and Silvello, G and Ferro, N}, title = {An extensible and unifying approach to retrospective clinical data modeling: the BrainTeaser Ontology.}, journal = {Journal of biomedical semantics}, volume = {15}, number = {1}, pages = {16}, pmid = {39210467}, issn = {2041-1480}, support = {101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Biological Ontologies ; Humans ; Retrospective Studies ; Amyotrophic Lateral Sclerosis ; Multiple Sclerosis ; Semantics ; }, abstract = {Automatic disease progression prediction models require large amounts of training data, which are seldom available, especially when it comes to rare diseases. A possible solution is to integrate data from different medical centres. Nevertheless, various centres often follow diverse data collection procedures and assign different semantics to collected data. Ontologies, used as schemas for interoperable knowledge bases, represent a state-of-the-art solution to homologate the semantics and foster data integration from various sources. This work presents the BrainTeaser Ontology (BTO), an ontology that models the clinical data associated with two brain-related rare diseases (ALS and MS) in a comprehensive and modular manner. BTO assists in organizing and standardizing the data collected during patient follow-up. It was created by harmonizing schemas currently used by multiple medical centers into a common ontology, following a bottom-up approach. As a result, BTO effectively addresses the practical data collection needs of various real-world situations and promotes data portability and interoperability. BTO captures various clinical occurrences, such as disease onset, symptoms, diagnostic and therapeutic procedures, and relapses, using an event-based approach. Developed in collaboration with medical partners and domain experts, BTO offers a holistic view of ALS and MS for supporting the representation of retrospective and prospective data. Furthermore, BTO adheres to Open Science and FAIR (Findable, Accessible, Interoperable, and Reusable) principles, making it a reliable framework for developing predictive tools to aid in medical decision-making and patient care. Although BTO is designed for ALS and MS, its modular structure makes it easily extendable to other brain-related diseases, showcasing its potential for broader applicability.Database URL https://zenodo.org/records/7886998 .}, } @article {pmid39209890, year = {2024}, author = {Prabhakaran, A and Thirumoorthi, P and Sri Dhivya Krishnan, K}, title = {Design and development of an intelligent zone based master electronic control unit for power optimization in electric vehicles.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20142}, pmid = {39209890}, issn = {2045-2322}, abstract = {The development of electric vehicles (EVs) has been incremental because EVs satisfy a significant demand for energy sources. Electronic control unit (ECU) is an important component that processes the electric signals received from various sensors for generating the control signals for the actuators. Automotive control systems were initially operated manually throughout the automotive revolution based on the responses of input signals received from ECUs and drivers. Most of the functions in EV are controlled by the ECU and every ECU consumes power at all times even if it is not in use. The larger power consumption of passive ECUs like adaptive lighting systems (ALS), automatic wiper systems (AWS) brake light systems (BLS), etc., affect the life of ECUs and the range of EVs. This article is primarily concerned with limiting power consumption by switching the power supply to the passive ECUs based on their requirements. Hence, to achieve the objective, the intelligent zone (i-zone) based master ECU is triggered to activate the slave ECUs. Designing suites including Proteus and KiCAD were used for designing the circuits including master as well as slave ECU. This prototype is built using three secondary ECUs such as ALS & AWS and BLS which are controlled using i-zone-based master ECU. The performance of this implemented design is evaluated, and it is discovered that almost 40% of the battery consumption is reduced. This i-zone-based master ECU and all its slave ECUs manage power while ensuring the safety and reliability of EVs.}, } @article {pmid39208794, year = {2024}, author = {Choi, ES and Hnath, B and Sha, CM and Dokholyan, NV}, title = {Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells.}, journal = {Structure (London, England : 1993)}, volume = {32}, number = {10}, pages = {1776-1792.e5}, pmid = {39208794}, issn = {1878-4186}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Male ; Mice ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Brain/metabolism ; Cell Cycle Proteins ; Models, Molecular ; *Motor Neurons/metabolism ; Muscle, Skeletal/metabolism ; *Protein Binding ; *Protein Multimerization ; *Septins/metabolism/genetics/chemistry ; Spinal Cord/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; }, abstract = {Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome-a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers and found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We discovered SOD1 trimer-selective enrichment of genes. We performed detailed computational and biochemical characterization of SOD1 trimer protein binding for septin-7. Our investigation highlights key proteins and pathways within distinct tissues, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.}, } @article {pmid39207717, year = {2024}, author = {Ling, Y and Crotti, A}, title = {Emerging Microglial Therapies and Targets in Clinical Trial.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {623-637}, pmid = {39207717}, issn = {2190-5215}, mesh = {*Microglia/metabolism ; Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/drug therapy/therapy/metabolism ; Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.}, } @article {pmid39207711, year = {2024}, author = {Holtman, IR and Glass, CK and Nott, A}, title = {Interpretation of Neurodegenerative GWAS Risk Alleles in Microglia and their Interplay with Other Cell Types.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {531-544}, pmid = {39207711}, issn = {2190-5215}, mesh = {Humans ; *Microglia/metabolism ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; *Genetic Predisposition to Disease ; Alleles ; Alzheimer Disease/genetics ; }, abstract = {Microglia have been implicated in numerous neurodegenerative and neuroinflammatory disorders; however, the causal contribution of this immune cell type is frequently debated. Genetic studies offer a unique vantage point in that they infer causality over a secondary consequence. Genome-wide association studies (GWASs) have identified hundreds of loci in the genome that are associated with susceptibility to neurodegenerative disorders. GWAS studies implicate microglia in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and to a lesser degree suggest a role for microglia in vascular dementia (VaD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and other neurodegenerative and neuropsychiatric disorders. The contribution and function of GWAS risk loci on disease progression is an ongoing field of study, in which large genomic datasets, and an extensive framework of computational tools, have proven to be crucial. Several GWAS risk loci are shared between disorders, pointing towards common pleiotropic mechanisms. In this chapter, we introduce key concepts in GWAS and post-GWAS interpretation of neurodegenerative disorders, with a focus on GWAS risk genes implicated in microglia, their interplay with other cell types and shared convergence of GWAS risk loci on microglia.}, } @article {pmid39207709, year = {2024}, author = {Awogbindin, I and Wanklin, M and Verkhratsky, A and Tremblay, MÈ}, title = {Microglia in Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {497-512}, pmid = {39207709}, issn = {2190-5215}, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Animals ; Parkinson Disease/metabolism ; }, abstract = {Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitive symptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, although the majority of cases are sporadic and linked to various environmental risk factors, with yet an unknown aetiology. Neuroglial changes are fundamental and often lead to the pathophysiology of neurodegenerative diseases. In particular, microglial cells, which are essential for maintaining CNS health, become compromised in their physiological functions with the exposure to environmental risk factors, genetic variants or mutations, as well as disease pathology. In this chapter, we cover the contribution of neuroglia, especially microglia, to several neurodegenerative diseases, including Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, infectious disease-associated neurodegeneration, and metal-precipitated neurodegeneration. Future research perspectives for the field pertaining to the therapeutic targeting of microglia across these disease conditions are also discussed.}, } @article {pmid39207520, year = {2024}, author = {Bjelica, B and Petri, S}, title = {Narrative review of diagnosis, management and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6508-6513}, pmid = {39207520}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; *Sialorrhea/etiology/therapy/diagnosis ; *Deglutition Disorders/etiology/therapy/diagnosis/physiopathology ; Disease Management ; }, abstract = {The degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) frequently leads bulbar symptoms like dysarthria, dysphagia, and sialorrhea, in approximately one-third of cases being the initial symptom. Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. In this review, we aimed to offer an updated overview of dysphagia and sialorrhea in ALS, covering its diagnosis, monitoring, and treatment in clinical practice. Regular assessment of dysphagia and sialorrhea during each patient visit is essential and should be a standard aspect of ALS care. Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. Furthermore, this review highlights and discusses potential areas for improvement in both clinical practice and research.}, } @article {pmid39207268, year = {2024}, author = {Han, H and Guo, G and Zhang, S and Peng, R and Xia, C}, title = {Reduced Surface Area for the Oxygen Reduction Reaction in Porous Electrode via Electrical Conductivity Relaxation.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {68}, pages = {e202402785}, doi = {10.1002/chem.202402785}, pmid = {39207268}, issn = {1521-3765}, support = {(2021YFB4001401//the National Key R&D Program of China/ ; 52272247//the National Natural Science Foundation of China/ ; }, abstract = {Oxygen reduction reaction (ORR) performance of porous electrodes is critical for solid oxide fuel cells (SOFCs). However, the effects of gas diffusion on the ORR in porous media need further investigation, although some issues, such as nonthermal surface oxygen exchange, have been attributed to gas diffusion. Herein, La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF) with various porosity, pore radii, and gas permeability were investigated via the electrical conductivity relaxation method and analysed via the distributed of characteristic time (DCT) model. The ORR is revealed with three characteristic times, which are gas diffusion, oxygen exchange via the surface corresponding to small pores, and oxygen exchange to large pores. Gas diffusion delays the oxygen surface exchange reaction, resulting in a very low chemical oxygen surface exchange coefficient compared with that obtained with dense samples under the assumption that all the surfaces are active for the ORR. Reduced surface area is thus defined to quantitatively represent the gas diffusion effects. The reduced surface area increases with increasing gas permeability, demonstrating the importance of electrode engineering for fast gas transport. Moreover, reduced surface area is suggested for replacing the specific surface area to calculate the electrode polarization impedance via the ALS model.}, } @article {pmid39206899, year = {2024}, author = {Ma, J and Liu, J and Chen, S and Zhang, W and Wang, T and Cao, M and Yang, Y and Du, Y and Cui, G and Du, Z}, title = {Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {8}, pages = {291}, doi = {10.31083/j.fbl2908291}, pmid = {39206899}, issn = {2768-6698}, support = {81602893//National Natural Science Foundation of China (NSFC)/ ; ZR2015YL049//Natural Science Foundation of Shandong Province/ ; ZR2021MH218//Natural Science Foundation of Shandong Province/ ; ZR2022MH184//Natural Science Foundation of Shandong Province/ ; 202104020224//Shandong Province Medical and Health Technology Development Plan/ ; 202312010854//Shandong Province Medical and Health Technology Development Plan/ ; Z-2023114//Shandong Province Traditional Chinese Medicine Science and Technology Plan/ ; 202328074//Jinan Science and Technology Plan/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Iron/metabolism ; Animals ; Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.}, } @article {pmid39206288, year = {2024}, author = {Cui, Y and Li, C and Ke, B and Xiao, Y and Wang, S and Jiang, Q and Zheng, X and Lin, J and Huang, J and Shang, H}, title = {Protective role of serum albumin in dementia: a prospective study from United Kingdom biobank.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1458184}, pmid = {39206288}, issn = {1664-2295}, abstract = {BACKGROUND: A number of studies have explored the link between neurodegenerative disorders (NDDs) and albumin, the main protein in human plasma. However, the results have been inconsistent, highlighting the necessity for a detailed systemic analysis.

METHODS: Utilizing data from the United Kingdom Biobank, we investigated the relationship between baseline levels of serum and urine albumin and the occurrence of common NDDs, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and dementia, employing Cox proportional hazards regression analysis.

RESULTS: Our results reveal that elevated baseline serum albumin levels are linked to a decreased risk of developing dementia (beta = -0.024, SE = 0.004, p < 0.001). Subgroup and interaction analyses highlighted the impact of factors like body mass index (BMI), age, and alcohol consumption on this relationship. Specifically, participants with higher BMI, younger age, or lower alcohol intake exhibited a stronger protective effect. On the other hand, a higher baseline level of urine microalbumin was connected to a slight increase in dementia risk (beta = 0.003, SE = 3.30E-04, p < 0.001). No significant associations were found between albumin levels and the risk of PD or ALS.

CONCLUSION: Our study underscores the potential role of serum albumin as a biomarker associated with reduced dementia risk. These findings contribute valuable insights into the understanding of albumin's impact on NDDs, suggesting its utility as a biomarker for dementia in clinical settings and informing future therapeutic strategies in clinical trials.}, } @article {pmid39206217, year = {2024}, author = {Uzelac, Z and Schwäble, B and Dorst, J and Rosenbohm, A and Wollinsky, K and Wurster, CD and Steinbreier, JS and Ludolph, AC}, title = {Pattern of pareses in 5q-spinal muscular atrophy.}, journal = {Therapeutic advances in neurological disorders}, volume = {17}, number = {}, pages = {17562864241263420}, pmid = {39206217}, issn = {1756-2856}, abstract = {BACKGROUND: This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring.

METHODS: Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6 ± 15.2 years) were included in the study. Most patients had SMA type II (n = 28) or SMA type III (n = 28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system.

RESULTS: In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5-3.5); lower limbs: 1.5 (0.5-3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5-2.6); p < 0.001; lower limbs: 0.5 (0.5-1.5); p < 0.001). Thenar muscles were stronger than other small hand muscles (3.0 (2.0-3.5) vs 3.0 (1.5-3.5); p = 0.004). Muscles had more strength in upper (2.3 (1.5-3.1)) compared to lower limbs (1.1 (0.5-2.3); p < 0.001) and in flexors compared to extensors.

CONCLUSION: We identified a specific pattern of muscle paresis in SMA which is different from the pattern of paresis in ALS and SBMA. As a rule of thumb, the pattern of pareses is similar, but not identical to ALS in distal, but different in proximal muscle groups.}, } @article {pmid39205388, year = {2024}, author = {Jafarinia, H and Van der Giessen, E and Onck, PR}, title = {C9orf72 polyPR interaction with the nuclear pore complex.}, journal = {Biophysical journal}, volume = {123}, number = {20}, pages = {3533-3539}, pmid = {39205388}, issn = {1542-0086}, mesh = {*Nuclear Pore/metabolism/chemistry ; *C9orf72 Protein/genetics/metabolism/chemistry ; *Molecular Dynamics Simulation ; Nuclear Pore Complex Proteins/metabolism/chemistry/genetics ; Protein Binding ; Saccharomyces cerevisiae/metabolism/genetics ; Active Transport, Cell Nucleus ; Humans ; }, abstract = {The C9orf72 gene associated with amyotrophic lateral sclerosis/frontotemporal dementia is translated to five dipeptide repeat proteins, among which poly-proline-arginine (PR) is the most toxic in cell and animal models, contributing to a variety of cellular defects. It has been proposed that polyPR disrupts nucleocytoplasmic transport (NCT) through several mechanisms including accumulation in the nuclear pore complex (NPC), accumulation in the nucleolus, and direct interactions with transport receptors. The NPC, which is the key regulator of transport between the cytoplasm and nucleus, plays a central role in these suggested mechanisms. Exploring polyPR interaction with the NPC provides valuable insight into the molecular details of polyPR-mediated NCT defects. To address this, we use coarse-grained molecular dynamics models of polyPR and the yeast NPC lined with intrinsically disordered FG-nucleoporins (FG-Nups). Our findings indicate no aggregation of polyPR within the NPC or permanent binding to FG-Nups. Instead, polyPR translocates through the NPC, following a trajectory through the central low-density region of the pore. In the case of longer polyPRs, we observe a higher energy barrier for translocation and a narrower translocation channel. Our study shows that polyPR and FG-Nups are mainly engaged in steric interactions inside the NPC with only a small contribution of specific cation-pi, hydrophobic, and electrostatic interactions, allowing polyPR to overcome the entropic barrier of the NPC in a size-dependent manner.}, } @article {pmid39204741, year = {2024}, author = {Xu, X and Zhao, B and Shen, B and Qi, Z and Wang, J and Cui, H and Li, B and Chen, S and Wang, G and Liu, X}, title = {Using RNA-Seq Analysis to Select Key Genes Related to Seed Dormancy in ALS-Inhibiting Resistant Descurainia sophia with Pro-197-Thr Mutation.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {16}, pages = {}, pmid = {39204741}, issn = {2223-7747}, support = {2024060203//Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences/ ; 2023LYS03//HAAFS Youth Innovation Fund Project/ ; 2022KJCXZX-LYS-13//HAAFS Science and Technology Innovation Special Project/ ; }, abstract = {Flixweed (Descurainia sophia) is a weed that seriously affects wheat fields in China. Over the past 20 years, it has evolved resistance to the herbicide tribenuron-methyl. In the present study, a resistant D. sophia population with a Pro-197-Thr mutation of acetolactate synthetase (ALS) was found to have a resistance index of 457.37 for tribenuron-methyl. Under the same growth conditions, the seeds of resistant (R) and susceptible (S) populations exhibited similar vitality but the germination rates of R seeds were higher than those of S seeds. This result demonstrated that seed dormancy periods were shorter in the R seeds. RNA-Seq transcriptome analysis was then used to choose candidate genes that could regulate seed dormancy pathways in the R population. A total of 504,976,046 clean reads were selected from nine RNA-Seq libraries and assembled into 79,729 unigenes. Among these, 33,476 unigenes were assigned to 51 GO subgroups, and 26,117 unigenes were assigned to 20 KEGG secondary metabolic pathways. Next, 2473 differentially expressed genes (DEGs) were divided into three groups, as follows: G-24 h (germinating seeds) vs. D (dormant seeds); G-48 h (germinated seeds) vs. D; and G-48 h vs. G-24 h. From these 2473 DEGs, 8 were selected as candidate dormancy unigenes for the R population if their expression levels continuously decreased during the seed germination progress and their functional annotations were related to plant seed dormancy. One candidate unigene was annotated as CYP707A2; two unigenes were annotated as the transcription factors TGA4 and TGA2; one unigene was annotated as the cystathionine beta-synthase gene; and four unigenes could not be annotated as any gene listed in the six public databases. However, qRT-PCR-validated results showed that, during the germination of R seeds, the expression of the three candidate unigenes first decreased and then increased, indicating that they may have other growth-regulating functions in R populations. In brief, the dormancy function of the eight candidate dormancy unigenes needs to be further studied.}, } @article {pmid39204338, year = {2024}, author = {O'Neill, R and Yoo, O and Burcham, P and Lim, LY}, title = {Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.}, journal = {Pharmaceutics}, volume = {16}, number = {8}, pages = {}, pmid = {39204338}, issn = {1999-4923}, support = {000990//Australian Government Research Training Program, Stan Perron Charitable Foundation/ ; }, abstract = {Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.}, } @article {pmid39203762, year = {2024}, author = {Zarco-Martín, MT and Freire, C and Andreo-López, MC and Leyva-Martínez, S and Fernández-Soto, ML}, title = {Malnutrition in Amyotrophic Lateral Sclerosis: Insights from Morphofunctional Assessment and Global Leadership Initiative on Malnutrition Criteria.}, journal = {Nutrients}, volume = {16}, number = {16}, pages = {}, pmid = {39203762}, issn = {2072-6643}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Female ; Male ; *Malnutrition/epidemiology/diagnosis ; Middle Aged ; Aged ; Cross-Sectional Studies ; *Nutrition Assessment ; Hand Strength ; Prevalence ; Nutritional Status ; Electric Impedance ; Severity of Illness Index ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease frequently accompanied by malnutrition due to weight loss, increased energy expenditure, and muscle mass loss. This study aimed to evaluate morphofunctional assessment tools as predictors of malnutrition and to investigate their relationship with muscle status and disease severity in ALS patients. A cross-sectional study was conducted with 45 ALS patients at the San Cecilio University Hospital in Granada. Malnutrition was assessed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Morphofunctional assessment was performed using Bioimpedance Vectorial Analysis (BIVA), handgrip strength (HGS), and Short Physical Performance Battery (SPPB). Malnutrition prevalence was 38% according to GLIM criteria. Significant differences were observed between malnourished and non-malnourished groups in age (70 ± 9 vs. 62 ± 10 years, p = 0.01), sex (female prevalence: 58.8% vs. 25.0%, p = 0.02), dysphagia prevalence (83% vs. 29%, p < 0.001), PEG/PRG use (35.3% vs. 3.6%, p = 0.01), and ALSFRS-R scores (30 ± 12 vs. 34 ± 12, p = 0.02). Malnourished patients had lower values in anthropometric measurements, muscle mass obtained by BIVA, and phase angle (PA) (4.05 ± 0.8° vs. 5.09 ± 0.8°, p < 0.001). No significant differences were found in muscle strength or functional status. PA showed significant correlations with muscle strength (r = 0.52, p < 0.001) and muscle mass measures (r = 0.48, p < 0.001). Moreover, PA was associated with poorer disease progression and physical performance. In our sample, BIVA metrics such as PA (<4.3°), SPA (<-0.8), body cell mass (<9.2 kg/m), and extracellular water (>49.75%) were identified as malnutrition risk factors. The study underscores the critical importance of comprehensive morphofunctional assessment and the use of advanced diagnostic criteria, for early identification and intervention in malnutrition among people with ALS. Further research is warranted to validate these findings and develop targeted nutritional strategies into routine clinical practice.}, } @article {pmid39202683, year = {2024}, author = {Gianferrari, G and Zucchi, E and Martinelli, I and Simonini, C and Fini, N and Ferro, S and Mercati, A and Ferri, L and Filippini, T and Vinceti, M and Mandrioli, J}, title = {Trends in Hospital Admissions for Patients with Amyotrophic Lateral Sclerosis: Insights from a Retrospective Cohort Study in a Province in Northern Italy.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {39202683}, issn = {2075-1729}, support = {//Servizio sanitario dell'Emilia-Romagna/ ; not available//Emilia Romagna Regional Health Authority/ ; }, abstract = {ALS is characterized by a highly heterogeneous course, ranging from slow and uncomplicated to rapid progression with severe extra-motor manifestations. This study investigated ALS-related hospitalizations and their connection to clinical aspects, comorbidities, and prognosis. We performed a retrospective cohort study including patients residing in Modena, Italy, newly diagnosed between 2007 and 2017 and followed up until 31 December 2022. Data were obtained from the Emilia Romagna ALS registry, regional hospitals, and medical records. Among the 249 patients, there were 492 hospital admissions, excluding those for diagnostic purposes; 63% of the patients had at least one hospitalization post-diagnosis, with an average stay of 19.90 ± 23.68 days. Younger patients were more likely to be hospitalized multiple times and experienced longer stays (44.23 ± 51.71 days if <65 years; 26.46 ± 36.02 days if older, p < 0.001). Patients who were hospitalized at least once more frequently underwent gastrostomy (64.97%) or non-invasive (66.24%) and invasive (46.50%) ventilation compared to those never hospitalized (21.74%, 31.52%, 13.04%, respectively, p < 0.001 for all). Emergency procedures led to longer hospitalizations (62.84 ± 48.91 days for non-invasive ventilation in emergencies vs. 39.88 ± 46.46 days electively, p = 0.012). Tracheostomy-free survival was not affected by hospitalizations. In conclusion, younger ALS patients undergo frequent and prolonged hospitalizations, especially after emergency interventions, although these do not correlate with reduced survival.}, } @article {pmid39201793, year = {2024}, author = {Martin, LJ and Koh, SJ and Price, A and Park, D and Kim, BW}, title = {Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201793}, issn = {1422-0067}, support = {NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cell Nucleus/metabolism ; Disease Models, Animal ; *DNA Damage ; *Induced Pluripotent Stem Cells/metabolism ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; NADPH Oxidases/metabolism/genetics ; *Oxidative Stress ; Phenotype ; Spinal Cord/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.}, } @article {pmid39201731, year = {2024}, author = {Fang, C and Wu, J and Liang, W}, title = {Systematic Investigation of Aluminum Stress-Related Genes and Their Critical Roles in Plants.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201731}, issn = {1422-0067}, support = {242102111164; 222301420106//Key R&D and Promotion Projects in Henan Province; Henan Science & Technology Research and Development Plan Joint Fund/ ; }, mesh = {*Aluminum/toxicity ; *Stress, Physiological/genetics ; *Gene Expression Regulation, Plant/drug effects ; Plant Proteins/genetics/metabolism ; Zea mays/genetics/growth & development/metabolism/drug effects ; Plants/genetics/metabolism/drug effects ; Genes, Plant ; }, abstract = {Aluminum (Al) stress is a dominant obstacle for plant growth in acidic soil, which accounts for approximately 40-50% of the world's potential arable land. The identification and characterization of Al stress response (Al-SR) genes in Arabidopsis, rice, and other plants have deepened our understanding of Al's molecular mechanisms. However, as a crop sensitive to acidic soil, only eight Al-SR genes have been identified and functionally characterized in maize. In this review, we summarize the Al-SR genes in plants, including their classifications, subcellular localizations, expression organs, functions, and primarily molecular regulatory networks. Moreover, we predict 166 putative Al-SR genes in maize based on orthologue analyses, facilitating a comprehensive understanding of the impact of Al stress on maize growth and development. Finally, we highlight the potential applications of alleviating Al toxicity in crop production. This review deepens our understanding of the Al response in plants and provides a blueprint for alleviating Al toxicity in crop production.}, } @article {pmid39201466, year = {2024}, author = {Strong, MJ and McLellan, C and Kaplanis, B and Droppelmann, CA and Junop, M}, title = {Phase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201466}, issn = {1422-0067}, support = {201806SOP-411481/CAPMC/CIHR/Canada ; not applicable//Temerty Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *SARS-CoV-2/metabolism/chemistry ; *Coronavirus Nucleocapsid Proteins/metabolism/chemistry/genetics ; *Protein Domains ; COVID-19/virology/metabolism ; Protein Binding ; Biomolecular Condensates/metabolism/chemistry ; RNA, Viral/metabolism/genetics ; Phosphoproteins/metabolism/chemistry ; Phase Separation ; }, abstract = {The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependent on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modeling suggests that the biomolecular condensate that forms in the presence of RNA is composed of an N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.}, } @article {pmid39201350, year = {2024}, author = {Bedja-Iacona, L and Richard, E and Marouillat, S and Brulard, C and Alouane, T and Beltran, S and Andres, CR and Blasco, H and Corcia, P and Veyrat-Durebex, C and Vourc'h, P}, title = {Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201350}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Protein Processing, Post-Translational ; *Superoxide Dismutase-1/genetics/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; DNA-Binding Proteins/metabolism/genetics ; Protein Serine-Threonine Kinases/metabolism/genetics ; Mutation ; Animals ; Phosphorylation ; Acetylation ; }, abstract = {Post-translational modifications (PTMs) affecting proteins during or after their synthesis play a crucial role in their localization and function. The modification of these PTMs under pathophysiological conditions, i.e., their appearance, disappearance, or variation in quantity caused by a pathological environment or a mutation, corresponds to post-translational variants (PTVs). These PTVs can be directly or indirectly involved in the pathophysiology of diseases. Here, we present the PTMs and PTVs of four major amyotrophic lateral sclerosis (ALS) proteins, SOD1, TDP-43, FUS, and TBK1. These modifications involve acetylation, phosphorylation, methylation, ubiquitination, SUMOylation, and enzymatic cleavage. We list the PTM positions known to be mutated in ALS patients and discuss the roles of PTVs in the pathophysiological processes of ALS. In-depth knowledge of the PTMs and PTVs of ALS proteins is needed to better understand their role in the disease. We believe it is also crucial for developing new therapies that may be more effective in ALS.}, } @article {pmid39200952, year = {2024}, author = {Schwarzenbacher, L and Wassermann, L and Rezar-Dreindl, S and Reiter, GS and Schmidt-Erfurth, U and Stifter, E}, title = {An Analysis of Ocular Biometrics: A Comprehensive Retrospective Study in a Large Cohort of Pediatric Cataract Patients.}, journal = {Journal of clinical medicine}, volume = {13}, number = {16}, pages = {}, pmid = {39200952}, issn = {2077-0383}, abstract = {Objectives: This study aims to provide a comprehensive analysis of ocular biometric parameters in pediatric patients with cataracts to optimize surgical outcomes. By evaluating various biometric data, we seek to enhance the decision-making process for intraocular lens (IOL) placement, particularly with advanced technologies like femtosecond lasers. Methods: This retrospective comparative study included pediatric patients with cataracts who underwent ocular biometric measurements and cataract extraction with anterior vitrectomy at the Medical University of Vienna between January 2019 and December 2021. Parameters measured included corneal diameter (CD), axial length (AL), corneal thickness (CT) and flat and steep keratometry (Kf and Ks). The study explored the correlations between these parameters and IOL placement. Results: A total of 136 eyes from 68 pediatric patients were included in the study. Significant positive correlations were found between corneal diameter, age and AL. The mean CD was 11.4 mm, mean AL was 19.5 mm, CT was 581.2 ± 51.8 µm, Kf was 7.76 ± 0.55 mm and Ks 7.41 ± 0.59 mm, respectively. Older pediatric patients with larger corneal diameters and longer ALs were more likely to receive in-the-bag IOL implantation. Conversely, younger patients often required alternative IOL placements or remained aphakic. Our data indicated that over 95% of the study population and all patients aged one year and older had a corneal diameter of 10 mm or larger. Conclusions: Detailed ocular biometric analysis is crucial for optimizing both surgical outcomes and postoperative care in pediatric cataract patients. The positive correlations between CD, age and AL underline the importance of individualized surgical planning tailored to each patient's unique anatomical features. Additionally, our findings suggest that the use of a femtosecond laser is both feasible and safe for pediatric patients aged one year and older, potentially offering enhanced surgical precision and improved outcomes.}, } @article {pmid39200200, year = {2024}, author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Jeon, JE and Chung, JH and Lee, SY}, title = {Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200200}, issn = {2227-9059}, abstract = {UNLABELLED: The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients.

METHODS: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure.

RESULTS: While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases.

CONCLUSIONS: Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results.}, } @article {pmid39200158, year = {2024}, author = {Zhao, M and Wang, J and Liu, M and Xu, Y and Huang, J and Zhang, Y and He, J and Gu, A and Liu, M and Liu, X}, title = {KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200158}, issn = {2227-9059}, support = {2016YFC0905100//the National Key Research and Development Program of China/ ; 2021JJ30801//the Natural Science Foundation of Hunan Province, China/ ; kq2202077//the Natural Science Foundation of Changsha, China/ ; CX20230291//the Postgraduate Freedom Explo-ration Project of Central South University/ ; }, abstract = {Mutations in the C-terminal of KIF1A (Kinesin family member 1A) may lead to amyotrophic lateral sclerosis (ALS) through unknown mechanisms that are not yet understood. Using iPSC reprogramming technology and motor neuron differentiation techniques, we generated iPSCs from a healthy donor and two ALS patients with KIF1A mutations (R1457Q and P1688L) and differentiated them into spinal motor neurons (iPSC-MN) to investigate KIF1A-related ALS pathology. Our in vitro iPSC-iMN model faithfully recapitulated specific aspects of the disease, such as neurite fragmentation. Through this model, we observed that these mutations led to KIF1A aggregation at the proximal axon of motor neurons and abnormal accumulation of its transport cargo, LAMP1, resulting in autophagy dysfunction and cell death. RNAseq analysis also indicated that the functions of the extracellular matrix, structure, and cell adhesion were significantly disturbed. Notably, using rapamycin during motor neuron differentiation can effectively prevent motor neuron death.}, } @article {pmid39199527, year = {2024}, author = {Ail, BE and Ramele, R and Gambini, J and Santos, JM}, title = {An Intrinsically Explainable Method to Decode P300 Waveforms from EEG Signal Plots Based on Convolutional Neural Networks.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199527}, issn = {2076-3425}, support = {ITBACyT-2020//Instituto Tecnológico de Buenos Aires (ITBA)/ ; }, abstract = {This work proposes an intrinsically explainable, straightforward method to decode P300 waveforms from electroencephalography (EEG) signals, overcoming the black box nature of deep learning techniques. The proposed method allows convolutional neural networks to decode information from images, an area where they have achieved astonishing performance. By plotting the EEG signal as an image, it can be both visually interpreted by physicians and technicians and detected by the network, offering a straightforward way of explaining the decision. The identification of this pattern is used to implement a P300-based speller device, which can serve as an alternative communication channel for persons affected by amyotrophic lateral sclerosis (ALS). This method is validated by identifying this signal by performing a brain-computer interface simulation on a public dataset from ALS patients. Letter identification rates from the speller on the dataset show that this method can identify the P300 signature on the set of 8 patients. The proposed approach achieves similar performance to other state-of-the-art proposals while providing clinically relevant explainability (XAI).}, } @article {pmid39199512, year = {2024}, author = {Turner, N and Faull, C and Palmer, J and Armstrong, A and Bedford, J and Turner, MR and Wilson, E}, title = {Understanding Quality of Life for People with Motor Neurone Disease Who Use Tracheostomy Ventilation and Family Members: A Scoping Review.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199512}, issn = {2076-3425}, support = {Wilson/Oct21/968-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Tracheostomy ventilation (TV) can increase survival time for people living with motor neurone disease (MND); however, the use of TV varies between countries. Concerns regarding anticipated quality of life (QoL) are among the reasons given by healthcare professionals for not recommending this intervention, yet little is known about QoL in this context. This scoping review was conducted to examine the evidence on QoL for those with MND who use TV and family members involved in their care. Using the methodological guidance of the Joanna Briggs Institute, 23 papers were identified for inclusion, and findings were inductively analysed to identify key themes. We found that people living with MND tend to rate QoL post TV more positively than anticipated by healthcare professionals or family members. QoL was found to be related to positive relationships and activities the person could maintain. Feeling able to make a choice and an adequate level of financial resources were also important factors. Family members tended to experience lower QoL, associated with the uncertainty surrounding an emergency procedure and the complexity of subsequently required care. More evidence on QoL from the perspectives of people with MND who use TV is needed to support decision making and inform guidance.}, } @article {pmid39199498, year = {2024}, author = {Kleinerova, J and McKenna, MC and Finnegan, M and Tacheva, A and Garcia-Gallardo, A and Mohammed, R and Tan, EL and Christidi, F and Hardiman, O and Hutchinson, S and Bede, P}, title = {Clinical, Cortical, Subcortical, and White Matter Features of Right Temporal Variant FTD.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199498}, issn = {2076-3425}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {UNLABELLED: The distinct clinical and radiological characteristics of right temporal variant FTD have only been recently recognized.

METHODS: Eight patients with right temporal variant FTD were prospectively recruited and underwent a standardised neuropsychological assessment, clinical MRI, and quantitative neuroimaging.

RESULTS: Our voxelwise grey analyses captured bilateral anterior and mesial temporal grey matter atrophy with a clear right-sided predominance. Bilateral hippocampal involvement was also observed, as well as disease burden in the right insular and opercula regions. White matter integrity alterations were also bilateral in anterior temporal and sub-insular regions with a clear right-hemispheric predominance. Extra-temporal white matter alterations have also been observed in orbitofrontal and parietal regions. Significant bilateral but right-predominant thalamus, putamen, hippocampus, and amygdala atrophy was identified based on subcortical segmentation. The clinical profile of our patients was dominated by progressive indifference, decline in motivation, loss of interest in previously cherished activities, incremental social withdrawal, difficulty recognising people, progressive language deficits, increasingly rigid routines, and repetitive behaviours.

CONCLUSIONS: Right temporal variant FTD has an insidious onset and may be mistaken for depression at symptom onset. It manifests in a combination of apathy, language, and behavioural features. Quantitative MR imaging captures a characteristic bilateral but right-predominant temporal imaging signature with extra-temporal frontal and parietal involvement.}, } @article {pmid39199454, year = {2024}, author = {Calma, AD and van den Bos, M and Pavey, N and Santos Silva, C and Menon, P and Vucic, S}, title = {Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199454}, issn = {2076-3425}, abstract = {Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.}, } @article {pmid39199265, year = {2024}, author = {Proaño, B and Benlloch, M and Sancho-Castillo, S and Privado, J and Bargues-Navarro, G and Sanchis-Sanchis, CE and Martínez Bolós, P and Carriquí-Suárez, AB and Cubero-Plazas, L and Platero Armero, JL and Escriva, D and Ceron, JJ and Tvarijonaviciute, A and de la Rubia Ortí, JE}, title = {Paraoxonase I Activity and Its Relationship with Nutrition in Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199265}, issn = {2076-3921}, support = {2021-203-003//Catholic University of Valencia San Vicente Mártir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, with oxidative stress playing a key role. Paraoxonase 1 (PON1) is an antioxidant enzyme that may influence ALS progression. This study aimed to establish a predictive model for the influence of PON1 activity on functionality in ALS patients and explore its relationship with nutrition. Methods: In this observational cross-sectional study, 70 ALS patients underwent assessments of PON1 activity, lipid profile, functional capacity, respiratory function, and heart rate variability. A structural equation model was developed to determine the relationships between variables. Nutritional intake was analyzed in 65 patients. Results: The predictive model showed that PON1 activity and LDL levels positively influenced functionality, both directly and indirectly through respiratory capacity. Heart rate variability moderately predicted functionality independently. HDL levels were not significantly associated with functionality. Weak to moderate correlations were found between PON1 activity and intake of certain nutrients, with positive associations for monounsaturated fats and vitamin D, and negative associations for carbohydrates, proteins, and some micronutrients. Conclusions: PON1 activity appears to play an important role in ALS patient functionality, both directly and through effects on respiratory capacity. However, its relationship with nutritional intake was not strongly evident in this sample population.}, } @article {pmid39199129, year = {2024}, author = {Percio, A and Cicchinelli, M and Masci, D and Summo, M and Urbani, A and Greco, V}, title = {Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199129}, issn = {2076-3921}, abstract = {Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.}, } @article {pmid39198773, year = {2024}, author = {Lei, Y and Zhang, X and Liu, H and Xu, Z and Xu, P}, title = {Amyotrophic lateral sclerosis associated with Sjögren's syndrome: a case report.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {300}, pmid = {39198773}, issn = {1471-2377}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy/pathology ; *Sjogren's Syndrome/complications/diagnosis/drug therapy/pathology ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals.

CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sjögren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen.

CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.}, } @article {pmid39197801, year = {2025}, author = {Zhan, Y and Huang, J and Tang, X and Du, B and Yang, B}, title = {Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {336}, number = {}, pages = {118741}, doi = {10.1016/j.jep.2024.118741}, pmid = {39197801}, issn = {1872-7573}, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; *Membrane Proteins/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nucleotidyltransferases/metabolism ; Male ; Signal Transduction/drug effects ; Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy ; Spinal Cord/drug effects/metabolism/pathology ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive.

AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms.

MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1[G93A] NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway.

RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1β mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-β mRNA, but also the levels of cGAS and STING protein in hSOD1[G93A] NSC-34 cells.

CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.}, } @article {pmid39197036, year = {2024}, author = {Sapaly, D and Cheguillaume, F and Weill, L and Clerc, Z and Biondi, O and Bendris, S and Buon, C and Slika, R and Piller, E and Sundaram, VK and da Silva Ramos, A and Amador, MDM and Lenglet, T and Debs, R and Le Forestier, N and Pradat, PF and Salachas, F and Lacomblez, L and Hesters, A and Borderie, D and Devos, D and Desnuelle, C and Rolland, AS and Periou, B and Vasseur, S and Chapart, M and Le Ber, I and Fauret-Amsellem, AL and Millecamps, S and Maisonobe, T and Leonard-Louis, S and Behin, A and Authier, FJ and Evangelista, T and Charbonnier, F and Bruneteau, G and , }, title = {Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae270}, pmid = {39197036}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole-body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analyzed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from thirteen ALS patients and ten asymptomatic ALS-mutation gene carriers compared to sixteen controls. Using human control primary myotubes, we further investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.}, } @article {pmid39196396, year = {2024}, author = {Radakovic, R and Carroll, A and Altiero, A and Reichwein, C and Walsh, S and Niven, E and Abrahams, S and Simmons, Z}, title = {Self-perceived quality of life, cognitive and behavioural impairment in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6822-6838}, pmid = {39196396}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; *Quality of Life/psychology ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; Cognitive Dysfunction/etiology/physiopathology/psychology ; Cohort Studies ; Self Concept ; Mental Disorders/psychology/etiology ; Adult ; }, abstract = {BACKGROUND: Self-perceived quality of life (QoL) is important in amyotrophic lateral sclerosis (ALS). Although caregiver burden and strain have been related to cognitive and behavioural impairment, there has been no comprehensive research looking at these impairments and how they may influence self-perceived QoL subdomains.

AIMS: To explore how cognitive and behavioural impairment are related to different areas of self-perceived QoL using disease-specific measures.

METHODS: This was a quantitative, cross-sectional, observational cohort study, utilising existing specialist ALS clinic data. Clinical and demographic variables were available as well as multidimensional measures, ALS-specific QoL Short Form (ALSsQoL-SF) results and the data from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Group comparison and regression analyses were performed.

RESULTS: Data from 121 participants with ALS were analysed. 61.2% (N = 74) had either cognitive and/or behavioural impairment, with 28.9% (N = 35) with cognitive impairment (ALSci), 14.1% (N = 17) with behavioural impairment (ALSbi) and 18.2% (N = 22) with both (ALScbi). 38.8% (N = 47) were classified as having no impairments (ALSni). Those with ALSbi had significantly lower QoL in the domains of negative emotions and the interaction with people and the environment compared to those with ALSci and ALSni (ps < 0.05). Further, those with ALScbi had significantly lower QoL in the intimacy domains than those with ALSci and ALSni (ps < 0.05). Regression analysis showed specific cognitive and behavioural (inclusive of psychosis) predictors associated with specific QoL subdomains.

CONCLUSIONS: Behavioural impairments effect QoL in specific subdomains, namely relating to internalising (negative emotions) and externalising (interaction with people and the environment subdomains, intimacy).}, } @article {pmid39194682, year = {2024}, author = {Sacharczuk, M and Mickael, ME and Kubick, N and Kamińska, A and Horbańczuk, JO and Atanasov, AG and Religa, P and Ławiński, M}, title = {The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.}, journal = {Current issues in molecular biology}, volume = {46}, number = {8}, pages = {7846-7861}, pmid = {39194682}, issn = {1467-3045}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a poorly understood and fatal disease. It has a low prevalence and a 2-4 year survival period. Various theories and hypotheses relating to its development process have been proposed, albeit with no breakthrough in its treatment. Recently, the role of the adaptive immune system in ALS, particularly CD4+ T cells, has begun to be investigated. CD4+ T cells are a heterogeneous group of immune cells. They include highly pro-inflammatory types such as Th1 and Th17, as well as highly anti-inflammatory cells such as Tregs. However, the landscape of the role of CD4+ T cells in ALS is still not clearly understood. This review covers current hypotheses that elucidate how various CD4+ T cells can contribute to ALS development. These hypotheses include the SWITCH model, which suggests that, in the early stages of the disease, Tregs are highly capable of regulating the immune response. However, in the later stages of the disease, it seems that pro-inflammatory cells such as Th1 and Th17 are capable of overwhelming Treg function. The reason why this occurs is not known. Several research groups have proposed that CD4+ T cells as a whole might experience aging. Others have proposed that gamma delta T cells might directly target Tregs. Additionally, other research groups have argued that less well-known CD4+ T cells, such as Emoes+ CD4+ T cells, may be directly responsible for neuron death by producing granzyme B. We propose that the ALS landscape is highly complicated and that there is more than one feasible hypothesis. However, it is critical to take into consideration the differences in the ability of different populations of CD4+ T cells to infiltrate the blood-brain barrier, taking into account the brain region and the time of infiltration. Shedding more light on these still obscure factors can help to create a personalized therapy capable of regaining the balance of power in the battle between the anti-inflammatory and pro-inflammatory cells in the central nervous system of ALS patients.}, } @article {pmid39193833, year = {2025}, author = {Jalaiei, A and Asadi, MR and Daneshmandpour, Y and Rezazadeh, M and Ghafouri-Fard, S}, title = {Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16200}, doi = {10.1111/jnc.16200}, pmid = {39193833}, issn = {1471-4159}, mesh = {Humans ; *Receptors, Nicotinic/genetics ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; }, abstract = {The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.}, } @article {pmid39193573, year = {2024}, author = {Soresi, M and Giannitrapani, L}, title = {Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease.}, journal = {World journal of gastroenterology}, volume = {30}, number = {30}, pages = {3541-3547}, pmid = {39193573}, issn = {2219-2840}, mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor/agonists ; *Non-alcoholic Fatty Liver Disease/drug therapy/pathology/metabolism ; *Glucagon-Like Peptides/therapeutic use ; Liver/drug effects/pathology/metabolism ; Insulin Resistance ; Drug Therapy, Combination/methods ; Glucagon-Like Peptide 1/agonists/metabolism ; Treatment Outcome ; Hypoglycemic Agents/therapeutic use/pharmacology ; Disease Progression ; Incretins/therapeutic use ; }, abstract = {In this editorial, we comment on Yin et al's recently published Letter to the editor. In particular, we focus on the potential use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) alone, but even more so in combination therapy, as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease (MASLD), the new definition of an old condition, non-alcoholic fatty liver disease, which aims to better define the spectrum of steatotic pathology. It is well known that GLP-1RAs, having shown outstanding performance in fat loss, weight loss, and improvement of insulin resistance, could play a role in protecting the liver from progressive damage. Several clinical trials have shown that, among GLP-1RAs, semaglutide is a safe, well-studied therapeutic choice for MASLD patients; however, most studies demonstrate that, while semaglutide can reduce steatosis, including steatohepatitis histological signs (in terms of inflammatory cell infiltration and hepatocyte ballooning), it does not improve fibrosis. Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease. In particular, GLP-1RAs associated with antifibrotic drug therapy, dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis, liver biochemistry, and non-invasive fibrosis tests than monotherapy. Therefore, although to date there are no definitive indications from international drug agencies, there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD, one that will certainly include the use of GLP-1RAs as combination therapy.}, } @article {pmid39193017, year = {2024}, author = {Chen, X and Cai, L and Fan, W and Yang, Q and Mao, X and Yao, L}, title = {Causal relationships between rheumatoid arthritis and neurodegenerative diseases: a two-sample univariable and multivariable Mendelian randomization study.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1439344}, pmid = {39193017}, issn = {2296-858X}, abstract = {BACKGROUND: Observational research has highlighted a potential relationship between rheumatoid arthritis (RA) and neurodegenerative diseases (NDs). However, the confirmation of a causal connection is impeded by the inherent limitations of such studies, including vulnerability to confounding factors and the possibility of reverse causality. This study employs a two-sample Mendelian randomization (MR) approach to assess the causal impact of RA on three NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS: We aggregated data from genome-wide association studies (GWASs) targeting RA or NDs within populations of European descent. Single nucleotide polymorphisms (SNPs) with robust associations to RA were identified as instrumental variables (IVs). To estimate the association between RA and AD, PD, and ALS, we utilized the inverse variance weighted (IVW) method in our univariable MR (UVMR) analysis. Validation of the IVW results ensued through supplementary analyses using MR-Egger and weighted median methods. The multivariable MR (MVMR) analysis was conducted, adjusting for body mass index (BMI), alcohol drinking, and type 2 diabetes mellitus (T2DM).

RESULTS: The UVMR analysis, based on the IVW method, revealed a significantly positive causal association between RA and late-onset (LO) AD (OR [95% CI] = 1.084 [1.020-1.153]; p = 9.980 × 10[-3]), while suggesting a possible inverse relationship with PD (OR [95% CI] = 0.727 [0.563-0.938]; p = 0.014). Our study did not detect any causal connections between RA and early-onset (EO) AD, atypical or mixed (AM) AD, and ALS (all p > 0.05). The MVMR analysis results indicated that after adjusting for alcohol drinking, RA remains a risk factor for LOAD (OR [95% CI] = 1.094 [1.024-1.169]; p = 0.008). However, MVMR analysis revealed no causal connections between RA and PD after adjustments for BMI, alcohol drinking, or T2DM (all p > 0.05). Sensitivity analyses showed no evidence of heterogeneity and horizontal pleiotropy.

CONCLUSIONS: This research provides genetic evidence indicating that RA potentially causes an increased risk of developing LOAD and PD. Such a revelation underscores the importance for individuals suffering from RA to be vigilant about the potential emergence of LOAD and PD. Ongoing monitoring and prompt detection are essential for successfully managing and intervening in this possible risk.}, } @article {pmid39192891, year = {2024}, author = {Murtazina, A and Subbotin, D and Kuchina, A and Gilvanova, O and Degterev, D and Shchagina, O and Cherevatova, T and Bulakh, M and Sherstyukova, D and Ryzhkova, O and Kurushina, O and Skoblov, M and Borovikov, A and Kutsev, S}, title = {Asymmetric scapuloperoneal phenotype of MATR3-related distal myopathy: case series.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1414928}, pmid = {39192891}, issn = {1664-8021}, abstract = {Recent research has sparked a discussion on the spectrum of diseases linked to the MATR3 gene associated with amyotrophic lateral sclerosis and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). To date, fewer than 50 cases of VCPDM have been reported in the literature. We aim to build upon the work of previous researchers by gathering additional information about VCPDM. In this study, we present six patients from four unrelated families affected by VCPDM. Our observations include patients exhibiting both the typical phenotype associated with MATR3-related distal myopathy and rare symptomatic manifestations of the disease. Notably, two cases presented with an asymmetric scapuloperoneal phenotype, leading in one case to an initial misdiagnosis of facioscapulohumeral muscular dystrophy.}, } @article {pmid39192797, year = {2024}, author = {Luo, RC and Wu, XY and Yu, WW and Zheng, YJ and Wang, D}, title = {[Research progress on the relationship between TRAF6 and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {76}, number = {4}, pages = {653-662}, pmid = {39192797}, issn = {0371-0874}, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/etiology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology/genetics/etiology ; Multiple Sclerosis/metabolism/physiopathology/etiology ; *Neurodegenerative Diseases/metabolism/etiology ; Parkinson Disease/metabolism/physiopathology ; *TNF Receptor-Associated Factor 6/metabolism/genetics/physiology ; Ubiquitination ; }, abstract = {Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.}, } @article {pmid39192497, year = {2024}, author = {Lee, I and Garret, MA and Wuu, J and Harrington, EA and Berry, JD and Miller, TM and Harms, M and Benatar, M and Shneider, N}, title = {Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {672-679}, pmid = {39192497}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *C9orf72 Protein/genetics ; *Body Mass Index ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Heterozygote ; Adult ; Cohort Studies ; Genotype ; DNA Repeat Expansion/genetics ; Aged ; }, abstract = {Objective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3-4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9-4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5-4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers.}, } @article {pmid39192451, year = {2024}, author = {Yan, Y and Huang, SY and Feng, YJ and Zhao, CY and Sheng, GX and Chen, J and Jiang, JJ and Gao, F and Mao, SS}, title = {[Pediatric amyotrophic lateral sclerosis caused by FUS gene variation in 2 cases].}, journal = {Zhonghua er ke za zhi = Chinese journal of pediatrics}, volume = {62}, number = {9}, pages = {893-895}, doi = {10.3760/cma.j.cn112140-20240315-00184}, pmid = {39192451}, issn = {0578-1310}, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA Mutational Analysis ; Exons ; Fatal Outcome ; Heterozygote ; *Mutation ; *RNA-Binding Protein FUS/genetics ; Child ; Adolescent ; }, } @article {pmid39191336, year = {2024}, author = {Sirtori, CR and Castiglione, S and Pavanello, C}, title = {Metformin: From diabetes to cancer to prolongation of life.}, journal = {Pharmacological research}, volume = {208}, number = {}, pages = {107367}, doi = {10.1016/j.phrs.2024.107367}, pmid = {39191336}, issn = {1096-1186}, mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; Animals ; *Neoplasms/drug therapy/metabolism ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus/drug therapy/metabolism ; Longevity/drug effects ; Antineoplastic Agents/therapeutic use/pharmacology ; }, abstract = {The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.}, } @article {pmid39191178, year = {2024}, author = {Ruotolo, G and D'Anzi, A and Giovenale, AMG and Giacometti, C and Ferrari, D and Vulcano, E and D'Asdia, C and Lattante, S and Sabatelli, M and Codazzi, F and Consalez, G and Marano, M and Di Lazzaro, V and Pennuto, M and Vescovi, A and Rosati, J}, title = {Induced pluripotent stem cell production (CSSi019-A)(14432) from an asymptomatic subject carrying a expansion of C9orf72 gene.}, journal = {Stem cell research}, volume = {81}, number = {}, pages = {103540}, doi = {10.1016/j.scr.2024.103540}, pmid = {39191178}, issn = {1876-7753}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; Aged ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; DNA Repeat Expansion ; Male ; Female ; }, abstract = {One of the genetic mutations most associated with the onset of amyotrophic lateral sclerosis, both in sporadic and familial cases, is the expansion of the C9orf72 gene. The presence of more than 30 repeats (GGGGCC) correlates with uncertain ALS symptomatology. Here we collected a dermal biopsy from a subject carrying 36 hexanucleotide repeats and reprogrammed it into an induced pluripotent stem cell line. Despite the number of repeat elements, the subject had no symptoms at the age of the biopsy (76 years), thus resulting in a healthy carrier of the mutation.}, } @article {pmid39191031, year = {2024}, author = {He, Q and Wang, Y and Zhao, F and Wei, S and Li, X and Zeng, G}, title = {APE1: A critical focus in neurodegenerative conditions.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {179}, number = {}, pages = {117332}, doi = {10.1016/j.biopha.2024.117332}, pmid = {39191031}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Animals ; }, abstract = {The global growth of the aging population has resulted in an increased prevalence of neurodegenerative diseases, characterized by the progressive loss of central nervous system (CNS) structure and function. Given the high incidence and debilitating nature of neurodegenerative diseases, there is an urgent need to identify potential biomarkers and novel therapeutic targets thereof. Apurinic/apyrimidinic endonuclease 1 (APE1), has been implicated in several neurodegenerative diseases, as having a significant role. Abnormal APE1 expression has been observed in conditions including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and epilepsy. However, whether this dysregulation is protective or harmful remains unclear. This review aims to comprehensively review the current understanding of the involvement of APE1 in neurodegenerative diseases.}, } @article {pmid39190906, year = {2024}, author = {Yu, J and Chen, S and Zhang, H and Zhang, S and Dong, D}, title = {Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.}, journal = {JMIR public health and surveillance}, volume = {10}, number = {}, pages = {e57353}, pmid = {39190906}, issn = {2369-2960}, mesh = {Humans ; China/epidemiology ; *Rare Diseases/epidemiology/economics ; Male ; Adult ; Female ; Cross-Sectional Studies ; Middle Aged ; *Cost of Illness ; Adolescent ; Child ; *Internet ; Child, Preschool ; Young Adult ; Surveys and Questionnaires ; Aged ; Infant ; }, abstract = {BACKGROUND: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population.

OBJECTIVE: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants.

METHODS: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership.

RESULTS: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity.

CONCLUSIONS: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.}, } @article {pmid39190080, year = {2024}, author = {Jensen, BK}, title = {Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.}, journal = {Advances in neurobiology}, volume = {39}, number = {}, pages = {285-318}, pmid = {39190080}, issn = {2190-5215}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Astrocytes/metabolism ; *Disease Progression ; *Motor Neurons/metabolism/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex disease impacting motor neurons of the brain, brainstem, and spinal cord. Disease etiology is quite heterogeneous with over 40 genes causing the disease and a vast ~90% of patients having no prior family history. Astrocytes are major contributors to ALS, particularly through involvement in accelerating disease progression. Through study of genetic forms of disease including SOD1, TDP43, FUS, C9orf72, VCP, TBK1, and more recently patient-derived cells from sporadic individuals, many biological mechanisms have been identified to cause intrinsic or glial-mediated neurotoxicity to motor neurons. Overall, many of the normally supportive and beneficial roles that astrocytes contribute to neuronal health and survival instead switch to become deleterious and neurotoxic. While the exact pathways may differ based on disease-origin, altered astrocyte-neuron communication is a common feature of ALS. Within this chapter, distinct genetic forms are examined in detail, along with what is known from sporadic patient-derived cells. Overall, this chapter highlights the interplay between astrocytes and neurons in this complex disease and describes the key features underlying: astrocyte-mediated motor neuron toxicity, excitotoxicity, oxidative/nitrosative stress, protein dyshomeostasis, metabolic imbalance, inflammation, trophic factor withdrawal, blood-brain/blood-spinal cord barrier involvement, disease spreading, and the extracellular matrix/cell adhesion/TGF-β signaling pathways.}, } @article {pmid39189114, year = {2024}, author = {Rivera Flores, IV and Monopoli, K and Jackson, S and Echeverria, D and O'Reilly, D and Brown, RH and Khvorova, A}, title = {Near Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy.}, journal = {Nucleic acid therapeutics}, volume = {34}, number = {5}, pages = {234-244}, pmid = {39189114}, issn = {2159-3345}, support = {S10 OD020012/OD/NIH HHS/United States ; R01 NS104022/NS/NINDS NIH HHS/United States ; T32 GM135751/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *RNA, Small Interfering/genetics/chemistry ; Humans ; Dogs ; Mice ; Rats ; *Superoxide Dismutase-1/genetics ; *Species Specificity ; Sheep ; Base Pair Mismatch/genetics ; Cell Line ; }, abstract = {Small interfering RNAs (siRNAs) represent a novel class of drugs capable of potent and sustained modulation of genes across various tissues. Preclinical development of siRNAs necessitates assessing efficacy and toxicity in animal models. While identifying therapeutic leads with cross-species activity can expedite development, it may compromise efficacy and be infeasible for certain gene targets. Here, we investigate whether deriving species-active siRNAs from potent human-targeting leads-an approach termed mismatch conversion-can yield potent compounds. We systematically altered potent siRNAs targeting human genes associated with diseases-SOD1 (ALS), JAK1 (inflammation), and HTT (HD)-to generate species-matching variants with full complementarity to their target in NHPs, mice, rats, sheep, and dogs. Variants potency and efficacy were measured in corresponding cell lines. We demonstrate that sequence, position, and number of mismatches significantly influence the ability to generate potent species-active compounds via mismatch conversion. Across tested sequences, mismatch conversion strategy ability to identify a species-active lead varied from 0% to 70%. For SOD1, lead compounds identified from species-focus screening in mouse and dog cells were more potent than leads obtained from mismatch conversion. Thus, a focused screening of therapeutic lead and model compounds may represent a more reliable strategy for the clinical advancement of siRNAs.}, } @article {pmid39188590, year = {2024}, author = {Roca-Pereira, S and Domínguez, R and Moreno León, I and Colomina, MJ and Martínez Yélamos, A and Martínez Yélamos, S and Povedano, M and Andrés-Benito, P}, title = {Increased CXCL12, a potential CSF biomarker for differential diagnosis of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae271}, pmid = {39188590}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential.}, } @article {pmid39187524, year = {2024}, author = {Femiano, C and Bruno, A and Gilio, L and Buttari, F and Dolcetti, E and Galifi, G and Azzolini, F and Borrelli, A and Furlan, R and Finardi, A and Musella, A and Mandolesi, G and Storto, M and Centonze, D and Stampanoni Bassi, M}, title = {Inflammatory signature in amyotrophic lateral sclerosis predicting disease progression.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19796}, pmid = {39187524}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Female ; Male ; *Disease Progression ; Middle Aged ; *Cytokines/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; Aged ; Inflammation/cerebrospinal fluid ; Principal Component Analysis ; Adult ; Prognosis ; Case-Control Studies ; }, abstract = {Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression.}, } @article {pmid39187176, year = {2025}, author = {Althobaiti, NA}, title = {Heavy metals exposure and Alzheimer's disease: Underlying mechanisms and advancing therapeutic approaches.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115212}, doi = {10.1016/j.bbr.2024.115212}, pmid = {39187176}, issn = {1872-7549}, mesh = {Humans ; *Alzheimer Disease/chemically induced ; *Metals, Heavy/adverse effects ; Animals ; Oxidative Stress/drug effects/physiology ; Environmental Exposure/adverse effects ; Brain/drug effects/metabolism ; }, abstract = {Heavy metals such as lead, cadmium, mercury, and arsenic are prevalent in the environment due to both natural and anthropogenic sources, leading to significant public health concerns. These heavy metals are known to cause damage to the nervous system, potentially leading to a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and attention-deficit hyperactivity disorder (ADHD). The present study examines the complex relationship between heavy metal exposure and AD, focusing on the underlying mechanisms of toxicity and potential therapeutic approaches. This review article highlights how these metals can impair brain function through mechanisms such as oxidative stress, inflammation, and neurotransmitter disruption, ultimately contributing to neurodegenerative diseases like AD. It also addresses the challenges in diagnosing heavy metal-induced cognitive impairments and emphasizes the need for further research to explore effective treatment strategies and preventive measures against heavy metal exposure.}, } @article {pmid39187026, year = {2024}, author = {Rezaei, K and Mastali, G and Abbasgholinejad, E and Bafrani, MA and Shahmohammadi, A and Sadri, Z and Zahed, MA}, title = {Cadmium neurotoxicity: Insights into behavioral effect and neurodegenerative diseases.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143180}, doi = {10.1016/j.chemosphere.2024.143180}, pmid = {39187026}, issn = {1879-1298}, mesh = {*Cadmium/toxicity ; Humans ; *Neurodegenerative Diseases/chemically induced ; Animals ; Environmental Pollutants/toxicity ; Brain/drug effects/metabolism ; Neurotoxicity Syndromes/etiology ; Neurons/drug effects ; }, abstract = {Cadmium (Cd) induced neurotoxicity has become a growing concern due to its potential adverse effects on the Central Nervous System. Cd is a Heavy Metal (HM) that is released into the environment, through several industrial processes. It poses a risk to the health of the community by polluting air, water, and soil. Cd builds up in the brain and other neural tissues, raising concerns about its effect on the nervous system due to its prolonged biological half-life. Cd can enter into the neurons, hence increasing the production of Reactive Oxygen Species (ROS) in them and impairing their antioxidant defenses. Cd disrupts the Calcium (Ca[2+]) balance in neurons, affects the function of the mitochondria, and triggers cell death pathways. As a result of these pathways, the path to the development of many neurological diseases affected by environmental factors, especially Cd, such as Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) is facilitated. There are cognitive deficits associated with long exposure to Cd. Memory disorders are present in both animals and humans. Cd alters the brain's function and performance in critical periods. There are lifelong consequences of Cd exposure during critical brain development stages. The susceptibility to neurotoxic effects is increased by interactions with a variety of risk factors. Cd poses risks to neuronal function and behavior, potentially contributing to neurodegenerative diseases like Parkinson's disease (PD) and AD as well as cognitive issues. This article offers a comprehensive overview of Cd-induced neurotoxicity, encompassing risk assessment, adverse effect levels, and illuminating intricate pathways.}, } @article {pmid39185513, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J}, title = {Prognostic Clinical and Biological Markers for Amyotrophic Lateral Sclerosis Disease Progression: Validation and Implications for Clinical Trial Design and Analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39185513}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; R01 AG066152/AG/NIA NIH HHS/United States ; U01 NS107027/NS/NINDS NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; T32 AG076411/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.

METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.

FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of ~0.5 and 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ~25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.

INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.

FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, } @article {pmid39185360, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Doretti, A and Boscarino, M and Maderna, L and Colombo, E and Soranna, D and Zambon, A and Ticozzi, N and Musumeci, G and Capone, F and Silani, V}, title = {Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101019}, pmid = {39185360}, issn = {2666-7762}, abstract = {BACKGROUND: Enhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS.

METHODS: In this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed.

FINDINGS: Forty participants were randomly assigned to real (n = 21) or placebo stimulation (n = 19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean ± Standard deviation; Real: 1.02 ± 0.62, Sham: 1.02 ± 0.57, p-value = 1.00) and treatment period (Real: 0.90 ± 0.55, Sham: 0.94 ± 0.55, p-value = 0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio = 0.27 95% Confidence interval 0.09-0.80, p-value = 0.019).

INTERPRETATION: tSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies.

FUNDING: The "Fondazione 'Nicola Irti' per le opere di carità e di cultura", Rome, Italy, supported present study.}, } @article {pmid39184484, year = {2024}, author = {Ozceylan, O and Sezgin-Bayindir, Z}, title = {Current Overview on the Use of Nanosized Drug Delivery Systems in the Treatment of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {9}, number = {33}, pages = {35223-35242}, pmid = {39184484}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, prion disease, and Huntington's disease, present a growing health concern as human life expectancy increases. Despite this, effective treatments to halt disease progression remain elusive due to various factors, including challenges in drug delivery across physiological barriers like the blood-brain barrier and patient compliance issues leading to treatment discontinuation. In response, innovative treatment approaches leveraging noninvasive techniques with higher patient compliance are emerging as promising alternatives. This Review aims to synthesize current treatment options and the challenges encountered in managing neurodegenerative diseases, while also exploring innovative treatment modalities. Specifically, noninvasive strategies such as intranasal administration and nanosized drug delivery systems are gaining prominence for their potential to enhance treatment efficacy and patient adherence. Nanosized drug delivery systems, including liposomes, polymeric micelles, and nanoparticles, are evaluated within the context of outstanding studies. The advantages and disadvantages of these approaches are discussed, providing insights into their therapeutic potential and limitations. Through this comprehensive examination, this Review contributes to the ongoing discourse surrounding the development of effective treatments for neurodegenerative diseases.}, } @article {pmid39184100, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-4750719/v1}, pmid = {39184100}, issn = {2693-5015}, abstract = {Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.}, } @article {pmid39183919, year = {2024}, author = {Ma, S and Cao, Y and Shi, YF and Shang, C and He, L and Liu, ZP}, title = {Data-driven discovery of active phosphine ligand space for cross-coupling reactions.}, journal = {Chemical science}, volume = {15}, number = {33}, pages = {13359-13368}, pmid = {39183919}, issn = {2041-6520}, abstract = {The design of highly active catalysts is a main theme in organic chemistry, but it still relies heavily on expert experience. Herein, powered by machine-learning global structure exploration, we forge a Metal-Phosphine Catalyst Database (MPCD) with a meticulously designed ligand replacement energy metric, a key descriptor to describe the metal-ligand interactions. It pushes the rational design of organometallic catalysts to a quantitative era, where a ±10 kJ mol[-1] window of relative ligand binding strength, a so-called active ligand space (ALS), is identified for highly effective catalyst screening. We highlight the chemistry interpretability and effectiveness of ALS for various C-N, C-C and C-S cross-coupling reactions via a Sabatier-principle-based volcano plot and demonstrate its predictive power in discovering low-cost ligands in catalyzing Suzuki cross-coupling involving aryl chloride. The advent of the MPCD provides a data-driven new route for speeding up organometallic catalysis and other applications.}, } @article {pmid39183185, year = {2024}, author = {Adiningrat, DP and Schlund, M and Skidmore, AK and Abdullah, H and Wang, T and Heurich, M}, title = {Mapping temperate old-growth forests in Central Europe using ALS and Sentinel-2A multispectral data.}, journal = {Environmental monitoring and assessment}, volume = {196}, number = {9}, pages = {841}, pmid = {39183185}, issn = {1573-2959}, support = {397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; }, mesh = {*Forests ; *Environmental Monitoring/methods ; Europe ; *Remote Sensing Technology ; Conservation of Natural Resources/methods ; Biodiversity ; Satellite Imagery ; Climate Change ; Lasers ; }, abstract = {Old-growth forests are essential to preserve biodiversity and play an important role in sequestering carbon and mitigating climate change. However, their existence across Europe is vulnerable due to the scarcity of their distribution, logging, and environmental threats. Therefore, providing the current status of old-growth forests across Europe is essential to aiding informed conservation efforts and sustainable forest management. Remote sensing techniques have proven effective for mapping and monitoring forests over large areas. However, relying solely on remote sensing spectral or structural information cannot capture comprehensive horizontal and vertical structure complexity profiles associated with old-growth forest characteristics. To overcome this issue, we combined spectral information from Sentinel-2A multispectral imagery with 3D structural information from high-density point clouds of airborne laser scanning (ALS) imagery to map old-growth forests over an extended area. Four features from the ALS data and fifteen from Sentinel-2A comprising raw band (spectral reflectance), vegetation indices (VIs), and texture were selected to create three datasets used in the classification process using the random forest algorithm. The results demonstrated that combining ALS and Sentinel-2A features improved the classification performance and yielded the highest accuracy for old-growth class, with an F1-score of 92% and producer's and user's accuracies of 93% and 90%, respectively. The findings suggest that features from ALS and Sentinel-2A data sensitive to forest structure are essential for identifying old-growth forests. Integrating open-access satellite imageries, such as Sentinel-2A and ALS data, can benefit forest managers, stakeholders, and conservationists in monitoring old-growth forest preservation across a broader spatial extent.}, } @article {pmid39182937, year = {2024}, author = {Silva, ST and Costa, IM and Souza, AA and Pondofe, K and Melo, LP and Resqueti, VR and Valentim, R and Gonçalves, F and Ribeiro, TS}, title = {Physical therapy for the management of global function, fatigue and quality of life in amyotrophic lateral sclerosis: systematic review and meta-analyses.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e076541}, pmid = {39182937}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Quality of Life ; *Physical Therapy Modalities ; *Fatigue/therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVES: To critically evaluate the effectiveness of physical therapy interventions in improving global function, quality of life and fatigue in individuals with amyotrophic lateral sclerosis (ALS).

DESIGN: Systematic review and meta-analyses.

DATA SOURCES: MEDLINE, EMBASE, Cochrane Library (CENTRAL) and Physiotherapy Evidence Database (PEDro) were searched through 31 January 2023.

ELIGIBILITY CRITERIA: We included randomised clinical trials (RCTs) that compared physical therapy interventions that act on global function, fatigue and quality of life in individuals with ALS with any other non-physiotherapeutic methods and techniques, placebo or non-intervention. The primary outcome measure was the evaluation of global function. Secondary outcomes were quality of life, fatigue and adverse events.

DATA EXTRACTION AND SYNTHESIS: Two independent authors used a researcher-developed extraction form and the Rayyan software to search, screen and code included studies. The risk of bias was assessed using the PEDro scale. Meta-analyses were conducted employing random effects. Outcomes were succinctly presented in Grading of Recommendations, Assessment, Development and Evaluation evidence profiles.

RESULTS: Our searches identified 39 415 references. After study selection, three studies were included in the review. Such studies involved 62 participants with a mean age of 54.6 years. In the evaluated trials, 40 were male, while 22 participants were female. Regarding the type of onset of the disease, 58 participants had spinal onset of ALS, and four had bulbar.

CONCLUSIONS: Physical therapy intervention may improve the global function of individuals with ALS in the short term; however, clinically, it was inconclusive. In terms of quality of life and fatigue, physical therapy intervention is not more effective than control in the short term. Adverse events are not increased by physical therapy intervention in the short term. Due to significant methodological flaws, small sample sizes, wide CIs and clinical interpretation, our confidence in the effect estimate is limited.

PROSPERO REGISTRATION NUMBER: CRD42021251350.}, } @article {pmid39182589, year = {2024}, author = {Pupillo, E and Bianchi, E and Bonetto, V and Pasetto, L and Bendotti, C and Paganoni, S and Mandrioli, J and Mazzini, L and , }, title = {Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {122}, number = {}, pages = {456-462}, doi = {10.1016/j.bbi.2024.08.044}, pmid = {39182589}, issn = {1090-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; Middle Aged ; Double-Blind Method ; Vital Capacity ; Aged ; *Disease Progression ; Biomarkers/blood ; Treatment Outcome ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS).

OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.

STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.

RESULTS: Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3 years in low NfL - placebo group; 1.9 years in high NfL - RNS60 group; 1.8 years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 - RNS60 group; 2.3 years in low MCP-1 - placebo group; 2.8 years in high MCP-1 - RNS60 group; 2.6 years in high MCP-1 - placebo group) levels at baseline.

CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.

TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.}, } @article {pmid39182251, year = {2024}, author = {Peng, Y and Liu, G and Li, S and Li, Z and Song, J}, title = {A machine learning system for artificial ligaments with desired mechanical properties in ACL reconstruction applications.}, journal = {Journal of the mechanical behavior of biomedical materials}, volume = {159}, number = {}, pages = {106691}, doi = {10.1016/j.jmbbm.2024.106691}, pmid = {39182251}, issn = {1878-0180}, mesh = {*Machine Learning ; *Mechanical Phenomena ; *Anterior Cruciate Ligament Reconstruction/methods ; Materials Testing ; Humans ; Anterior Cruciate Ligament/surgery ; Neural Networks, Computer ; Biomechanical Phenomena ; Ligaments/surgery ; Artificial Organs ; Mechanical Tests ; }, abstract = {The anterior cruciate ligament is one of the important tissues to maintain the stability of the human knee joint, but it is difficult for this ligament to self-heal after injury. Consequently, transplantation of artificial ligaments (ALs) has gained widespread attention as an important alternative treatment method in recent years. However, accurately predicting the intricate mechanical properties of ALs remains a formidable challenge, particularly when employing theoretical frameworks such as braiding theory. This obstacle presents a significant impediment to achieving optimal AL design. Therefore, in this study, a high-precision machine learning model based on an artificial neural network was developed to rapidly and accurately predict the mechanical properties of ALs. The results showed that the proposed model achieved a reduction of 45.22% and 50.17% in the normalized root mean square error on the testing set when compared to traditional machine learning models (Random Forest and Support Vector Machine), demonstrating its higher accuracy. In addition, the design of ALs with desired mechanical properties was achieved by optimizing the braiding parameters, and its effectiveness was verified through experiments. The mechanical properties of the prepared ALs were able to fully meet the desired targets and were at least 2% higher. Finally, the influence weights of different braiding parameters on the mechanical properties of ALs were analyzed by feature importance.}, } @article {pmid39182178, year = {2024}, author = {Serizawa, S}, title = {Exploration of the Factors Impacting Sustained Clinical Care by Multidisciplinary Professionals for Amyotrophic Lateral Sclerosis.}, journal = {The Tokai journal of experimental and clinical medicine}, volume = {49}, number = {3}, pages = {110-116}, pmid = {39182178}, issn = {2185-2243}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Surveys and Questionnaires ; *Patient Care Team ; Japan ; Female ; Male ; Self-Assessment ; Motivation ; Health Personnel ; Middle Aged ; Adult ; Time Factors ; }, abstract = {OBJECTIVE: This study examined the experiences of multidisciplinary medical professionals in providing daily clinical care for patients with amyotrophic lateral sclerosis (ALS), with a focus placed on their persistence in sustaining clinical care for this patient group.

METHODS: A questionnaire survey was administered to multidisciplinary medical professionals involved in ALS care at three hospitals in western Kanagawa Prefecture, Japan. The questionnaire results were used to examine the relationships between years of medical experience, years of ALS care experience, self-evaluation, and motivation to continue providing clinical care to patients with ALS.

RESULTS: Of the 269 questionnaires distributed and 164 collected by the multidisciplinary medical professionals, 143 (53%) were deemed valid. Analysis revealed an association between "years of medical experience" with both "self-assessment of clinical care for ALS patients practice experience" and "commitment to continue clinical care for ALS patients," as well as between "years of ALS medical experience" and "self-assessment of clinical care for ALS patients."

CONCLUSION: Medical professionals with more than ten years of medical experience expressed their commitment to continue providing medical care in a comprehensive self-assessment of both the positive and negative aspects of their practice. Negative evaluations can be used to identify and improve ALS medical practices.}, } @article {pmid39182146, year = {2024}, author = {Kill, C and Manegold, RK and Fistera, D and Risse, J}, title = {Airway management and ventilation techniques in resuscitation during advanced life support: an update.}, journal = {Journal of anesthesia, analgesia and critical care}, volume = {4}, number = {1}, pages = {58}, pmid = {39182146}, issn = {2731-3786}, abstract = {For many years, ventilation has been an essential part of advanced life support (ALS) in cardiopulmonary resuscitation (CPR). Nevertheless, there is little evidence about the best method of ventilation during resuscitation for both out-of-hospital cardiac arrest (OHCA) and inhospital cardiac arrest (IHCA) patients. Effective ventilation is one of the two main keys to successful resuscitation. In this context, the question always arises as to which airway management, along with which ventilation mode, constitutes the best strategy. Conventional ventilation modes are not designed for cardiac arrest and show important limitations that must be considered when used in CPR. Manual ventilation without the use of an automated transport ventilator (ATV) could be shown to be uncontrolled in applied volumes and pressures and should be avoided. Mechanical ventilation with an ATV is therefore superior to manual ventilation, but both volume- and pressure-controlled ventilation modes are significantly influenced by chest compressions. With the newly designed chest compression synchronized ventilation (CCSV), a special ventilation mode for resuscitation is available. Further research should be conducted to obtain more evidence of the effect of ventilation during CPR on outcomes following OHCA and not only about how to secure the airway for ventilation during CPR.}, } @article {pmid39181624, year = {2024}, author = {Mousele, C and Holden, D and Gnanapavan, S}, title = {Neurofilaments in neurologic disease.}, journal = {Advances in clinical chemistry}, volume = {123}, number = {}, pages = {65-128}, doi = {10.1016/bs.acc.2024.06.010}, pmid = {39181624}, issn = {2162-9471}, mesh = {Humans ; *Nervous System Diseases/pathology/metabolism/diagnosis ; *Biomarkers ; Neurofilament Proteins/cerebrospinal fluid/metabolism ; Intermediate Filaments/metabolism ; Animals ; }, abstract = {Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.}, } @article {pmid39181183, year = {2024}, author = {Ko, YH and Lokareddy, RK and Doll, SG and Yeggoni, DP and Girdhar, A and Mawn, I and Klim, JR and Rizvi, NF and Meyers, R and Gillilan, RE and Guo, L and Cingolani, G}, title = {Single Acetylation-mimetic Mutation in TDP-43 Nuclear Localization Signal Disrupts Importin α1/β Signaling.}, journal = {Journal of molecular biology}, volume = {436}, number = {20}, pages = {168751}, pmid = {39181183}, issn = {1089-8638}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; S10 OD017987/OD/NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; R35 GM140733/GM/NIGMS NIH HHS/United States ; S10 OD023479/OD/NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {*Nuclear Localization Signals/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *alpha Karyopherins/metabolism/genetics ; *beta Karyopherins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Acetylation ; *Signal Transduction ; Mutation ; Protein Processing, Post-Translational ; Active Transport, Cell Nucleus ; Protein Binding ; Cell Nucleus/metabolism ; }, abstract = {Cytoplasmic aggregation of the TAR-DNA binding protein of 43 kDa (TDP-43) is the hallmark of sporadic amyotrophic lateral sclerosis (ALS). Most ALS patients with TDP-43 aggregates in neurons and glia do not have mutations in the TDP-43 gene but contain aberrantly post-translationally modified TDP-43. Here, we found that a single acetylation-mimetic mutation (K82Q) near the TDP-43 minor Nuclear Localization Signal (NLS) box, which mimics a post-translational modification identified in an ALS patient, can lead to TDP-43 mislocalization to the cytoplasm and irreversible aggregation. We demonstrate that the acetylation mimetic disrupts binding to importins, halting nuclear import and preventing importin α1/β anti-aggregation activity. We propose that perturbations near the NLS are an additional mechanism by which a cellular insult other than a genetically inherited mutation leads to TDP-43 aggregation and loss of function. Our findings are relevant to deciphering the molecular etiology of sporadic ALS.}, } @article {pmid39181135, year = {2024}, author = {Wu, R and Ye, Y and Dong, D and Zhang, Z and Wang, S and Li, Y and Wright, N and Redding-Ochoa, J and Chang, K and Xu, S and Tu, X and Zhu, C and Ostrow, LW and Roca, X and Troncoso, JC and Wu, B and Sun, S}, title = {Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3434-3451.e11}, pmid = {39181135}, issn = {1097-4199}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice ; Animals ; *RNA Splicing/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Neurons/metabolism ; Male ; Female ; }, abstract = {Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.}, } @article {pmid39180957, year = {2024}, author = {Harkins, AL and Ambegaokar, PP and Keeler, AM}, title = {Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {4}, pages = {e00435}, pmid = {39180957}, issn = {1878-7479}, mesh = {Humans ; *Dependovirus/genetics/immunology ; *Genetic Therapy/methods ; *Genetic Vectors/immunology/administration & dosage ; Animals ; Central Nervous System/immunology ; Gene Transfer Techniques ; Central Nervous System Diseases/therapy/immunology ; }, abstract = {Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.}, } @article {pmid39180748, year = {2024}, author = {Liu, Z and Zhang, H and Lu, K and Chen, L and Zhang, Y and Xu, Z and Zhou, H and Sun, J and Xu, M and Ouyang, Q and Thompson, GJ and Yang, Y and Su, N and Cai, X and Cao, L and Zhao, Y and Jiang, L and Zheng, Y and Zhang, X}, title = {Low-intensity pulsed ultrasound modulates disease progression in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114660}, doi = {10.1016/j.celrep.2024.114660}, pmid = {39180748}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Disease Progression ; *Ultrasonic Waves ; *Mice, Transgenic ; *Motor Cortex/pathology/metabolism ; TRPV Cation Channels/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Cerebrovascular Circulation ; Ultrasonic Therapy/methods ; Mice, Inbred C57BL ; Male ; Endothelial Cells/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord, and there are no effective drug treatments. Low-intensity pulsed ultrasound (LIPUS) has garnered attention as a promising noninvasive neuromodulation method. In this study, we investigate its effects on the motor cortex and underlying mechanisms using the SOD1[G93A] mouse model of ALS. Our results show that LIPUS treatment delays disease onset and prolongs lifespan in ALS mice. LIPUS significantly increases cerebral blood flow in the motor cortex by preserving vascular endothelial cell integrity and increasing microvascular density, which may be mediated via the ion channel TRPV4. RNA sequencing analysis reveals that LIPUS substantially reduces the expression of genes associated with neuroinflammation. These findings suggest that LIPUS applied to the motor cortex may represent a potentially effective therapeutic tool for the treatment of ALS.}, } @article {pmid39180568, year = {2024}, author = {Yang, J and Tang, C}, title = {Causal relationship between imaging-derived phenotypes and neurodegenerative diseases: a Mendelian randomization study.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {35}, number = {4}, pages = {711-723}, pmid = {39180568}, issn = {1432-1777}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/diagnostic imaging ; *Phenotype ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Alzheimer Disease/genetics/diagnostic imaging ; Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Parkinson Disease/genetics/diagnostic imaging ; Brain/diagnostic imaging/pathology/metabolism ; Multiple Sclerosis/genetics/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies.}, } @article {pmid39180054, year = {2024}, author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A}, title = {User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {42}, pmid = {39180054}, issn = {2524-3489}, abstract = {OBJECTIVE: Robotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device.

METHODS: A prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4-6; range 0-12 points). User expectations before provision (expectation group, n = 85) and user experiences after provision (experience group, n = 14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed.

RESULTS: In the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0-9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n = 85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n = 14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n = 10), and 28.6% (n = 4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was + 57 demonstrating strong patient satisfaction.

CONCLUSIONS: Initiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.}, } @article {pmid39179240, year = {2025}, author = {Sisti, HM and Beebe, A and Gabrielsson, E and Bishop, M}, title = {Postmovement Beta Rebound in Real and Imagined Movement.}, journal = {Motor control}, volume = {29}, number = {1}, pages = {53-68}, doi = {10.1123/mc.2023-0033}, pmid = {39179240}, issn = {1087-1640}, mesh = {Humans ; *Imagination/physiology ; Male ; Female ; Adult ; *Beta Rhythm/physiology ; *Electroencephalography ; *Movement/physiology ; *Psychomotor Performance/physiology ; Young Adult ; Sensorimotor Cortex/physiology ; }, abstract = {Movement disorders, such as stroke and amyotrophic lateral sclerosis, result in loss of upper limb function and, hence, severe impairments of bimanual coordination. Although motor imagery is increasingly used to enhance neurorehabilitation, cognitive and neurophysiological parameters that inform effective strategies remain elusive. The aim of the present study is to elucidate the neural dynamics that underlie learning during real and imagined movement using both unimanual and bimanual coordination patterns. The post movement beta rebound (PMBR) has been implicated as a biomarker of motor control and therefore was the focus of this study. Healthy adults (n = 21) learned a visuomotor tracking task in a single session using either one or both hands while brainwaves were captured using electroencephalography. Postmovement beta rebound was evident in the sensorimotor cortex for both unimanual and bimanual conditions. Task-related power of the beta band demonstrated that actual unimanual movement requires greater contralateral activity compared with both actual bimanual movement and imagined movement of either condition. Notably, the PMBR was evident even in imagined movement, although to a lesser extent than real movement. Neurophysiological results support a functional role for beta band in movement. Results of these data may inform neurorehabilitation strategies for patients recovering from movement disorders of the upper limbs.}, } @article {pmid39178140, year = {2024}, author = {Briois, V and Itié, JP and Polian, A and King, A and Traore, AS and Marceau, E and Ersen, O and La Fontaine, C and Barthe, L and Beauvois, A and Roudenko, O and Belin, S}, title = {Hyperspectral full-field quick-EXAFS imaging at the ROCK beamline for monitoring micrometre-sized heterogeneity of functional materials under process conditions.}, journal = {Journal of synchrotron radiation}, volume = {31}, number = {Pt 5}, pages = {1084-1104}, pmid = {39178140}, issn = {1600-5775}, support = {ANR-10-EQPX-0045//Agence Nationale de la Recherche/ ; ANR-20-CE42-007//Agence Nationale de la Recherche/ ; ANR-07-Stock-E-0 PULSSE//Agence Nationale de la Recherche/ ; }, abstract = {Full-field transmission X-ray microscopy has been recently implemented at the hard X-ray ROCK-SOLEIL quick-EXAFS beamline, adding micrometre spatial resolution to the second time resolution characterizing the beamline. Benefiting from a beam size versatility due to the beamline focusing optics, full-field hyperspectral XANES imaging has been successfully used at the Fe K-edge for monitoring the pressure-induced spin transition of a 150 µm × 150 µm Fe(o-phen)2(NCS)2 single crystal and the charge of millimetre-sized LiFePO4 battery electrodes. Hyperspectral imaging over 2000 eV has been reported for the simultaneous monitoring of Fe and Cu speciation changes during activation of a FeCu bimetallic catalyst along a millimetre-sized catalyst bed. Strategies of data acquisition and post-data analysis using Jupyter notebooks and multivariate data analysis are presented, and the gain obtained using full-field hyperspectral quick-EXAFS imaging for studies of functional materials under process conditions in comparison with macroscopic information obtained by non-spatially resolved quick-EXAFS techniques is discussed.}, } @article {pmid39177232, year = {2024}, author = {Witzel, S and Huss, A and Nagel, G and Rosenbohm, A and Rothenbacher, D and Peter, RS and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Naegele, A and Sommer, N and Lindner, A and Alexudis, C and Bachhuber, F and Halbgebauer, S and Brenner, D and Ruf, W and Weiland, U and Mayer, B and Schuster, J and Dorst, J and Tumani, H and Ludolph, AC and , }, title = {Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1040-1057}, doi = {10.1002/ana.27054}, pmid = {39177232}, issn = {1531-8249}, support = {577631//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Biomarkers/blood ; *Neurofilament Proteins/blood ; Middle Aged ; Female ; Male ; Aged ; Prognosis ; Intermediate Filaments/metabolism ; Adult ; }, abstract = {OBJECTIVE: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.

METHODS: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.

RESULTS: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.

INTERPRETATION: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.}, } @article {pmid39177131, year = {2024}, author = {Sheremeta, CL and Yarlagadda, S and Smythe, ML and Noakes, PG}, title = {Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets.}, journal = {Current drug targets}, volume = {25}, number = {13}, pages = {885-908}, pmid = {39177131}, issn = {1873-5592}, support = {Project grant,//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Prostaglandins/metabolism ; Animals ; *Central Nervous System/metabolism/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Signal Transduction/drug effects ; Multiple Sclerosis/drug therapy/metabolism ; Inflammation/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.}, } @article {pmid39176909, year = {2024}, author = {Tiffet, T and Pikaar, A and Trombert-Paviot, B and Jaulent, MC and Bousquet, C}, title = {Comparing a Large Language Model with Previous Deep Learning Models on Named Entity Recognition of Adverse Drug Events.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {781-785}, doi = {10.3233/SHTI240528}, pmid = {39176909}, issn = {1879-8365}, mesh = {*Deep Learning ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; Natural Language Processing ; Adverse Drug Reaction Reporting Systems ; }, abstract = {The ability to fine-tune pre-trained deep learning models to learn how to process a downstream task using a large training set allow to significantly improve performances of named entity recognition. Large language models are recent models based on the Transformers architecture that may be conditioned on a new task with in-context learning, by providing a series of instructions or prompt. These models only require few examples and such approach is defined as few shot learning. Our objective was to compare performances of named entity recognition of adverse drug events between state of the art deep learning models fine-tuned on Pubmed abstracts and a large language model using few-shot learning. Hussain et al's state of the art model (PMID: 34422092) significantly outperformed the ChatGPT-3.5 model (F1-Score: 97.6% vs 86.0%). Few-shot learning is a convenient way to perform named entity recognition when training examples are rare, but performances are still inferior to those of a deep learning model fine-tuned with several training examples. Perspectives are to evaluate few-shot prompting with GPT-4 and perform fine-tuning on GPT-3.5.}, } @article {pmid39176644, year = {2024}, author = {Turner, J and Impey, S and Gibbons, F and Bolger, A and Stephens, G and Hederman, L and Hamed, R and O'Meara, C and de la Varga, F and Kommala, J and Nicholson, M and Farrell, D and Galvin, M and Heverin, M and Mac Domhnaill, É and McFarlane, R and Meldrum, D and Murray, D and Hardiman, O}, title = {Data and Process Harmonisation of Multi-National, Multi-Site Research Data.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {1411-1412}, doi = {10.3233/SHTI240675}, pmid = {39176644}, issn = {1879-8365}, mesh = {Humans ; *Data Collection ; Amyotrophic Lateral Sclerosis/therapy ; Biomedical Research ; }, abstract = {To achieve a single fully harmonised research data set suitable for analysis from data collected at multiple sites requires not only semantic integration of collection concepts and convergence onto single collection units, but harmonisation of data collection processes. We describe our experience of identifying harmonisation challenges in the Precision ALS project, with particular focus on process alignment challenges in a multi-site multi-national research data collection project.}, } @article {pmid39176177, year = {2024}, author = {Al Dera, H and AlQahtani, B}, title = {Molecular mechanisms and antisense oligonucleotide therapies of familial amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102271}, pmid = {39176177}, issn = {2162-2531}, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, presents considerable challenges in both diagnosis and treatment. It is categorized into sporadic and familial amyotrophic lateral sclerosis (fALS); the latter accounts for approximately 10% of cases and is primarily inherited in an autosomal dominant manner. This review summarizes the molecular genetics of fALS, highlighting key mutations that contribute to its pathogenesis, such as mutations in SOD1, FUS, and C9orf72. Central to this discourse is exploring antisense oligonucleotides (ASOs) that target these genetic aberrations, providing a promising therapeutic strategy. This review provides a detailed overview of the molecular mechanisms underlying fALS and the potential therapeutic value of ASOs, offering new insights into treating neurodegenerative diseases.}, } @article {pmid39175128, year = {2024}, author = {Wu, A and Lee, D and Xiong, WC}, title = {VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.}, journal = {Expert opinion on therapeutic targets}, volume = {28}, number = {8}, pages = {701-712}, pmid = {39175128}, issn = {1744-7631}, support = {R01 AG045781/AG/NIA NIH HHS/United States ; RF1 AG045781/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/drug therapy ; *Vesicular Transport Proteins/metabolism ; Animals ; *Molecular Targeted Therapy ; Protein Transport ; Parkinson Disease/physiopathology/drug therapy ; Mutation, Missense ; Drug Development ; }, abstract = {INTRODUCTION: Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge.

AREAS COVERED: This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target.

EXPERT OPINION: VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.}, } @article {pmid39174972, year = {2024}, author = {Zhou, J and Li, F and Jia, B and Wu, Z and Huang, Z and He, M and Weng, H and So, KF and Qu, W and Fu, QL and Zhou, L}, title = {Intranasal delivery of small extracellular vesicles reduces the progress of amyotrophic lateral sclerosis and the overactivation of complement-coagulation cascade and NF-ĸB signaling in SOD1[G93A] mice.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {503}, pmid = {39174972}, issn = {1477-3155}, support = {202310183302//2023 University Innovation and Entrepreneurship Training Plan/ ; 2022YFA1104900//National Key Research and Development Program of China/ ; 2021B1515120062//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023B03J1233, 20220600003//Guangzhou Key R&D Program/ ; }, mesh = {Animals ; Male ; Mice ; Administration, Intranasal ; *Amyotrophic Lateral Sclerosis/metabolism ; Blood Coagulation ; Disease Models, Animal ; *Extracellular Vesicles/metabolism ; Mesenchymal Stem Cells/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motoneuron degeneration, and effective clinical treatments are lacking. In this study, we evaluated whether intranasal delivery of mesenchymal stem cell-derived small extracellular vesicles (sEVs) is a strategy for ALS therapy using SOD1[G93A] mice. In vivo tracing showed that intranasally-delivered sEVs entered the central nervous system and were extensively taken up by spinal neurons and some microglia. SOD1[G93A] mice that intranasally received sEV administration showed significant improvements in motor performances and survival time. After sEV administration, pathological changes, including spinal motoneuron death and synaptic denervation, axon demyelination, neuromuscular junction degeneration and electrophysiological defects, and mitochondrial vacuolization were remarkably alleviated. sEV administration attenuated the elevation of proinflammatory cytokines and glial responses. Proteomics and transcriptomics analysis revealed upregulation of the complement and coagulation cascade and NF-ĸB signaling pathway in SOD1[G93A] mouse spinal cords, which was significantly inhibited by sEV administration. The changes were further confirmed by detecting C1q and NF-ĸB expression using Western blots. In conclusion, intranasal administration of sEVs effectively delays the progression of ALS by inhibiting neuroinflammation and overactivation of the complement and coagulation cascades and NF-ĸB signaling pathway and is a potential option for ALS therapy.}, } @article {pmid39174694, year = {2024}, author = {Layalle, S and Aimond, F and Brugioti, V and Guissart, C and Raoul, C and Soustelle, L}, title = {The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19540}, pmid = {39174694}, issn = {2045-2322}, mesh = {Animals ; *Kinesins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Humans ; Drosophila Proteins/genetics/metabolism ; Drosophila ; Neuromuscular Junction/metabolism/pathology ; Drosophila melanogaster/genetics ; Synaptic Transmission/genetics ; Disease Models, Animal ; Axons/metabolism/pathology ; Larva/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS.}, } @article {pmid39174305, year = {2025}, author = {Mohamed Yusoff, AA and Mohd Khair, SZN}, title = {Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {1}, pages = {53-90}, pmid = {39174305}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Mitochondria/metabolism ; Animals ; Mitochondrial Dynamics/physiology ; Mitochondrial Diseases/metabolism ; Mitophagy/physiology ; }, abstract = {Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.}, } @article {pmid39174072, year = {2024}, author = {Yoon, R and Wong, JP and Chung-Lee, L and Akbarian, A and Abdulai, AF and Hou, R and Ho, M and Zinaic, R and Anoushka, A}, title = {Scoping review protocol: what is the state of evidence for the use of communication apps with immigrant seniors in long-term care and community settings?.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e089939}, pmid = {39174072}, issn = {2044-6055}, mesh = {Humans ; *Emigrants and Immigrants ; *Long-Term Care ; *Mobile Applications ; Aged ; Research Design ; Review Literature as Topic ; Communication Barriers ; }, abstract = {INTRODUCTION: First language care is critical for older immigrant adults with limited English proficiency, especially in long-term care settings where most residents require staff assistance and experience complex chronic conditions, resulting in multiple communication interactions where language poses a barrier. Although there are a myriad of cultural-language translation apps and devices available, there is a gap in both research and practice on the acceptability and feasibility of these digital resources within the context of long-term care and community settings for older immigrant adults, from a cultural relevance and digital health equity perspective. Our paper outlines a scoping review protocol to examine the state of the literature on the extent to which cultural-language translation apps are used in long-term care settings and community-based elder care. We will also examine the extent to which such apps bridge or further gaps in equitable, accessible and acceptable care for older immigrant adults with limited English language proficiency.

METHODS AND ANALYSIS: This scoping review protocol will employ an adapted five-stage framework outlined by Arksey and O'Malley guided by enhancements recommended by Levac et al and Colquhoun et al. Using the Joanna Briggs Institute's population, concept and context framework, we defined the scope of the scoping review by identifying the target population, concepts for investigation and the context within which the research is situated. We will conduct a search of the literature from 2005 to 2024 using five bibliographic databases from health sciences (Healthstar OVID, MEDLINE OVID and Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO), engineering (Engineering Village Elsevier) and a cross-disciplinary database (Web of Science Clarivate). The research team will adopt a critical, equity-focused approach for the scoping review by integrating Richardson et al's framework for Digital Health Equity into our analysis of the findings. This will ensure that health and social equity perspectives are integrated within our methodology and analytical lens. Our analysis will specifically examine selected studies for their engagement with health equity and their ability to address issues such as ageism, ableism and the digital divide within geriatric care.

ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review as it involves secondary analysis of published works and no primary data collection involving human subjects. Findings of the review will be shared with community partners and disseminated through publications, conferences and peer-reviewed publications.}, } @article {pmid39174002, year = {2024}, author = {Javaudin, F and Papin, M and Le Bastard, Q and Thibault, M and Boishardy, T and Brau, F and Laribi, S and Petrovic, T and Peluchon, T and Markarian, T and Volteau, C and Arnaudet, I and Pes, P and Le Conte, P}, title = {Early point-of-care echocardiography as a predictive factor for absence of return of spontaneous circulatory in out-of-hospital cardiac arrests: A multicentre observational study.}, journal = {Resuscitation}, volume = {203}, number = {}, pages = {110373}, doi = {10.1016/j.resuscitation.2024.110373}, pmid = {39174002}, issn = {1873-1570}, mesh = {Humans ; Male ; Female ; *Out-of-Hospital Cardiac Arrest/therapy ; Aged ; Prospective Studies ; Middle Aged ; *Echocardiography/methods ; *Cardiopulmonary Resuscitation/methods ; *Return of Spontaneous Circulation ; *Predictive Value of Tests ; Point-of-Care Systems ; Prognosis ; }, abstract = {INTRODUCTION: Early assessment of the prognosis of a patient in cardiac arrest during cardiopulmonary resuscitation is highly challenging. This study aims to evaluate the predictive outcome value of early point-of-care ultrasound (POCUS) in out-of-hospital settings.

METHODS: This observational, prospective, multicentre study's primary endpoint was the positive predictive value (PPV) of POCUS cardiac standstill within the first 12 min of advanced life support (ALS) initiation in determining the absence of return of spontaneous circulation (ROSC). A multivariate logistic regression model was constructed with adjustments for known predictive variables typically used in termination of resuscitation (TOR) rules.

RESULTS: A total of 293 patients were analysed, with a mean age of 66.6 ± 14.6 years, and a majority were men (75.8%). POCUS was performed on average 7.9 ± 2.6 min after ALS initiation. Among patients with cardiac standstill (72.4%), 16.0% achieved ROSC compared with 48.2% in those with visible cardiac motions. The PPV of early POCUS cardiac standstill for the absence of ROSC was 84.0%, 95% CI [78.3-88.6]. In multivariable analysis, only POCUS cardiac standstill (adjusted odds ratio [aOR] 3.89, 95% CI [1.86-8.17]) and end-tidal CO2 (ETCO2) value ≤37 mmHg (aOR 4.27, 95% CI [2.21-8.25]) were associated with the absence of ROSC.

CONCLUSION: Early POCUS cardiac standstill during CPR for out-of-hospital cardiac arrest was a reliable predictor of the absence of ROSC. However, its presence alone was not sufficient to determine the termination of resuscitation efforts.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03494153. Registered March 29, 2018.}, } @article {pmid39173710, year = {2024}, author = {Weber, MP and Strobel, RJ and Norman, AV and Kareddy, A and Young, A and Young, S and El Moheb, M and Noona, SWW and Wisniewski, AM and Quader, M and Mazzeffi, M and Yarboro, LT and Teman, NR}, title = {Cardiac Surgical Unit-Advanced Life Support-certified centers are associated with improved failure to rescue after cardiac arrest: A propensity score-matched analysis.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtcvs.2024.08.014}, pmid = {39173710}, issn = {1097-685X}, abstract = {OBJECTIVE: The impact of Cardiac Surgical Unit-Advanced Life Support (CSU-ALS) training on failure to rescue after cardiac arrest (FTR-CA) is unknown. We hypothesized that institutional CSU-ALS certification would be associated with lower FTR-CA.

METHODS: Patients undergoing Society of Thoracic Surgeons index operations from 2020 to 2023 from a regional collaborative were analyzed. Each institution was surveyed regarding its status as a CSU-ALS-certified center. Patients stratified by CSU-ALS certification were 1:1 propensity score matched with subsequent multivariable model reviewing associations with FTR-CA.

RESULTS: A total of 12,209 patients were included in the study period across 15 institutions. Eight centers reported CSU-ALS certification. After propensity score matching, 2 patient cohorts were formed (n = 3557). Patients at CSU-ALS centers had greater rates of intensive care unit readmission (3.9% vs 2.3%, P < .01) and total operating room time (340 minutes vs 323 minutes, P < .01). Hospital readmission was less likely in the CSU-ALS centers (9.0% vs 10.1%, P < .01). There was no difference in the rate of postoperative cardiac arrest (1.8% vs 2.2%, P = .24) or operative mortality (2.5% vs 2.9%, P = .30). After risk adjustment, CSU-ALS centers (odds ratio, 0.30; 95% confidence interval, 0.12-0.72, P < .01) and greater-volume centers (odds ratio, 0.15; confidence interval, 0.03-0.74, P = .02) had reduced odds of FTR-CA.

CONCLUSIONS: Centers with CSU-ALS certification are associated with a lower risk-adjusted likelihood of FTR-CA. This highlights the importance of well-trained staff and treatment algorithms in the care of patients postcardiac surgery.}, } @article {pmid39172789, year = {2024}, author = {Ahmed, R and Liang, M and Hudson, RP and Rangadurai, AK and Huang, SK and Forman-Kay, JD and Kay, LE}, title = {Atomic resolution map of the solvent interactions driving SOD1 unfolding in CAPRIN1 condensates.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {35}, pages = {e2408554121}, pmid = {39172789}, issn = {1091-6490}, support = {FND-503573//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; 2015-04347//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; FDN-148375//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; PJT-190060//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/genetics ; Humans ; *Solvents/chemistry ; Protein Unfolding ; Protein Binding ; Protein Folding ; Models, Molecular ; Stress Granules/metabolism/chemistry ; RNA-Binding Proteins/metabolism/chemistry ; Protein Conformation ; Magnetic Resonance Spectroscopy ; }, abstract = {Biomolecules can be sequestered into membrane-less compartments, referred to as biomolecular condensates. Experimental and computational methods have helped define the physical-chemical properties of condensates. Less is known about how the high macromolecule concentrations in condensed phases contribute "solvent" interactions that can remodel the free-energy landscape of other condensate-resident proteins, altering thermally accessible conformations and, in turn, modulating function. Here, we use solution NMR spectroscopy to obtain atomic resolution insights into the interactions between the immature form of superoxide dismutase 1 (SOD1), which can mislocalize and aggregate in stress granules, and the RNA-binding protein CAPRIN1, a component of stress granules. NMR studies of CAPRIN1:SOD1 interactions, focused on both unfolded and folded SOD1 states in mixed phase and demixed CAPRIN1-based condensates, establish that CAPRIN1 shifts the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble, with little change to the structure of the folded conformation. Key contacts between CAPRIN1 and the H80-H120 region of unfolded SOD1 are identified, as well as SOD1 interaction sites near both the arginine-rich and aromatic-rich regions of CAPRIN1. Unfolding of immature SOD1 in the CAPRIN1 condensed phase is shown to be coupled to aggregation, while a more stable zinc-bound, dimeric form of SOD1 is less susceptible to unfolding when solvated by CAPRIN1. Our work underscores the impact of the condensate solvent environment on the conformational states of resident proteins and supports the hypothesis that ALS mutations that decrease metal binding or dimerization function as drivers of aggregation in condensates.}, } @article {pmid39171600, year = {2024}, author = {Nogueira-Machado, JA and Lima E Silva, FDC and Rocha E Silva, F and Gomes, N}, title = {Amyotrophic Lateral Sclerosis (ALS): An Overview of Genetic and Metabolic Signaling Mechanisms.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273315891240801065231}, pmid = {39171600}, issn = {1996-3181}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and incurable disease. Sporadic (sALS) accounts for ninety percent of ALS cases, while familial ALS (fALS) accounts for around fifteen percent. Reports have identified over 30 different forms of familial ALS. Multiple types of fALS exhibit comparable symptoms with mutations in different genes and possibly with different predominant metabolic signals. Clinical diagnosis takes into account patient history but not genetic mutations, misfolded proteins, or metabolic signaling. As research on genetics and metabolic pathways advances, it is expected that the intricate complexity of ALS will compound further. Clinicians discuss whether a gene's presence is a cause of the disease or just an association or consequence. They believe that a mutant gene alone is insufficient to diagnose ALS. ALS, often perceived as a single disease, appears to be a complex collection of diseases with similar symptoms. This review highlights gene mutations, metabolic pathways, and muscle-neuron interactions.}, } @article {pmid39170988, year = {2024}, author = {Baroni, LM and Funari, MP and So Taa Kum, A and Bestetti, AM and de Oliveira, LB and de Carvalho, MF and Franzini, TAP and de Moura, DTH and Bernardo, WM and de Moura, EGH}, title = {Endoscopic Versus Surgical Treatment for Ampullary Lesions: A Systematic Review With Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e65076}, pmid = {39170988}, issn = {2168-8184}, abstract = {Ampullary lesions (ALs) can be treated through either an endoscopic approach (EA) or a surgical approach (SA). However, it is important to note that EAs carry a significant risk of incomplete resection, while opting for surgical interventions can result in substantial morbidity. We performed a systematic review and meta-analysis for R0 resection, recurrence, adverse events in general, major adverse events, mortality, and length of hospital stay between SAs and EAs. Electronic databases were searched from inception to 2023. We identified nine independent studies. The risk difference was -0.32 (95% CI: -0.50, -0.15; p <0.001) for R0, 0.12 (95% CI: 0.06, 0.19; p < 0.001) for recurrence, -0.22 (95% CI: -0.43, 0.00; p 0.05) for overall adverse events, -0.11 (95% CI: -0.32, 0.10; p = 0.31) for major complications, -0.01 (95% CI: -0.02, 0.01; p = 0.43) for mortality, and -14.69 (95% CI: -19.91, -9.47; p < 0.001) for length of hospital stay. As expected, our data suggest a higher complete resection rate and lower recurrence from surgical interventions, but this is associated with an elevated risk of adverse events and a longer hospital stay.}, } @article {pmid39170265, year = {2024}, author = {Pain, O and Jones, A and Al Khleifat, A and Agarwal, D and Hramyka, D and Karoui, H and Kubica, J and Llewellyn, DJ and Ranson, JM and Yao, Z and Iacoangeli, A and Al-Chalabi, A}, title = {Harnessing transcriptomic signals for amyotrophic lateral sclerosis to identify novel drugs and enhance risk prediction.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e35342}, pmid = {39170265}, issn = {2405-8440}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.

METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.

RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R [2] = 5.1 %; p-value = 3.2 × 10[-27]) and clinical characteristics.

CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.}, } @article {pmid39170125, year = {2024}, author = {Wenzhi, Y and Xiangyi, L and Dongsheng, F}, title = {The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e34963}, pmid = {39170125}, issn = {2405-8440}, abstract = {Pathological proteins in amyotrophic lateral sclerosis (ALS), such as superoxide dismutase 1, TAR DNA-binding protein 43, and fused in sarcoma, exhibit a prion-like pattern. All these proteins have a low-complexity domain and seeding activity in cells. In this review, we summarize the studies on the prion-like effect of these proteins and list six prion-like protein targeting strategies that we believe have potential for ALS therapy, including antisense oligonucleotides, antibody-based technology, peptide, protein chaperone, autophagy enhancement, and heteromultivalent compounds. Considering the pathological complexity and heterogeneity of ALS, we believe that the final solution to ALS therapy is most likely to be an individualized cocktail therapy, including clearance of toxicity, blockage of pathological progress, and protection of neurons.}, } @article {pmid39170062, year = {2024}, author = {Wang, H and Yao, G and He, K and Wang, Z and Cheng, CK}, title = {ACL reconstruction combined with anterolateral structures reconstruction for treating ACL rupture and knee injuries: a finite element analysis.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {12}, number = {}, pages = {1437684}, pmid = {39170062}, issn = {2296-4185}, abstract = {Introduction: The biomechanical indication for combining anterolateral structures reconstruction (ASLR) with ACL reconstruction (ACLR) to reduce pivot shift in the knee remains unclear. This study aims to investigate knee functionality after ACL rupture with different combinations of injuries, and to compare the effectiveness of ALSR with ACLR for treating these injuries. Methods: A validated finite element model of a human cadaveric knee was used to simulate pivot shift tests on the joint in different states, including 1) an intact knee; 2) after isolated ACL rupture; 3) after ACL rupture combined with different knee injuries or defect, including a posterior tibial slope (PTS) of 20°, an injury to the anterolateral structures (ALS) and an injury to the posterior meniscotibial ligament of the lateral meniscus (LP); 4) after treating the different injuries using isolated ACLR; v. after treating the different injuries using ACLR with ALSR. The knee kinematics, maximum von Mises stress (Max.S) on the tibial articular cartilage (TC) and force in the ACL graft were compared among the different simulation groups. Results and discussion: Comparing with isolated ACL rupture, combined injury to the ALS caused the largest knee laxity, when a combined PTS of 20° induced the largest Max.S on the TC. The joint stability and Max.S on the TC in the knee with an isolated ACL rupture or a combined rupture of ACL and LP were restored to the intact level after being treated with isolated ACLR. The knee biomechanics after a combined rupture of ACL and ALS were restored to the intact level only when being treated with a combination of ACLR and ALSR using a large graft diameter (6 mm) for ALSR. However, for the knee after ACL rupture combined with a PTS of 20°, the ATT and Max.S on the TC were still greater than the intact knee even after being treated with a combination of ACLR and ALSR. The finite element analysis showed that ACLR should include ALSR when treating ACL ruptures accompanied by ALS rupture. However, pivot shift in knees with a PTS of 20° was not eliminated even after a combined ACLR and ALSR.}, } @article {pmid39168583, year = {2024}, author = {Memudu, AE and Olukade, BA and Adebayo, OS and Raza, ML}, title = {Coffee and amyotrophic lateral sclerosis (ALS).}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {81-105}, doi = {10.1016/bs.pbr.2024.06.003}, pmid = {39168583}, issn = {1875-7855}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Humans ; *Coffee ; Animals ; Neuroprotective Agents/pharmacology ; Oxidative Stress/physiology/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive loss of motor neurons. The effective treatments for ALS remain elusive, necessitating exploration into novel preventive strategies. ALS pathogenesis is triggered by oxidative stress which results in neuroinflammation, exicitotoxicity and neuronal cell death. Nutritional mechanism for halting progression of neurodegeneration is through dietary compounds with antioxidants, anti-inflammatory or neuromodulating activity. Coffee is a widely consumed beverage made up of polyphenols, caffeine and other compounds with possible antioxidants and neuro-protective roles. It is important to say that various epidemiological studies have documented association between coffee intake and ALS. This chapter is aimed to present a comprehensive review of existing literature on coffee consumption and ALS, involving epidemiological studies, preclinical research, and its mechanism of actions in animal model of ALS. It highlights key findings regarding the potential neuroprotective properties of coffee constituents such as caffeine, polyphenols, and other bioactive compounds. Furthermore, it discusses possible pathways through which coffee may modulate ALS pathogenesis, including suppressing oxidative stress and neuroinflammation while boosting adenosine function via the adenosine receptor two on the motor neuron cells membrane in the spinal cord to enhance motor function via the corticospinal tract. Overall, this chapter underscores the significance of further research to unravel the specific mechanisms by which coffee exerts its neuroprotective effects in ALS, with the ultimate goal of identifying dietary strategies for ALS prevention and management.}, } @article {pmid39168577, year = {2024}, author = {Rai, SP and Ansari, AH and Singh, D and Singh, S}, title = {Coffee, antioxidants, and brain inflammation.}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {123-150}, doi = {10.1016/bs.pbr.2024.06.005}, pmid = {39168577}, issn = {1875-7855}, mesh = {*Coffee/chemistry ; Humans ; *Antioxidants/pharmacology ; Animals ; Neurodegenerative Diseases ; Encephalitis ; Caffeine/pharmacology/administration & dosage ; Neuroinflammatory Diseases ; }, abstract = {Coffee is the most popular beverage in the world and, aside from tea and water, the most often consumed caffeine-containing beverage. Because of its high caffeine concentration, it is typically classified as a stimulant. There are other bioactive ingredients in coffee besides caffeine. The coffee beverage is a blend of several bioactive substances, including diterpenes (cafestol and kahweol), alkaloids (caffeine and trigonelline), and polyphenols (particularly chlorogenic acids in green beans and caffeic acid in roasted coffee beans). Caffeine has also been linked to additional beneficial benefits such as antioxidant and anti-inflammatory properties, which change cellular redox and inflammatory status in a dose-dependent manner. Pyrocatechol, a constituent of roasted coffee that is created when chlorogenic acid is thermally broken down, has anti-inflammatory properties as well. It is postulated that coffee consumption reduces neuroinflammation, which is intimately linked to the onset of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). This review provides an overview of the most recent studies regarding coffee's possible benefits in preventing brain inflammation and neurodegenerative disorders.}, } @article {pmid39168358, year = {2024}, author = {Ueno, Y and Morishima, Y and Hata, T and Shindo, A and Murata, H and Saito, T and Nakamura, Y and Shindo, K}, title = {Current progress in microRNA profiling of circulating extracellular vesicles in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106639}, doi = {10.1016/j.nbd.2024.106639}, pmid = {39168358}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/blood/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons, leading to death resulting mainly from respiratory failure, for which there is currently no curative treatment. Underlying pathological mechanisms for the development of ALS are diverse and have yet to be elucidated. Non-invasive testing to isolate circulating molecules including microRNA to diagnose ALS has been reported, but circulating extracellular vesicle (EV)-derived microRNA has not been fully studied in the ALS population.

METHODS: A systematic literature review to explore studies investigating the profile of microRNAs in EVs from blood samples of ALS patients was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.

RESULTS: Eleven studies including a total of 263 patients with ALS were included in the present systematic review. The majority of patients had sporadic ALS, though a small number of patients with ALS having genetic mutations were included. Seven studies used plasma-derived EVs, and the remaining four studies used serum-derived EVs. RNA sequencing or microarrays were used in eight studies, and quantitative PCR was used in eight studies, of which five studies used RNA sequencing or microarrays for screening and quantitative PCR for validation. There was overlap of miR-199a-3p and miR-199a-5p in three studies.

CONCLUSIONS: Overall, the systematic review addressed the current advances in the profiling of microRNAs in circulating EVs of ALS patients. Blood samples, isolation of EVs, and microRNA analysis were diverse. Although there was an overlap of miR-199a-3p and miR-199a-5p, collection of further evidence is warranted.}, } @article {pmid39167487, year = {2024}, author = {Alirzayeva, H and Loureiro, R and Koyuncu, S and Hommen, F and Nabawi, Y and Zhang, WH and Dao, TTP and Wehrmann, M and Lee, HJ and Vilchez, D}, title = {ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114626}, doi = {10.1016/j.celrep.2024.114626}, pmid = {39167487}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Histones/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; *Caenorhabditis elegans/metabolism/genetics ; Animals ; *Mutation/genetics ; *Poly (ADP-Ribose) Polymerase-1/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Poly ADP Ribosylation ; Induced Pluripotent Stem Cells/metabolism ; Protein Binding ; }, abstract = {The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes. Here, we define the interactome of the severe mutant FUS[P525L] variant in human induced pluripotent stem cell (iPSC)-derived motor neurons. We find increased interaction of FUS[P525L] with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons. Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUS[P525L] aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes. Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.}, } @article {pmid39167140, year = {2024}, author = {Yu, L and Wu, N and Choi, O and Nguyen, KD}, title = {Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {73}, number = {11}, pages = {1847-1857}, pmid = {39167140}, issn = {1420-908X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy ; *Immunity, Innate/drug effects ; *Glycolysis/drug effects ; *Spinal Cord/immunology/pathology/drug effects/metabolism ; *Mice, Transgenic ; Mice ; Inflammation ; Male ; Disease Models, Animal ; Monocytes/drug effects/immunology ; Mice, Inbred C57BL ; Microglia/drug effects/immunology/metabolism ; Female ; }, abstract = {BACKGROUND: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.

METHODS: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.

RESULTS: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45[hi] infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45[low] microglia and F4/80 + CD45[hi] infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice.

CONCLUSIONS: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.}, } @article {pmid39163160, year = {2024}, author = {Purcell, N and Manousakis, G}, title = {Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {42-46}, doi = {10.1097/CND.0000000000000501}, pmid = {39163160}, issn = {1537-1611}, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; *Distal Myopathies/genetics/diagnosis ; Founder Effect ; *Mutation ; *Pedigree ; *Phenotype ; T-Cell Intracellular Antigen-1/genetics ; Aged ; Aged, 80 and over ; }, abstract = {Welander distal myopathy is a rare myopathy with prominent and early involvement of distal upper extremity muscles, prevalent in individuals of Scandinavian origin, and caused by a founder mutation in the cytotoxic granule-associated RNA-binding protein (T-cell intracellular antigen-1; TIA1), E384K. Different pathogenic variants in the TIA1 gene, distinct from the founder 1, have recently been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), suggesting that TIA1-related disorders belong to the group of multisystem proteinopathies. We describe the first case of a two-generation family with the founder E384K TIA1 mutation demonstrating phenotypic variability; the mother manifested as Welander myopathy, whereas 2 daughters manifested as ALS. No other genetic cause of ALS was found in 1 of the affected daughters. We also discuss the possible mechanisms explaining this pleotropic presentation of the founder mutation.}, } @article {pmid39163156, year = {2024}, author = {Takahashi, K and Hamada, Y and Kobayashi, M and Kobayashi, S and Kanbayashi, T and Hatanaka, Y and Nakayama, T and Imafuku, I and Matsuno, H and Iguchi, Y and Katada, F and Fukutake, T and Ando, T and Mikata, T and Usui, T and Uchino, K and Nishiyama, K and Sonoo, M}, title = {Utility of the Repetitive Nerve Stimulation Test and Needle EMG in the Trapezius Muscle for the Early Diagnosis of ALS.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {1-11}, doi = {10.1097/CND.0000000000000479}, pmid = {39163156}, issn = {1537-1611}, support = {19K07966 and 22K07524//Ministry of Education, Science, Sports and Culture of Japan/ ; 19ek0109252h0003//AMED/ ; }, mesh = {Humans ; *Electromyography/methods ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Aged ; Retrospective Studies ; *Electric Stimulation ; *Superficial Back Muscles/physiopathology ; *Sensitivity and Specificity ; Adult ; Early Diagnosis ; }, abstract = {OBJECTIVES: To document the utility of decremental responses in the repetitive nerve stimulation test (RNS) and spontaneous activities in needle electromyography (EMG) in the trapezius muscle for the diagnosis of amyotrophic lateral sclerosis.

METHODS: Subjects were retrospectively identified from our EMG database. Cervical spondylosis was represented as a disease control group. We investigated the sensitivity and specificity of RNS and EMG in the trapezius muscle and those of diagnostic criteria including the Gold Coast criteria (GCC).

RESULTS: We reviewed 120 patients with amyotrophic lateral sclerosis and 17 patients with cervical spondylosis. "RNS or EMG" achieved the highest sensitivity (85%). The specificity was the highest for RNS (94%). Addition of RNS of the deltoid muscle achieved 98% sensitivity in the upper-limb onset amyotrophic lateral sclerosis. The sensitivity of the GCC was very high (88%).

CONCLUSIONS: Neurophysiological parameters investigated in this study having close to 100% specificities or sensitivities are useful as complements to the GCC.}, } @article {pmid39163111, year = {2024}, author = {Fenoy, A}, title = {Scientific plurality and amyotrophic lateral sclerosis (ALS): A philosophical and historical perspective on Charcot's texts.}, journal = {Journal of the history of the neurosciences}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/0964704X.2024.2380635}, pmid = {39163111}, issn = {1744-5213}, abstract = {The history of amyotrophic lateral sclerosis (ALS)-also known as Charcot's disease, Lou Gehrig's disease, and motor neuron disease (MND)-freezes the texts of the scientist and physician Jean-Martin Charcot in a hagiographic narrative describing a brilliant discovery, based on the anatomo-clinical method. This narrative is often used by biologists and physicians as a reference point. This article shows that the use of the hagiographic register faces limitations. In particular, it obscures points of interest from Charcot's texts on ALS, such as the epistemological and ontological implications of scientific plurality in medicine. Although Charcot recognized the importance of scientific plurality in medicine, he prioritized the approaches and conferred the most important epistemic authority on clinical and pathological observations. In his view, animal modeling remains secondary to the understanding of disease. The concept of ALS and its diagnostic operability are the result of symptoms and lesions. By studying the past, we can highlight the specific features of the present. Today, although the ALS concept retains its diagnostic and clinical relevance, it is increasingly called into question in etiological and mechanistic research. Despite these differences, Charcot's reflections are a reminder of the importance of theoretical thinking on scientific plurality, all the more so today in the context of ALS research, in which combining different approaches is increasingly valued to understand the phenotypic and genetic heterogeneity of ALS.}, } @article {pmid39162129, year = {2024}, author = {Mazzini, L and De Marchi, F and Buzanska, L and Follenzi, A and Glover, JC and Gelati, M and Lombardi, I and Maioli, M and Mesa-Herrera, F and Mitrečić, D and Olgasi, C and Pivoriūnas, A and Sanchez-Pernaute, R and Sgromo, C and Zychowicz, M and Vescovi, A and Ferrari, D}, title = {Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {24}, number = {9}, pages = {933-954}, doi = {10.1080/14712598.2024.2392307}, pmid = {39162129}, issn = {1744-7682}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Stem Cell Transplantation ; Disease Models, Animal ; Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published.

AREAS COVERED: This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined.

EXPERT OPINION: Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.}, } @article {pmid39161942, year = {2024}, author = {Marcu, IR and Rogoveanu, OC and Pădureanu, R and Pădureanu, V and Dop, D}, title = {Diagnostic elements in amyotrophic lateral sclerosis: A case report.}, journal = {Biomedical reports}, volume = {21}, number = {4}, pages = {141}, pmid = {39161942}, issn = {2049-9442}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that involves the degeneration of both upper and lower motor neurons responsible for controlling voluntary muscle activity. Most people with ALS die within 3-5 years due to respiratory failure. The current study presents the case of a 68-year-old woman diagnosed with ALS based on the subjective and objective findings from the patient's initial physiotherapy assessment and on neurophysiological tests. Physiotherapy interventions are aiming to maintain the patient's strength, balance and functional independence for as long as possible. The present case report aimed to highlight that a multidisciplinary team approach is necessary for the management of a progressive degenerative disease such as ALS.}, } @article {pmid39158304, year = {2024}, author = {Tong, Z and Zhang, X and Guo, X and Wu, G and Cao, S and Zhang, Y and Meng, X and Wang, T and Wang, Y and Song, Y and Yang, R and Du, Z}, title = {Delivery of Yersinia pestis antigens via Escherichia coli outer membrane vesicles offered improved protection against plague.}, journal = {mSphere}, volume = {9}, number = {9}, pages = {e0033024}, pmid = {39158304}, issn = {2379-5042}, support = {2022YFC2303503//National Key Research and Development of China/ ; 32070136//MOST | National Natural Science Foundation of China (NSFC)/ ; }, mesh = {Animals ; *Plague/prevention & control/immunology ; *Antigens, Bacterial/immunology/genetics ; *Bacterial Outer Membrane Proteins/immunology/genetics ; *Escherichia coli/genetics/immunology ; *Yersinia pestis/immunology/genetics ; Mice ; *Pore Forming Cytotoxic Proteins/immunology/genetics ; *Plague Vaccine/immunology/administration & dosage/genetics ; Female ; *Antibodies, Bacterial/blood/immunology ; Mice, Inbred BALB C ; Recombinant Fusion Proteins/immunology/genetics ; Bacterial Outer Membrane/immunology ; Bacterial Proteins ; }, abstract = {Outer membrane vesicles (OMVs) from Gram-negative bacteria can be used as a vaccine platform to deliver heterologous antigens. Here, the major protective antigens of Yersinia pestis, F1 and LcrV, were fused either with the leader sequence or the transmembrane domain of the outer membrane protein A (OmpA), resulting in chimeric proteins OmpA-ls-F1V and OmpA46-159-F1V, respectively. We show that OmpA-ls-F1V and OmpA46-159-F1V can be successfully delivered into the lumen and membrane of the OMVs of Escherichia coli, respectively. Mutation of ompA but not tolR in E. coli enhanced the delivery efficiency of OmpA-ls-F1V into OMVs. The OmpA-ls-F1V protein comprises up to 20% of the total protein in OMVs derived from the ompA mutant (OMVdA-ALS-F1V), a proportion significantly higher than the 1% observed for OmpA46-159-F1V in OMVs produced by an ompA mutant that expresses OmpA46-159-F1V, referred to as OMVdA-LATM5-F1V. Intramuscular (i.m.) immunization of mice with OMVdA-ALS-F1V induced significantly higher levels of serum anti-LcrV and anti-F1 IgG, and provided higher efficacy in protection against subcutaneous (s.c.) Y. pestis infection compared to OMVdA-LATM5-F1V and the purified recombinant F1V (rF1V) protein adsorbed to aluminum hydroxide. The three-dose i.m. immunization with OMVdA-ALS-F1V, administered at 14-day intervals, provides complete protection to mice against s.c. infection with 130 LD50 of Y. pestis 201 and conferred 80% against intranasal (i.n.) challenge with 11.4 LD50 of Y. pestis 201. Taken together, our findings indicate that the engineered OMVs containing F1V fused with the leader sequence of OmpA provide significantly higher protection than rF1V against both s.c. and i.n. infection of Y. pestis and more balanced Th1/Th2 responses.IMPORTANCEThe two major protective antigens of Y. pestis, LcrV and F1, have demonstrated the ability to elicit systemic and local mucosal immune responses as subunit vaccines. However, these vaccines have failed to provide adequate protection against pneumonic plague in African green monkeys. Here, Y. pestis F1 and LcrV antigens were successfully incorporated into the lumen and the surface of the outer membrane vesicles (OMVs) of E. coli by fusion either with the leader sequence or the transmembrane domain of OmpA. We compared the humoral immune response elicited by these OMV formulations and their protective efficacy in mice against Y. pestis. Our results demonstrate that the plague OMV vaccine candidates can induce robust protective immunity against both s.c. and i.n. Y. pestis infections, surpassing the effectiveness of rF1V. In addition, immunization with OMVs generated a relatively balanced Th1/Th2 immune response compared to rF1V immunization. These findings underscore the potential of OMVs-based plague vaccines for further development.}, } @article {pmid39157517, year = {2024}, author = {Zhang, Y and Zhang, Q and Liu, Q and Zhao, Y and Xu, W and Hong, C and Xu, C and Qi, X and Qi, X and Liu, B}, title = {Fine mapping and functional validation of the maize nicosulfuron-resistance gene CYP81A9.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1443413}, pmid = {39157517}, issn = {1664-462X}, abstract = {Nicosulfuron, a widely utilized herbicide, is detrimental to some maize varieties due to their sensitivity. Developing tolerant varieties with resistance genes is an economical and effective way to alleviate phytotoxicity. In this study, map-based cloning revealed that the maize resistance gene to nicosulfuron is Zm00001eb214410 (CYP81A9), which encodes a cytochrome P450 monooxygenase. qRT- PCR results showed that CYP81A9 expression in the susceptible line JS188 was significantly reduced compared to the resistant line B73 during 0-192 hours following 80 mg/L nicosulfuron spraying. Meanwhile, a CYP81A9 overexpression line exhibited normal growth under a 20-fold nicosulfuron concentration (1600 mg/L), while the transgenic acceptor background material Zong31 did not survive. Correspondingly, silencing CYP81A9 through CRISPR/Cas9 mutagenesis and premature transcription termination mutant EMS4-06e182 resulted in the loss of nicosulfuron resistance in maize. Acetolactate Synthase (ALS), the target enzyme of nicosulfuron, exhibited significantly reduced activity in the roots, stems, and leaves of susceptible maize post-nicosulfuron spraying. The CYP81A9 expression in the susceptible material was positively correlated with ALS activity in vivo. Therefore, this study identified CYP81A9 as the key gene regulating nicosulfuron resistance in maize and discovered three distinct haplotypes of CYP81A9, thereby laying a solid foundation for further exploration of the underlying resistance mechanisms.}, } @article {pmid39156974, year = {2024}, author = {Fenili, G and Scaricamazza, S and Ferri, A and Valle, C and Paronetto, MP}, title = {Physical exercise in amyotrophic lateral sclerosis: a potential co-adjuvant therapeutic option to counteract disease progression.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1421566}, pmid = {39156974}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the selective degeneration of upper and lower motor neurons, leading to progressive muscle weakness and atrophy. The mean survival time is two to five years. Although the hunt for drugs has greatly advanced over the past decade, no cure is available for ALS yet. The role of intense physical activity in the etiology of ALS has been debated for several decades without reaching a clear conclusion. The benefits of organized physical activity on fitness and mental health have been widely described. Indeed, by acting on specific mechanisms, physical activity can influence the physiology of several chronic conditions. It was shown to improve skeletal muscle metabolism and regeneration, neurogenesis, mitochondrial biogenesis, and antioxidant defense. Interestingly, all these pathways are involved in ALS pathology. This review will provide a broad overview of the effect of different exercise protocols on the onset and progression of ALS, both in humans and in animal models. Furthermore, we will discuss challenges and opportunities to exploit physiological responses of imposed exercise training for therapeutic purposes.}, } @article {pmid39156432, year = {2024}, author = {Kaye, AD and Sala, KR and Dethloff, D and Norton, M and Moss, C and Plessala, MJ and Derouen, AG and Lopez Torres, Y and Kim, J and Tirumala, S and Shekoohi, S and Varrassi, G}, title = {The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64846}, pmid = {39156432}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.}, } @article {pmid39154890, year = {2024}, author = {Brebner, C and Asamoah-Boaheng, M and Zaidel, B and Yap, J and Scheuermeyer, F and Mok, V and Hutton, J and Meckler, G and Schlamp, R and Christenson, J and Grunau, B}, title = {The association of intravenous vs. humeral-intraosseous vascular access with patient outcomes in adult out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {202}, number = {}, pages = {110360}, doi = {10.1016/j.resuscitation.2024.110360}, pmid = {39154890}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; *Infusions, Intraosseous/methods ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; *Registries ; Aged ; Humerus ; Emergency Medical Services/methods ; Treatment Outcome ; Adult ; Propensity Score ; }, abstract = {AIM: While intravenous (IV) vascular access for out-of-hospital cardiac arrest (OHCA) resuscitation is standard, humeral-intraosseous (IO) access is commonly used, despite few supporting data. We investigated the association between IV vs. humeral-IO and outcomes.

METHODS: We utilized BC Cardiac Arrest Registry data, including adult OHCA where the first-attempted intra-arrest vascular access route performed by advanced life support (ALS)-trained paramedics was IV or humeral-IO. We fit a propensity-score adjusted model with inverse probability treatment weighting to estimate the association between IV vs. humeral-IO routes and favorable neurological outcomes (CPC 1-2) and survival at hospital discharge. We repeated models within subgroups defined by initial cardiac rhythm.

RESULTS: We included 2,112 cases; the first-attempted route was IV (n = 1,575) or humeral-IO (n = 537). Time intervals from ALS-paramedic on-scene arrival to vascular access (6.6 vs. 6.9 min) and epinephrine administration (9.0 vs. 9.3 min) were similar between IV and IO groups, respectively. Among IV and humeral-IO groups, 98 (6.2%) and 20 (3.7%) had favorable neurological outcomes. Compared to humeral-IO, an IV-first approach was associated with improved hospital-discharge favorable neurological outcomes (AOR 1.7; 95% CI 1.1-2.7) and survival (AOR 1.5; 95% CI 1.0-2.3). Among shockable rhythm cases, an IV-first approach was associated with improved favorable neurological outcomes (AOR 4.2; 95% CI 2.1-8.2), but not among non-shockable rhythm cases (AOR 0.73; 95% CI 0.39-1.4).

CONCLUSION: An IV-first approach, compared to humeral-IO, for intra-arrest resuscitation was associated with an improved odds of favorable neurological outcomes and survival to hospital discharge. This association was seen among an initial shockable rhythm, but not non-shockable rhythm, subgroups.}, } @article {pmid39154745, year = {2024}, author = {Vu, D and Park, M and Alhusayen, R}, title = {Response to Chawla et al, "Response to Vu et al's "Efficacy of moxifloxacin as a mono-antibiotic therapy for hidradenitis suppurativa: A retrospective cohort study"".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e177-e178}, doi = {10.1016/j.jaad.2024.08.013}, pmid = {39154745}, issn = {1097-6787}, } @article {pmid39154744, year = {2024}, author = {Li, JN and Sechi, A and Tosti, A}, title = {Response to Costa Fechine et al's "Correlation of clinical and trichoscopy features with the degree of histologic inflammation in lichen planopilaris and frontal fibrosing alopecia in a cross-sectional study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e187-e188}, doi = {10.1016/j.jaad.2024.07.1495}, pmid = {39154744}, issn = {1097-6787}, } @article {pmid39153378, year = {2024}, author = {Maramai, S and Saletti, M and Paolino, M and Giuliani, G and Cazzola, J and Spaiardi, P and Talpo, F and Frosini, M and Pifferi, A and Ballarotto, M and Carotti, A and Poggialini, F and Vagaggini, C and Dreassi, E and Giorgi, G and Dondio, G and Cappelli, A and Rosario Biella, G and Anzini, M}, title = {Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents.}, journal = {Bioorganic & medicinal chemistry}, volume = {112}, number = {}, pages = {117872}, doi = {10.1016/j.bmc.2024.117872}, pmid = {39153378}, issn = {1464-3391}, mesh = {Animals ; Humans ; Dose-Response Relationship, Drug ; Ligands ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Riluzole/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; Thiazepines/chemical synthesis/chemistry/pharmacology ; }, abstract = {Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na[+] and K[+] currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.}, } @article {pmid39153346, year = {2025}, author = {Khazaei, K and Roshandel, P and Parastar, H}, title = {Visible-short wavelength near infrared hyperspectral imaging coupled with multivariate curve resolution-alternating least squares for diagnosis of breast cancer.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {324}, number = {}, pages = {124966}, doi = {10.1016/j.saa.2024.124966}, pmid = {39153346}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis ; Least-Squares Analysis ; *Principal Component Analysis ; *Spectroscopy, Near-Infrared/methods ; *Hyperspectral Imaging/methods ; Multivariate Analysis ; Discriminant Analysis ; }, abstract = {This study investigates the application of visible-short wavelength near-infrared hyperspectral imaging (Vis-SWNIR HSI) in the wavelength range of 400-950 nm and advanced chemometric techniques for diagnosing breast cancer (BC). The research involved 56 ex-vivo samples encompassing both cancerous and non-cancerous breast tissue from females. First, HSI images were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) to exploit pure spatial and spectral profiles of active components. Then, the MCR-ALS resolved spatial profiles were arranged in a new data matrix for exploration and discrimination between benign and cancerous tissue samples using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The PLS-DA classification accuracy of 82.1 % showed the potential of HSI and chemometrics for non-invasive detection of BC. Additionally, the resolved spectral profiles by MCR-ALS can be used to track the changes in the breast tissue during cancer and treatment. It is concluded that the proposed strategy in this work can effectively differentiate between cancerous and non-cancerous breast tissue and pave the way for further studies and potential clinical implementation of this innovative approach, offering a promising avenue for improving early detection and treatment outcomes in BC patients.}, } @article {pmid39153108, year = {2024}, author = {Hosseini, L and Babaie, S and Shahabi, P and Fekri, K and Shafiee-Kandjani, AR and Mafikandi, V and Maghsoumi-Norouzabad, L and Abolhasanpour, N}, title = {Klotho: molecular mechanisms and emerging therapeutics in central nervous system diseases.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {913}, pmid = {39153108}, issn = {1573-4978}, mesh = {*Klotho Proteins ; Humans ; *Central Nervous System Diseases/metabolism/drug therapy ; *Signal Transduction ; Animals ; Oxidative Stress ; Glucuronidase/metabolism/genetics ; Autophagy ; Aging/metabolism/genetics ; }, abstract = {Klotho is recognized as an aging-suppressor protein that is implicated in a variety of processes and signaling pathways. The anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-tumor bioactivities of klotho have extended its application in neurosciences and made the protein popular for its lifespan-extending capacity. Furthermore, it has been demonstrated that klotho levels would reduce with aging and numerous pathologies, particularly those related to the central nervous system (CNS). Evidence supports the idea that klotho can be a key therapeutic target in CNS diseases such as amyotrophic lateral sclerosis, Parkinson's disease, stroke, and Alzheimer's disease. Reviewing the literature suggests that the upregulation of klotho expression regulates various signaling pathways related to autophagy, oxidative stress, inflammation, cognition, and ferroptosis in neurological disorders. Therefore, it has been of great interest to develop drugs or agents that boost or restore klotho levels. In this regard, the present review was designed and aimed to gather the delegated documents regarding the therapeutic potential of Klotho in CNS diseases focusing on the molecular and cellular mechanisms.}, } @article {pmid39152573, year = {2024}, author = {Dubbioso, R and Iannotti, FA and Senerchia, G and Verde, R and Iuzzolino, VV and Spisto, M and Fasolino, I and Manganelli, F and Di Marzo, V and Piscitelli, F}, title = {Circulating endocannabinoidome signatures of disease activity in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {10}, pages = {e16400}, pmid = {39152573}, issn = {1468-1331}, support = {E53D23019760001//National Recovery and Resilience Plan (NRRP)/ ; E53D23011330006//Ministry of University and Research (MUR)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *Endocannabinoids/blood ; Male ; Female ; Middle Aged ; Aged ; Adult ; Disease Progression ; Longitudinal Studies ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so-called endocannabinoidome, and disease status and activity in ALS patients.

METHODS: Serum concentrations of 2-arachidonoylglycerol and N-arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosahexaenoylglycerol (2-DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels.

RESULTS: Most circulating mediators were higher in ALS than HCs (all p < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all p < 0.02), which were confirmed by the longitudinal study (all p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the 'severe' cluster showed significantly higher levels of OEA and PEA and lower levels of 2-DHG compared to NALS and HCs.

CONCLUSION: Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a 'one-fits-all', therapeutic approach targeting the endocannabinoidome.}, } @article {pmid39150867, year = {2024}, author = {Pienaar, K and Kelaita, P and Murphy, D}, title = {COVID-19 and the biopolitics of stigma in public housing: dividing practices and community boundaries in pandemic times.}, journal = {Health sociology review : the journal of the Health Section of the Australian Sociological Association}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/14461242.2024.2390019}, pmid = {39150867}, issn = {1446-1242}, abstract = {The COVID-19 'hard lockdowns' in Melbourne, Australia in 2020 targeted public housing estates thus trading on perceptions of risk associated with public housing as some of the most stigmatised sites in post-industrial cities. This article draws on interviews with Melbourne public housing tenants on their experience of COVID-19 lockdowns to analyse the place of stigma in residents' accounts. Pairing Wacquant et al's (2014) concept of 'territorial stigma' with sociological work on the biopolitics of stigma we consider the dynamics of stigma, tracing how it functions to delimit community boundaries and justify pandemic containment measures. Residents navigate multiple layers of stigma, including stereotypes of public housing, normative judgements of neighbouring residents, and a broader public housing system riven with structural issues. Members of these communities are both the targets of stigma and seek to distance themselves from those seen as vectors of stigma. Our participants report mobilising social distancing strategies couched in normative assessments of perceived risk based on physical appearance, presumed drug use and past conduct. We explore the implications of these enactments of territorial stigma and trace the logics of abjection that construct public housing as deprived urban zones, home to abject 'Others' perceived as threatening the health of the community.}, } @article {pmid39149866, year = {2024}, author = {Cabeza-Fernández, S and Hernández-Rojas, R and Casillas-Bajo, A and Patel, N and de la Fuente, AG and Cabedo, H and Gomez-Sanchez, JA}, title = {Schwann cell JUN expression worsens motor performance in an amyotrophic lateral sclerosis mouse model.}, journal = {Glia}, volume = {72}, number = {12}, pages = {2178-2189}, doi = {10.1002/glia.24604}, pmid = {39149866}, issn = {1098-1136}, support = {PID2019-109762RB-I00//Agencia Estatal de Investigación/ ; PID2022-141062OB-I00//Agencia Estatal de Investigación/ ; CIPROM/2021/048//Conselleria d'Educació, Investigació, Cultura i Esport/ ; GRISOLIAP/2021/026//Conselleria d'Educació, Investigació, Cultura i Esport/ ; }, mesh = {Animals ; *Schwann Cells/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/physiopathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Motor Neurons/pathology/metabolism ; Proto-Oncogene Proteins c-jun/metabolism/genetics ; Mice ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Axons/pathology/metabolism/physiology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1[G93A] mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1[G93A] mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.}, } @article {pmid39147172, year = {2024}, author = {Acton, S and O'Donnell, MM and Periyasamy, K and Dixit, B and Eishingdrelo, H and Hill, C and Paul Ross, R and Chesnel, L}, title = {LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models.}, journal = {Brain, behavior, and immunity}, volume = {121}, number = {}, pages = {384-402}, doi = {10.1016/j.bbi.2024.08.024}, pmid = {39147172}, issn = {1090-2139}, mesh = {*Bacillus/metabolism ; Animals ; Mice ; Humans ; *Neuroinflammatory Diseases/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Multiple Sclerosis/metabolism ; Male ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14-3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson's disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting that ADS024 treatment impacted a universal underlying neuroinflammatory mechanism regardless of the initiating cause of disease. We used the MOG-EAE mouse model to examine early events after disease initiation and found that ADS024 attenuated the increase in circulating lymphocytes and changes in neutrophil subtypes, and ADS024 attenuated the early loss of cell-surface LPA3 receptor expression on circulating white blood cells. ADS024 efficacy was partially inhibited by Ki16425 in vivo suggesting LPA3 may be part of its mechanism. Altogether, these data suggest that ADS024 and its LPA3 agonism activity should be investigated further as a possible treatment for diseases with a neuroinflammatory component.}, } @article {pmid39146882, year = {2024}, author = {Aizawa, H and Nagumo, S and Hideyama, T and Kato, H and Kwak, S and Terashi, H and Suzuki, Y and Kimura, T}, title = {Morphometric analysis of spinal motor neuron degeneration in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {464}, number = {}, pages = {123177}, doi = {10.1016/j.jns.2024.123177}, pmid = {39146882}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Male ; Female ; Middle Aged ; Aged ; *DNA-Binding Proteins/metabolism ; *Spinal Cord/pathology/metabolism ; *Nerve Degeneration/pathology ; Anterior Horn Cells/pathology ; Motor Neurons/pathology/metabolism ; }, abstract = {OBJECTIVES: This study aimed to clarify the relationship between 43-kDa TAR DNA-binding protein (TDP-43) pathology and spinal cord anterior horn motor neuron (AHMN) atrophy in sporadic amyotrophic lateral sclerosis (SALS).

METHODS: Eight patients with SALS and 12 controls were included in this study. Formalin-fixed specimens of lumbar spinal cord samples were paraffin-embedded and sectioned at the level of the fourth lumbar spinal cord with a 4 μm thickness. Using a microscope, the long diameters of the neurons with nucleoli were measured in spinal AHMNs stained with an anti-SMI-32 antibody. AHMNs were divided into medial and lateral nuclei for statistical analysis. We also used previously reported data to measure the long diameter of AHMNs with initial TDP-43 pathology, in which TDP-43 was present both in the nucleus and cytoplasm.

RESULTS: The long diameter of the lumbar spinal AHMNs in patients with SALS was smaller in the medial nucleus (42.54 ± 9.33 μm, n = 24) and the lateral nucleus (49.41 ± 13.86 μm, n = 129) than in controls (medial nucleus: 55.84 ± 13.49 μm, n = 85, p < 0.001; lateral nucleus: 62.39 ± 13.29 μm, n = 756, p < 0.001, Mann-Whitney U test). All 21 motor neurons with initial TDP-43 pathology were in the lateral nucleus, and their long diameter (67.60 ± 18.3 μm, p = 0.352) was not significantly different from that of controls.

CONCLUSION: Motor neuron atrophy in SALS does not occur during the initial stages of TDP-43 pathology, and TDP-43 pathology is already advanced in the atrophied motor neurons.}, } @article {pmid39146816, year = {2025}, author = {Sun, Q and Chai, L and Yang, X and Zhang, W and Li, Z}, title = {Hollow tubular sea-urchin structure with high catalytic activity of NiCo2Se4@CS2 cathodes for high-performance Al/S batteries.}, journal = {Journal of colloid and interface science}, volume = {677}, number = {Pt B}, pages = {284-292}, doi = {10.1016/j.jcis.2024.08.071}, pmid = {39146816}, issn = {1095-7103}, abstract = {The shuttle effect of aluminum polysulfides (AlPSs) have been a source of concern for studying Al/S batteries. Due to the weak adsorption of CS composites, research on cathode materials for Al/S batteries has been delayed. As it is generally known that Al2S3 decomposition demands a large Gibbs free energy, this work has tried to reduce the Al2S3 decomposition potential energy. Herein, the Ni/Co bimetallic selenide reduces the energy barrier conversion and mitigates the polarization effects, while morphology control enables the storage and anchoring of S, alleviating the shuttle effect. Additionally, the intermediate products serve as single-atom catalysts, increasing the active sites, synergistically enhancing the ion diffusion kinetics. DFT calculations verify that NiCo2Se4 has a moderate Gibbs free energy change during the rate-limiting step of S reduction and the most robust adsorption energy to Al2S3. NiCo2Se4@CS2/Al has a remaining capacity of 135 mAh/g after 450 cycles (at 200 mA g[-1]), pioneering novel ideas for the development of Al/S batteries.}, } @article {pmid39146722, year = {2024}, author = {Ginanneschi, F and Pucci, B and Casali, S and Lissandri, C and Giannini, F and Rossi, A}, title = {Factors associated with Edinburgh Cognitive and Behavioural ALS Screen (ECAS) alteration at time of diagnosis, in amyotrophic lateral sclerosis.}, journal = {Clinical neurology and neurosurgery}, volume = {245}, number = {}, pages = {108499}, doi = {10.1016/j.clineuro.2024.108499}, pmid = {39146722}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Neuropsychological Tests ; Adult ; Mutation ; Cohort Studies ; }, abstract = {BACKGROUND: Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a validated assessment designed to screen cognitive functions and behavioral disorders in amyotrophic lateral sclerosis (ALS). Objective of this study is to determine the factors associated with ECAS impairment in a cohort of ALS patients without a co-morbid diagnosis of dementia, at the time of diagnosis.

METHODS: We enrolled 71 non-demented ALS patient. We collected clinical and demographic data, ALS familiarity, analysis of the most commonly mutated genes in ALS, ALS Milano Torino Staging System and ALS Functional Rate Scale revised scores, progression rate; finally, we recorded whether symptoms onset involved spinal or bulbar area. The alteration of the ECAS was estimated based on age and education-adjusted-validated cut off for each of the items included in ECAS. A multivariable regression analysis was done.

RESULTS: The significant determinants of ECAS alterations were: bulbar onset in both ALS-specific test and total ECAS score; bulbar onset and familiarity in ALS-non-specific test; finally, familiarity and diagnosis delay in ALS-behavioral test. All the subjects carrying C9orf72 mutations had alteration of both total ECAS score and ALS-specific tests.

DISCUSSION: At diagnosis, bulbar-onset ALS, family history, diagnosis delay and C9orf72 hexanucleotide repeat expansion may contribute to impairment of ECAS.}, } @article {pmid39146246, year = {2024}, author = {Hutten, S and Chen, JX and Isaacs, AM and Dormann, D}, title = {Poly-GR Impairs PRMT1-Mediated Arginine Methylation of Disease-Linked RNA-Binding Proteins by Acting as a Substrate Sink.}, journal = {Biochemistry}, volume = {63}, number = {17}, pages = {2141-2152}, doi = {10.1021/acs.biochem.4c00308}, pmid = {39146246}, issn = {1520-4995}, mesh = {*Protein-Arginine N-Methyltransferases/metabolism/genetics ; Humans ; *Arginine/metabolism ; Methylation ; *Repressor Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics ; C9orf72 Protein/metabolism/genetics ; HEK293 Cells ; }, abstract = {Dipeptide repeat proteins (DPRs) are aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases characterized by the cytoplasmic mislocalization and aggregation of RNA-binding proteins (RBPs). In particular, arginine (R)-rich DPRs (poly-GR and poly-PR) have been suggested to promiscuously interact with multiple cellular proteins and thereby exert high cytotoxicity. Components of the protein arginine methylation machinery have been identified as modulators of DPR toxicity and/or potential cellular interactors of R-rich DPRs; however, the molecular details and consequences of such an interaction are currently not well understood. Here, we demonstrate that several members of the family of protein arginine methyltransferases (PRMTs) can directly interact with R-rich DPRs in vitro and in the cytosol. In vitro, R-rich DPRs reduce solubility and promote phase separation of PRMT1, the main enzyme responsible for asymmetric arginine-dimethylation (ADMA) in mammalian cells, in a concentration- and length-dependent manner. Moreover, we demonstrate that poly-GR interferes more efficiently than poly-PR with PRMT1-mediated arginine methylation of RBPs such as hnRNPA3. We additionally show by two alternative approaches that poly-GR itself is a substrate for PRMT1-mediated arginine dimethylation. We propose that poly-GR may act as a direct competitor for arginine methylation of cellular PRMT1 targets, such as disease-linked RBPs.}, } @article {pmid39145860, year = {2024}, author = {Gondo, TF and Huang, F and Marungruang, N and Heyman-Lindén, L and Turner, C}, title = {Investigating the quality of extraction and quantification of bioactive compounds in berries through liquid chromatography and multivariate curve resolution.}, journal = {Analytical and bioanalytical chemistry}, volume = {416}, number = {24}, pages = {5387-5400}, pmid = {39145860}, issn = {1618-2650}, support = {2018-01863//Svenska Forskningsrådet Formas/ ; }, mesh = {*Fruit/chemistry ; Multivariate Analysis ; Chromatography, Liquid/methods ; Polyphenols/analysis ; Least-Squares Analysis ; Plant Extracts/chemistry ; Anthocyanins/analysis/chemistry ; Phenols/analysis/chemistry ; Chromatography, High Pressure Liquid/methods ; Antioxidants/analysis/chemistry ; }, abstract = {Berries are a rich source of natural antioxidant compounds, which are essential to profile, as they add to their nutritional value. However, the complexity of the matrix and the structural diversity of these compounds pose challenges in extraction and chromatographic separation. By relying on multivariate curve resolution alternating least squares (MCR-ALS) ability to extract components from complex spectral mixtures, our study evaluates the contributions of various extraction techniques to interference, extractability, and quantifying different groups of overlapping compounds using liquid chromatography diode array detection (LC-DAD) data. Additionally, the combination of these methods extends its applicability to evaluate polyphenol degradation in stored berry smoothies, where evolving factor analysis (EFA) is also used to elucidate degradation products. Results indicate that among the extraction techniques, ultrasonication-assisted extraction employing 1% formic acid in methanol demonstrated superior extractability and selectivity for the different phenolic compound groups, compared with both pressurized liquid extraction and centrifugation of the fresh berry smoothie. Employing MCR-ALS on the LC-DAD data enabled reliable estimation of total amounts of compound classes with high spectral overlaps. Degradation studies revealed significant temperature-dependent effects on anthocyanins, with at least 50% degradation after 7 months of storage at room temperature, while refrigeration and freezing maintained fair stability for at least 12 months. The EFA model estimated phenolic derivatives as the main possible degradation products. These findings enhance the reliability of quantifying polyphenolic compounds and understanding their stability during the storage of berry products.}, } @article {pmid39145609, year = {2024}, author = {Adil, O and Adeyeye, C and Shamsi, MH}, title = {Electrografted Laser-Induced Graphene: Direct Detection of Neurodegenerative Disease Biomarker in Cerebrospinal Fluid.}, journal = {ACS sensors}, volume = {9}, number = {9}, pages = {4748-4757}, doi = {10.1021/acssensors.4c01150}, pmid = {39145609}, issn = {2379-3694}, mesh = {*Graphite/chemistry ; Humans ; *Biomarkers/cerebrospinal fluid ; *Electrochemical Techniques/methods ; *Lasers ; Immunoassay/methods ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Electrodes ; Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Limit of Detection ; Biosensing Techniques/methods ; }, abstract = {There are more than 50 neurodegenerative disorders, and amyotrophic lateral sclerosis (ALS) is one of the most common disorders that poses diagnostic and treatment challenges. The poly glycine-proline (polyGP) dipeptide repeat is a toxic protein that has been recognized as a pharmacodynamic biomarker of C9orf72-associated (c9+) ALS, a subtype of ALS that originates from genetic mutation. Early detection of polyGP will help healthcare providers start timely gene therapy. Herein, we developed a label-free electrochemical immunoassay for the simple detection of polyGP in unprocessed cerebrospinal fluid (CSF) samples collected from ALS patients in the National ALS Biorepository. For the first time, an electrografted laser-induced graphene (E-LIG) electrode system was employed in a sandwich format to detect polyGP using a label-free electrochemical impedance technique. The results show that the E-LIG-modified surface exhibited high sensitivity and selectivity in buffer and CSF media with limit of detection values of 0.19 and 0.27 ng/mL, respectively. The precision of the calibration model was better in CSF than in the buffer. The E-LIG immunosensor can easily select polyGP targets in the presence of other dipeptide proteins translated from the c9 gene. Further study with CSF samples from ALS patients demonstrated that the label-free E-LIG-based immunosensor not only quantified polyGP in the complex CSF matrix but also distinguished between c9+ and non-c9- ALS patients.}, } @article {pmid39144751, year = {2024}, author = {Szebényi, K and Vargová, I and Petrova, V and Turečková, J and Gibbons, GM and Řehořová, M and Abdelgawad, M and Sándor, A and Marekova, D and Kwok, JCF and Jendelová, P and Fawcett, JW and Lakatos, A}, title = {Inhibition of PHLDA3 expression in human superoxide dismutase 1-mutant amyotrophic lateral sclerosis astrocytes protects against neurotoxicity.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae244}, pmid = {39144751}, issn = {2632-1297}, abstract = {Pleckstrin homology-like domain family A-member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of pleckstrin homology-like domain family A-member 3 signalling was shown to vary across different cell types and states. It emerges that its expression and protein level are highly increased in amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates a supportive or detrimental function remains unexplored in the context of neurodegenerative pathologies. To directly address the role of pleckstrin homology-like domain family A-member 3 in healthy and ALS astrocytes, we used overexpression and knockdown strategies. We generated cultures of primary mouse astrocytes and also human astrocytes from control and ALS patient-derived induced pluripotent stem cells harbouring the superoxide dismutase 1 mutation. Then, we assessed astrocyte viability and the impact of their secretome on oxidative stress responses in human stem cell-derived cortical and spinal neuronal cultures. Here, we show that PHLDA3 overexpression or knockdown in control astrocytes does not significantly affect astrocyte viability or reactive oxygen species production. However, PHLDA3 knockdown in ALS astrocytes diminishes reactive oxygen species concentrations in their supernatants, indicating that pleckstrin homology-like domain family A-member 3 can facilitate stress responses in cells with altered homeostasis. In support, supernatants of PHLDA3-silenced ALS and even control spinal astrocytes with a lower pleckstrin homology-like domain family A-member 3 protein content could prevent sodium arsenite-induced stress granule formation in spinal neurons. Our findings provide evidence that reducing pleckstrin homology-like domain family A-member 3 levels may transform astrocytes into a more neurosupportive state relevant to targeting non-cell autonomous ALS pathology.}, } @article {pmid39144569, year = {2024}, author = {Choudhury, C and Egleton, JE and Butcher, NJ and Russell, AJ and Minchin, RF}, title = {Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {8}, pages = {2326-2332}, pmid = {39144569}, issn = {2575-9108}, abstract = {Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.}, } @article {pmid39144302, year = {2024}, author = {Chen, XF and Lin, JP and Zhou, H and Kang, BZ and Nayak, R and Gao, L and Jiang, SS and Wang, F}, title = {The relationship between the collagen score at the anastomotic site of esophageal squamous cell carcinoma and anastomotic leakage.}, journal = {Journal of thoracic disease}, volume = {16}, number = {7}, pages = {4515-4524}, pmid = {39144302}, issn = {2072-1439}, abstract = {BACKGROUND: Anastomotic leakage (AL) has always been one of the most serious complications of esophagectomy with gastric conduit reconstruction. There are many strong risk factors for AL in clinical practice. Notably, the tension at the esophagogastric anastomosis and the blood supply to the gastric conduit directly affect the integrity of the anastomosis. However, there has been a lack of quantitative research on the tension and blood supply of the gastric conduit. Changes in extracellular matrix collagen reflect tension and blood supply, which affect the quality of the anastomosis. This study aimed to establish a quantitative collagen score to describe changes in the collagen structure in the extracellular matrix and to identify patients at high risk of postoperative AL.

METHODS: A retrospective study of 213 patients was conducted. Clinical and pathological data were collected at baseline. Optical imaging of the "donut" specimen at the anastomotic gastric end and collagen feature extraction were performed. Least absolute shrinkage and selection operator (LASSO) regression models were used to select the significant collagen features, compute collagen scores, and validate the predictive efficacy of the collagen scores for ALs.

RESULTS: LASSO regression analysis revealed three collagen-related parameters in the gastric donuts: histogram mean, histogram variance, and histogram energy. Based on this analysis, we established a formula to calculate the collagen score. The results of the univariate analysis revealed significant differences in the preoperative low albumin values (P=0.002) and collagen scores between the AL and non-AL groups (P=0.001), while the results of the multivariate analysis revealed significant differences in the collagen scores between the AL and non-AL groups (P=0.002). The areas under the curve (AUCs) of the experimental and validation cohorts were 0.978 [95% confidence interval (CI): 0.931-0.996] and 0.900 (95% CI: 0.824-0.951), respectively.

CONCLUSIONS: The collagen score established herein was shown to be related to AL and can be used to predict AL in patients who underwent esophagectomy.}, } @article {pmid39144033, year = {2024}, author = {Xiao, XY and Zeng, JY and Cao, YB and Tang, Y and Zou, ZY and Li, JQ and Chen, HJ}, title = {Cortical microstructural abnormalities in amyotrophic lateral sclerosis: a gray matter-based spatial statistics study.}, journal = {Quantitative imaging in medicine and surgery}, volume = {14}, number = {8}, pages = {5774-5788}, pmid = {39144033}, issn = {2223-4292}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS)-related white-matter microstructural abnormalities have received considerable attention; however, gray-matter structural abnormalities have not been fully elucidated. This study aimed to evaluate cortical microstructural abnormalities in ALS and determine their association with disease severity.

METHODS: This study included 34 patients with ALS and 30 healthy controls. Diffusion-weighted data were used to estimate neurite orientation dispersion and density imaging (NODDI) parameters, including neurite density index (NDI) and orientation dispersion index (ODI). We performed gray matter-based spatial statistics (GBSS) in a voxel-wise manner to determine the cortical microstructure difference. We used the revised ALS Functional Rating Scale (ALSFRS-R) to assess disease severity and conducted a correlation analysis between NODDI parameters and ALSFRS-R.

RESULTS: In patients with ALS, the NDI reduction involved several cortical regions [primarily the precentral gyrus, postcentral gyrus, temporal cortex, prefrontal cortex, occipital cortex, and posterior parietal cortex; family-wise error (FWE)-corrected P<0.05]. ODI decreased in relatively few cortical regions (including the precentral gyrus, postcentral gyrus, prefrontal cortex, and inferior parietal lobule; FWE-corrected P<0.05). The NDI value in the left precentral and postcentral gyrus was positively correlated with the ALS disease severity (FWE-corrected P<0.05).

CONCLUSIONS: The decreases in NDI and ODI involved both motor-related and extra-motor regions and indicated the presence of gray-matter microstructural impairment in ALS. NODDI parameters are potential imaging biomarkers for evaluating disease severity in vivo. Our results showed that GBSS is a feasible method for identifying abnormalities in the cortical microstructure of patients with ALS.}, } @article {pmid39143255, year = {2024}, author = {Gehlen, M and Schwarz-Eywill, M and Mahn, K and Pfeiffer, A and Bauer, JM and Maier, A}, title = {[Sonography of muscles : Rheumatology-Neurology-Geriatrics-Sports medicine-Orthopedics].}, journal = {Zeitschrift fur Rheumatologie}, volume = {83}, number = {10}, pages = {829-843}, pmid = {39143255}, issn = {1435-1250}, mesh = {Humans ; *Ultrasonography/methods ; Magnetic Resonance Imaging ; Rheumatology/methods ; Muscle, Skeletal/diagnostic imaging ; Athletic Injuries/diagnostic imaging ; Sarcopenia/diagnostic imaging ; Sports Medicine/methods ; Rheumatic Diseases/diagnostic imaging ; Geriatrics ; Aged ; Neurology ; Muscular Diseases/diagnostic imaging ; Evidence-Based Medicine ; }, abstract = {Muscle sonography is used in rheumatology, neurology, geriatrics, sports medicine and orthopedics. Muscular atrophy with fatty and connective tissue degeneration can be visualized and must be interpreted in conjunction with the sonographic findings of the supplying nerves. Sonography is becoming increasingly more important for the early diagnosis of sarcopenia in rheumatology, geriatrics and osteology. Even if its significance has not yet been conclusively clarified, many publications confirm the high reliability of the method. Sonography can ideally be used in addition to magnetic resonance imaging (MRI) in the diagnostics of myositis as it can speed up the diagnosis, muscle groups that were not imaged by MRI can also be assessed sonographically and all muscle groups can be examined during the course of the procedure. Sonography also helps to make a quick and uncomplicated diagnosis of many sports injuries in addition to MRI and is therefore the basis for a targeted therapeutic approach.}, } @article {pmid39142444, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {RBM5 induces motor neuron apoptosis in hSOD1[G93A]-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways.}, journal = {Brain research bulletin}, volume = {216}, number = {}, pages = {111049}, doi = {10.1016/j.brainresbull.2024.111049}, pmid = {39142444}, issn = {1873-2747}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Apoptosis/physiology ; *RNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; *Signal Transduction/physiology ; *Proto-Oncogene Proteins c-akt/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism/genetics ; Male ; DNA-Binding Proteins ; Cell Cycle Proteins ; Tumor Suppressor Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by gradual depletion of motor neurons. RNA binding motif protein 5 (RBM5), an abundantly expressed RNA-binding protein, plays a critical role in the process of cellular death. However, little is known about the role of RBM5 in the pathogenesis of ALS. Here, we found that RBM5 was upregulated in ALS hSOD1[G93A]-NSC34 cell models and hSOD1[G93A] mice due to a reduction of miR-141-5p. The upregulation of RBM5 increased the apoptosis of motor neurons by inhibiting Rac1-mediated neuroprotection. In contrast, genetic knockdown of RBM5 rescued motor neurons from hSOD1[G93A]-induced degeneration by activating Rac1 signaling. The neuroprotective effect of RBM5-knockdown was significantly inhibited by the Rac1 inhibitor, NSC23766. These findings suggest that RBM5 could potentially serve as a therapeutic target in ALS by activating the Rac1 signalling.}, } @article {pmid39141854, year = {2024}, author = {Vansteensel, MJ and Leinders, S and Branco, MP and Crone, NE and Denison, T and Freudenburg, ZV and Geukes, SH and Gosselaar, PH and Raemaekers, M and Schippers, A and Verberne, M and Aarnoutse, EJ and Ramsey, NF}, title = {Longevity of a Brain-Computer Interface for Amyotrophic Lateral Sclerosis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {619-626}, pmid = {39141854}, issn = {1533-4406}, support = {INTENSE, 17619//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; UH3 NS114439/NS/NINDS NIH HHS/United States ; U01DC016686/DC/NIDCD NIH HHS/United States ; U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3NS114439/NS/NINDS NIH HHS/United States ; UGT7685, Economic Affairs SSM06011 and STW 12803//Netherlands Institute of Government/ ; }, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/rehabilitation ; *Atrophy/diagnostic imaging/etiology/prevention & control ; Brain/diagnostic imaging ; *Brain-Computer Interfaces ; Communication Aids for Disabled ; Time Factors ; Treatment Failure ; Electrodes, Implanted ; }, abstract = {The durability of communication with the use of brain-computer interfaces in persons with progressive neurodegenerative disease has not been extensively examined. We report on 7 years of independent at-home use of an implanted brain-computer interface for communication by a person with advanced amyotrophic lateral sclerosis (ALS), the inception of which was reported in 2016. The frequency of at-home use increased over time to compensate for gradual loss of control of an eye-gaze-tracking device, followed by a progressive decrease in use starting 6 years after implantation. At-home use ended when control of the brain-computer interface became unreliable. No signs of technical malfunction were found. Instead, the amplitude of neural signals declined, and computed tomographic imaging revealed progressive atrophy, which suggested that ALS-related neurodegeneration ultimately rendered the brain-computer interface ineffective after years of successful use, although alternative explanations are plausible. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02224469.).}, } @article {pmid39141853, year = {2024}, author = {Card, NS and Wairagkar, M and Iacobacci, C and Hou, X and Singer-Clark, T and Willett, FR and Kunz, EM and Fan, C and Vahdati Nia, M and Deo, DR and Srinivasan, A and Choi, EY and Glasser, MF and Hochberg, LR and Henderson, JM and Shahlaie, K and Stavisky, SD and Brandman, DM}, title = {An Accurate and Rapidly Calibrating Speech Neuroprosthesis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {609-618}, pmid = {39141853}, issn = {1533-4406}, support = {U01DC17844/DC/NIDCD NIH HHS/United States ; AL220043//Congressionally Directed Medical Research Programs/ ; U01 DC019430/DC/NIDCD NIH HHS/United States ; R01 MH060974/MH/NIMH NIH HHS/United States ; 872146SPI//Simons Foundation/ ; A2295-R//U.S. Department of Veterans Affairs/ ; DP2DC021055/DC/NIDCD NIH HHS/United States ; U01DC019430/DC/NIDCD NIH HHS/United States ; I01 RX002295/RX/RRD VA/United States ; DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation ; *Brain-Computer Interfaces ; Calibration ; Communication Aids for Disabled ; *Dysarthria/rehabilitation/etiology ; Electrodes, Implanted ; Microelectrodes ; Quadriplegia/etiology/rehabilitation ; *Speech ; }, abstract = {BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy.

METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice.

RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours.

CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).}, } @article {pmid39141064, year = {2024}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6667-6679}, pmid = {39141064}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; Germany ; Middle Aged ; Aged ; *Disease Progression ; Mutation ; Adult ; Phenotype ; }, abstract = {Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.}, } @article {pmid39140323, year = {2024}, author = {Nakamura, T and He, X and Hattori, N and Hida, E and Hirata, M}, title = {Dilemma in patients with amyotrophic lateral sclerosis and expectations from brain-machine interfaces.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2386516}, pmid = {39140323}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Brain-Computer Interfaces ; Male ; Female ; Middle Aged ; Aged ; Surveys and Questionnaires ; *Motivation ; *Caregivers/psychology ; *Anxiety/psychology/etiology ; Adult ; Tracheostomy ; Caregiver Burden/psychology ; Locked-In Syndrome/psychology ; }, abstract = {OBJECTIVE: We hypothesized that patients with amyotrophic lateral sclerosis (ALS) face a dilemma between motivation to live and difficulty in living, and brain-machine interfaces (BMIs) can reduce this dilemma. This study aimed to investigate the present situation of patients with ALS and their expectations from BMIs.

MATERIALS AND METHODS: Our survey design consisted of an anonymous mail-in questionnaire comprising questions regarding the use of tracheostomy positive pressure ventilation (TPPV), motivation to live, anxiety about the totally locked-in state (TLS), anxiety about caregiver burden, and expectations regarding the use of BMI. Primary outcomes were scores for motivation to live and anxiety about caregiver burden and the TLS. Outcomes were evaluated using the visual analogue scale.

RESULTS: Among 460 participants, 286 (62.6%) were already supported by or had decided to use TPPV. The median scores for motivation to live, anxiety about TLS, and anxiety about caregiver burden were 8.0, 9.0, and 7.0, respectively. Overall, 49% of patients intended to use BMI. Among patients who had refused TPPV, 15.9% intended to use BMI and TPPV. Significant factors for the use of BMI were motivation to live (p = .003), anxiety about TLS (p < .001), younger age (p < .001), and advanced disease stage (p < .001).

CONCLUSIONS: These results clearly revealed a serious dilemma among patients with ALS between motivation to live and their anxiety about TLS and caregiver burden. Patients expected BMI to reduce this dilemma. Thus, the development of better BMIs may meet these expectations.}, } @article {pmid39139642, year = {2024}, author = {Liu, X and Li, Y and Huang, L and Kuang, Y and Wu, X and Ma, X and Zhao, B and Lan, J}, title = {Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1450704}, pmid = {39139642}, issn = {1663-9812}, abstract = {The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.}, } @article {pmid39139312, year = {2024}, author = {Kaur, B and Samagh, N and Narang, A and Paliwal, S}, title = {Anesthetic Management of a Neurosurgical Patient With Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64492}, pmid = {39139312}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive form of neurological disorder that affects both the upper and lower motor neurons. Anesthesia management in these patients is always challenging as they can develop respiratory complications because of pre-existing muscle involvement. We report a middle-aged male with ALS posted for chronic subdural hematoma evacuation (CSDH) surgery. Surgery was done under scalp block with monitored anesthesia care. The choice of anesthesia in these patients should be one that interferes the least with the disease pattern while still providing optimal conditions for surgery.}, } @article {pmid39138961, year = {2024}, author = {Rosano, A and Bicaj, M and Cillerai, M and Ponzano, M and Cabona, C and Gemelli, C and Caponnetto, C and Pardini, M and Signori, A and Uccelli, A and Schenone, A and Ferraro, PM}, title = {Psychological resilience is protective against cognitive deterioration in motor neuron diseases.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {717-725}, doi = {10.1080/21678421.2024.2385690}, pmid = {39138961}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Resilience, Psychological ; *Motor Neuron Disease/psychology/complications ; Aged ; *Cognitive Dysfunction/psychology/etiology ; Neuropsychological Tests ; Longitudinal Studies ; Adult ; }, abstract = {OBJECTIVES: Recent studies suggest that psychological resilience (PR) is associated with more well-preserved cognition in healthy subjects (HS), but an investigation of such phenomenon in patients with motor neuron diseases (MNDs) is still lacking. The aim of our study was therefore to evaluate PR and its relationship with baseline cognitive/behavioral and mood symptoms, as well as longitudinal cognitive functioning, in MNDs.

METHODS: 94 MND patients and 87 demographically matched HS were enrolled. PR was assessed using the Connor-Davidson Resilience Scale (CD-RISC). Patients were further evaluated both at baseline and every 6 months for cognitive/behavioral disturbances using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and for mood symptoms using the Hospital Anxiety and Depression Scale (HADS). CD-RISC scores were compared between patients and HS using the Mann-Whitney U test, and regression models were applied to evaluate the role of CD-RISC scores in predicting baseline cognitive/behavioral and mood measures, as well as longitudinal cognitive performances, in MND patients.

RESULTS: MND cases showed significantly greater PR compared to HS (p from <0.001 to 0.02). In MNDs, higher PR levels were significant predictors of both greater cognitive performance (p from 0.01 to 0.05) and milder mood symptoms (p from <0.001 to 0.04) at baseline, as well as less severe memory decline (p from 0.001 to 0.04) longitudinally.

CONCLUSIONS: PR is an important protective factor against the onset and evolution of cognitive/mood disturbances in MNDs, suggesting the usefulness of resilience enhancement psychological interventions to prevent or delay cognitive and mood disorders in these neurodegenerative conditions.}, } @article {pmid39138578, year = {2024}, author = {Wasielewska, JM and Chaves, JCS and Cabral-da-Silva, MC and Pecoraro, M and Viljoen, SJ and Nguyen, TH and Bella, V and Oikari, LE and Ooi, L and White, AR}, title = {A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {65}, pmid = {39138578}, issn = {2045-8118}, support = {PhD Scholarship//University of Queensland/ ; PhD Top-Up Scholarship//QIMR Berghofer Medical Research Institute/ ; APP1125796 and 1118452//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Microbubbles ; *DNA-Binding Proteins/metabolism ; Drug Delivery Systems/methods ; Endothelial Cells/metabolism ; Antibodies/administration & dosage ; Ultrasonic Waves ; Cells, Cultured ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS[+ MB]) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS[+ MB]-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS[+ MB] on human ALS BBB cells remain unexplored.

METHODS: Here we established the first FUS[+ MB]-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS[+ MB] bioeffects in vitro.

RESULTS: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS[+ MB] as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS[+ MB] treated cells. This was accompanied by the molecular bioeffects of FUS[+ MB] in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS[+ MB] in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS[+ MB] can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model.

CONCLUSIONS: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS[+ MB] and provides a fully-human platform for FUS[+ MB]-mediated drug delivery screening on an ALS BBB in vitro model.}, } @article {pmid39138120, year = {2024}, author = {Euler, L and Deinert, K and Wagener, F and Walpurgis, K and Thevis, M}, title = {Identification of human metabolites of fast skeletal troponin activators Tirasemtiv and Reldesemtiv for doping control purposes.}, journal = {Drug testing and analysis}, volume = {}, number = {}, pages = {}, doi = {10.1002/dta.3786}, pmid = {39138120}, issn = {1942-7611}, support = {//Federal Ministry of Interior, Building and Community/ ; //Manfred-Donike-Institute for Doping Analysis/ ; }, abstract = {The fast skeletal troponin activators (FSTAs) Reldesemtiv and Tirasemtiv were developed for patients suffering from neuro-degenerative diseases of the motor nervous system, e.g. amyotrophic lateral sclerosis (ALS). The drug candidates can increase the sensitivity of troponin C to calcium by selectively activating the troponin complex resulting in increased skeletal muscle contraction. Although the development of the drug candidates is currently discontinued because of missed end points in phase III clinical studies with patients with ALS, phase I clinical trials showed an increase in muscle contraction force in healthy humans. This effect could be abused by athletes to enhance performance in sports. As the substances are listed on the 2024 edition of the World Anti-Doping Agency's Prohibited List, the aim of this study was to identify and characterize metabolites of Reldesemtiv and Tirasemtiv to ensure their reliable identification in doping control analyses. The biotransformation of the drug candidates was studied in vitro using pooled human liver microsomes and 3D cultivated human hepatic cells of the cell line HepaRG, yielding a total of 11 metabolites of Reldesemtiv and eight of Tirasemtiv. In addition, a human elimination study was conducted to investigate the metabolism and elimination profile of Tirasemtiv and Reldesemtiv in vivo, suggesting the N-glucuronide of Tirasemtiv and hydroxylated 3-fluoro-2-(3-fluoro-1-methylcyclobutyl)pyridine as well as its glucuronide as suitable target analytes for routine doping controls. Applying a validating HPLC-MS/MS method, optimized to detect Reldesemtiv and Tirasemtiv in human urine, microdosing (50 μg) of each substance was traceable for 24-72 h.}, } @article {pmid39138039, year = {2024}, author = {Candelo, E and Vasudevan, SS and Orellana, D and Williams, AM and Rutt, AL}, title = {Exploring the Impact of Amyotrophic Lateral Sclerosis on Otolaryngological Functions.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2024.07.025}, pmid = {39138039}, issn = {1873-4588}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons at the spinal or bulbar level.

OBJECTIVE: We aim to describe the most frequent otolaryngology (ORL) complaints and voice disturbances in patients with bulbar onset ALS.

DESIGN: Retrospective cohort study.

SETTING: Single-center study with combined ORL and ALS clinic evaluation.

PARTICIPANTS: Patients with a confirmed diagnosis of ALS following an ORL visit and who underwent comprehensive voice assessments between January 2021 and January 2023.

EXPOSURE: Objective voice assessments.

MAIN OUTCOMES AND MEASURES: Glottal functional index (GFI), voice handicap index (VHI), reflux system index (RSI), and voice quality characteristics such as shimmer, jitter, maximum phonation time (MPT), and other essential parameters were assessed.

RESULTS: One hundred and thirty-three patients (age 62.17 ± 10.79, 54.48% female) were included. Three patients were referred from the ORL department to the ALS clinic. The most frequent symptoms were; dysphagia, dysarthria, facial weakness, pseudobulbar affect, and sialorrhea. The mean of forced vital capacity was 59.85%, EAT-10 15.91 ± 11.66, RSI 25.84 ± 9.03, GFI 14.12 ± 5.58, VHI-10 42.81 ± 34.94, MPT 15.22 s ± 8.06. Many patients reported voice impairments mainly related to spastic dysarthria and the combination of lower and upper motor neuron dysarthria, hypernasality, reduced verbal expression, and articulatory accuracy. Shimmer was increased to 8.46% ± 7.20, and jitter to 2.26% ± 1.39.

CONCLUSIONS AND RELEVANCE: Based on our cohort, this population with bulbar onset ALS has a higher frequency of voice disturbance characterized by hypernasality, spastic dysarthria, and reduced verbal expression.

LEVEL OF EVIDENCE: Level 3.}, } @article {pmid39137976, year = {2024}, author = {Pavey, N and Hannaford, A and Higashihara, M and van den Bos, M and Geevasinga, N and Vucic, S and Menon, P}, title = {Cortical inexcitability in ALS: correlating a clinical phenotype.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-333928}, pmid = {39137976}, issn = {1468-330X}, abstract = {BACKGROUND: Cortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic and clinical characteristics were contrasted with normal or hyperexcitable ALS cohorts to assess the impact of cortical inexcitability on ALS phenotype and survival.

METHODS: Threshold-tracking transcranial magnetic stimulation (TMS) technique with measurement of mean short interval intracortical inhibition (SICI) differentiated ALS patients into three groups (1) inexcitable (no TMS response at maximal stimulator output in the setting of preserved lower motor neuron (LMN) function), (2) hyperexcitable (SICI≤5.5%) and (3) normal cortical excitability (SICI>5.5%). Clinical phenotyping and neurophysiological assessment of LMN function were undertaken, and survival was recorded in the entire cohort.

RESULTS: 417 ALS patients were recruited, of whom 26.4% exhibited cortical inexcitability. Cortical inexcitability was associated with a younger age of disease onset (p<0.05), advanced Awaji criteria (p<0.01) and Kings stage (p<0.01) scores. Additionally, patients with cortical inexcitability had higher UMN score (p<0.01), lower revised ALS Functional Rating Scale score (p<0.01) and reduced upper limb strength score (MRC UL, p<0.01). Patient survival (p=0.398) was comparable across the groups, despite lower riluzole use in the cortical inexcitability patient group (p<0.05).

CONCLUSION: The present study established that cortical inexcitability was associated with a phenotype characterised by prominent UMN signs, greater motor and functional decline, and a younger age of onset. The present findings inform patient management and could improve patient stratification in clinical trials.}, } @article {pmid39135084, year = {2024}, author = {Ma, H and Zhu, M and Chen, M and Li, X and Feng, X}, title = {The role of macrophage plasticity in neurodegenerative diseases.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {81}, pmid = {39135084}, issn = {2050-7771}, support = {PX2023037//Beijing Municipal Administration of Hospitals Incubating Program/ ; }, abstract = {Tissue-resident macrophages and recruited macrophages play pivotal roles in innate immunity and the maintenance of brain homeostasis. Investigating the involvement of these macrophage populations in eliciting pathological changes associated with neurodegenerative diseases has been a focal point of research. Dysregulated states of macrophages can compromise clearance mechanisms for pathological proteins such as amyloid-β (Aβ) in Alzheimer's disease (AD) and TDP-43 in Amyotrophic lateral sclerosis (ALS). Additionally, recent evidence suggests that abnormalities in the peripheral clearance of pathological proteins are implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, numerous genome-wide association studies have linked genetic risk factors, which alter the functionality of various immune cells, to the accumulation of pathological proteins. This review aims to unravel the intricacies of macrophage biology in both homeostatic conditions and neurodegenerative disorders. To this end, we initially provide an overview of the modifications in receptor and gene expression observed in diverse macrophage subsets throughout development. Subsequently, we outlined the roles of resident macrophages and recruited macrophages in neurodegenerative diseases and the progress of targeted therapy. Finally, we describe the latest advances in macrophage imaging methods and measurement of inflammation, which may provide information and related treatment strategies that hold promise for informing the design of future investigations and therapeutic interventions.}, } @article {pmid39134696, year = {2024}, author = {Visser, BS and Lipiński, WP and Spruijt, E}, title = {The role of biomolecular condensates in protein aggregation.}, journal = {Nature reviews. Chemistry}, volume = {8}, number = {9}, pages = {686-700}, pmid = {39134696}, issn = {2397-3358}, mesh = {Humans ; *Biomolecular Condensates/metabolism/chemistry ; *Protein Aggregates ; Neurodegenerative Diseases/metabolism ; Amyloid/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {There is an increasing amount of evidence that biomolecular condensates are linked to neurodegenerative diseases associated with protein aggregation, such as Alzheimer's disease and amyotrophic lateral sclerosis, although the mechanisms underlying this link remain elusive. In this Review, we summarize the possible connections between condensates and protein aggregation. We consider both liquid-to-solid transitions of phase-separated proteins and the partitioning of proteins into host condensates. We distinguish five key factors by which the physical and chemical environment of a condensate can influence protein aggregation, and we discuss their relevance in studies of protein aggregation in the presence of biomolecular condensates: increasing the local concentration of proteins, providing a distinct chemical microenvironment, introducing an interface wherein proteins can localize, changing the energy landscape of aggregation pathways, and the presence of chaperones in condensates. Analysing the role of biomolecular condensates in protein aggregation may be essential for a full understanding of amyloid formation and offers a new perspective that can help in developing new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid39134599, year = {2024}, author = {Mikawy, NN and Magdy, N and Mohamed, MH and El-Kosasy, AM}, title = {Green highly sensitive and selective spectroscopic detection of guaifenesin in multiple dosage forms and spiked human plasma.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18694}, pmid = {39134599}, issn = {2045-2322}, mesh = {*Guaifenesin/analysis/administration & dosage ; Humans ; *Limit of Detection ; *Spectrometry, Fluorescence/methods ; Tablets ; Green Chemistry Technology/methods ; }, abstract = {Guaifenesin (GUA) is determined in dosage forms and plasma using two methods. The spectrofluorimetric technique relies on the measurement of native fluorescence intensity at 302 nm upon excitation wavelength "223 nm". The method was validated according to ICH and FDA guidelines. A concentration range of 0.1-1.1 μg/mL was used, with limit of detection (LOD) and quantification (LOQ) values 0.03 and 0.08 µg/mL, respectively. This method was used to measure GUA in tablets and plasma, with %recovery of 100.44% ± 0.037 and 101.03% ± 0.751. Furthermore, multivariate chemometric-assisted spectrophotometric methods are used for the determination of GUA, paracetamol (PARA), oxomemazine (OXO), and sodium benzoate (SB) in their lab mixtures. The concentration ranges of 2.0-10.0, 4.0-16.0, 2.0-10.0, and 3.0-10.0 µg/mL for OXO, GUA, PARA, and SB; respectively, were used. LOD and LOQ were 0.33, 0.68, 0.28, and 0.29 µg/mL, and 1.00, 2.06, 0.84, and 0.87 µg/mL for PARA, GUA, OXO, and SB. For the suppository application, the partial least square (PLS) model was used with %recovery 98.49% ± 0.5, 98.51% ± 0.64, 100.21% ± 0.36 & 98.13% ± 0.51, although the multivariate curve resolution alternating least-squares (MCR-ALS) model was used with %recovery 101.39 ± 0.45, 99.19 ± 0.2, 100.24 ± 0.12, and 98.61 ± 0.32 for OXO, GUA, PARA, and SB. Analytical Eco-scale and Analytical Greenness Assessment were used to assess the greenness level of our techniques.}, } @article {pmid39131911, year = {2024}, author = {Ikeda, A and Meng, H and Taniguchi, D and Mio, M and Funayama, M and Nishioka, K and Yoshida, M and Li, Y and Yoshino, H and Inoshita, T and Shiba-Fukushima, K and Okubo, Y and Sakurai, T and Amo, T and Aiba, I and Saito, Y and Saito, Y and Murayama, S and Atsuta, N and Nakamura, R and Tohnai, G and Izumi, Y and Morita, M and Tamura, A and Kano, O and Oda, M and Kuwabara, S and Yamashita, T and Sone, J and Kaji, R and Sobue, G and Imai, Y and Hattori, N}, title = {CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca[2+] homeostasis.}, journal = {PNAS nexus}, volume = {3}, number = {8}, pages = {pgae319}, pmid = {39131911}, issn = {2752-6542}, abstract = {CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca[2+] buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca[2+]-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca[2+] facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca[2+] dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.}, } @article {pmid39130445, year = {2024}, author = {Phipps, AJ and Dwyer, S and Collins, JM and Kabir, F and Atkinson, RA and Chowdhury, MA and Matthews, L and Dixit, D and Terry, RS and Smith, J and Gueven, N and Bennett, W and Cook, AL and King, AE and Perry, S}, title = {HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1[G93A] mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {14}, pages = {e34587}, pmid = {39130445}, issn = {2405-8440}, abstract = {The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1[G93A] mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1[G93A] mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.}, } @article {pmid39128808, year = {2024}, author = {Farhangian, M and Azarafrouz, F and Valian, N and Dargahi, L}, title = {The role of interferon beta in neurological diseases and its potential therapeutic relevance.}, journal = {European journal of pharmacology}, volume = {981}, number = {}, pages = {176882}, doi = {10.1016/j.ejphar.2024.176882}, pmid = {39128808}, issn = {1879-0712}, mesh = {Humans ; Animals ; *Interferon-beta/therapeutic use/metabolism ; Nervous System Diseases/drug therapy/metabolism ; Signal Transduction/drug effects ; }, abstract = {Interferon beta (IFNβ) is a member of the type-1 interferon family and has various immunomodulatory functions in neuropathological conditions. Although the level of IFNβ is low under healthy conditions, it is increased during inflammatory processes to protect the central nervous system (CNS). In particular, microglia and astrocytes are the main sources of IFNβ upon inflammatory insult in the CNS. The protective effects of IFNβ are well characterized in reducing the progression of multiple sclerosis (MS); however, little is understood about its effects in other neurological/neurodegenerative diseases. In this review, different types of IFNs and their signaling pathways will be described. Then we will focus on the potential role and therapeutic effect of IFNβ in several CNS-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury, prion disease and spinocerebellar ataxia 7.}, } @article {pmid39128727, year = {2024}, author = {George, G and Ajayan, A and Varkey, J and Pandey, NK and Chen, J and Langen, R}, title = {TDP43 and huntingtin Exon-1 undergo a conformationally specific interaction that strongly alters the fibril formation of both proteins.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {9}, pages = {107660}, pmid = {39128727}, issn = {1083-351X}, mesh = {*Huntingtin Protein/metabolism/genetics/chemistry ; Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Exons ; Amyloid/metabolism/chemistry ; Protein Aggregates ; Protein Aggregation, Pathological/metabolism/genetics ; Protein Binding ; Protein Conformation ; Protein Domains ; }, abstract = {Protein aggregation is a common feature of many neurodegenerative diseases. In Huntington's disease, mutant huntingtin is the primary aggregating protein, but the aggregation of other proteins, such as TDP43, is likely to further contribute to toxicity. Moreover, mutant huntingtin is also a risk factor for TDP pathology in ALS. Despite this co-pathology of huntingtin and TDP43, it remains unknown whether these amyloidogenic proteins directly interact with each other. Using a combination of biophysical methods, we show that the aggregation-prone regions of both proteins, huntingtin exon-1 (Httex1) and the TDP43 low complexity domain (TDP43-LCD), interact in a conformationally specific manner. This interaction significantly slows Httex1 aggregation, while it accelerates TDP43-LCD aggregation. A key intermediate responsible for both effects is a complex formed by liquid TDP43-LCD condensates and Httex1 fibrils. This complex shields seeding competent surfaces of Httex1 fibrils from Httex1 monomers, which are excluded from the condensates. In contrast, TDP43-LCD condensates undergo an accelerated liquid-to-solid transition upon exposure to Httex1 fibrils. Cellular studies show co-aggregation of untagged Httex1 with TDP43. This interaction causes mislocalization of TDP43, which has been linked to TDP43 toxicity. The protection from Httex1 aggregation in lieu of TDP43-LCD aggregation is interesting, as it mirrors what has been found in disease models, namely that TDP43 can protect from huntingtin toxicity, while mutant huntingtin can promote TDP43 pathology. These results suggest that direct protein interaction could, at least in part, be responsible for the linked pathologies of both proteins.}, } @article {pmid39128005, year = {2024}, author = {Knupp, J and Chen, YJ and Wang, E and Arvan, P and Tsai, B}, title = {Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114619}, pmid = {39128005}, issn = {2211-1247}, support = {F31 DK128868/DK/NIDDK NIH HHS/United States ; R01 DK111174/DK/NIDDK NIH HHS/United States ; }, mesh = {*Receptors, sigma/metabolism/genetics ; *Sigma-1 Receptor ; *Autophagy ; *Microtubule-Associated Proteins/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; Humans ; *RNA, Messenger/metabolism/genetics ; *3' Untranslated Regions/genetics ; *Protein Biosynthesis ; Ribosomes/metabolism ; Animals ; Autophagosomes/metabolism ; HeLa Cells ; }, abstract = {Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3' UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3' UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3' UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3' UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.}, } @article {pmid39127445, year = {2024}, author = {Wang, MY and Zhou, Y and Li, WL and Zhu, LQ and Liu, D}, title = {Friend or foe: Lactate in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102452}, doi = {10.1016/j.arr.2024.102452}, pmid = {39127445}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Lactic Acid/metabolism ; Animals ; }, abstract = {Lactate, a byproduct of glycolysis, was considered as a metabolic waste until identified by studies on the Warburg effect. Increasing evidence elucidates that lactate functions as energy fuel, signaling molecule, and donor for protein lactylation. Altered lactate utilization is a common metabolic feature of the onset and progression of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. This review offers an overview of lactate metabolism from the perspective of production, transportation and clearance, and the role of lactate in neurodegenerative progression, as well as a summary of protein lactylation and the signaling function of lactate in neurodegenerative diseases. Besides, this review delves into the dual roles of changed lactate metabolism during neurodegeneration and explores prospective therapeutic methods targeting lactate. We propose that elucidating the correlation between lactate and neurodegeneration is pivotal for exploring innovative therapeutic interventions for neurodegenerative diseases.}, } @article {pmid39126873, year = {2024}, author = {Vacchiano, V and Di Stasi, V and Teodorani, L and Faini, C and Morabito, F and Liguori, R}, title = {Comparative assessment of MScanFit MUNE and quantitative EMG in amyotrophic lateral sclerosis diagnosis: A prospective study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {166}, number = {}, pages = {66-73}, doi = {10.1016/j.clinph.2024.07.017}, pmid = {39126873}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Electromyography/methods ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; *Motor Neurons/physiology ; *Action Potentials/physiology ; *Muscle, Skeletal/physiopathology ; Adult ; }, abstract = {OBJECTIVE: Motor Unit Number Estimation (MUNE) techniques are crucial in assessing lower motor neuron loss. MScanFit MUNE (MScanFit) is a novel tool which estimates MUNE values from compound muscle action potential (CMAP) scans by considering the probabilistic nature of motor unit firing. We conducted a prospective study to evaluate the diagnostic utility of MScanFit compared to quantitative electromyography (qEMG) in ALS patients.

METHODS: We enrolled 35 patients diagnosed with amyotrophic lateral sclerosis (ALS) and 14 healthy controls, assessing qEMG and MScanFit MUNE in abductor pollicis brevis, abductor digiti minimi and tibialis anterior muscles.

RESULTS: We found higher sensitivity of qEMG in detecting abnormalities compared to MScanFit, with a high concordance rate between the two techniques. Notably, a few muscles exhibited abnormal MUNE but normal qEMG findings, suggesting a potential complementary role for MScanFit in ALS diagnosis. Neurophysiological parameters from MScanFit showed good correlations with qEMG measures. Subclinical neurophysiological involvement was observed in muscles with normal strength, emphasizing the importance of sensitive diagnostic tools.

CONCLUSION: MScanFit demonstrated validity in distinguishing ALS patients from healthy subjects and correlated well with qEMG parameters.

SIGNIFICANCE: Our study confirmed the diagnostic utility of MScanFit MUNE in ALS, highlighting its role as a supplementary diagnostic tool.}, } @article {pmid39126786, year = {2024}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Multimodal speech biomarkers for remote monitoring of ALS disease progression.}, journal = {Computers in biology and medicine}, volume = {180}, number = {}, pages = {108949}, pmid = {39126786}, issn = {1879-0534}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; *Disease Progression ; Female ; Middle Aged ; Aged ; Speech/physiology ; Biomarkers ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.}, } @article {pmid39126203, year = {2024}, author = {Tabuchi, R and Momozawa, Y and Hayashi, Y and Noma, H and Ichijo, H and Fujisawa, T}, title = {SoDCoD: a comprehensive database of Cu/Zn superoxide dismutase conformational diversity caused by ALS-linked gene mutations and other perturbations.}, journal = {Database : the journal of biological databases and curation}, volume = {2024}, number = {}, pages = {0}, pmid = {39126203}, issn = {1758-0463}, support = {JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology ; Humans ; *Mutation ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Databases, Protein ; Protein Conformation ; Databases, Genetic ; Superoxide Dismutase/genetics/chemistry/metabolism ; }, abstract = {A structural alteration in copper/zinc superoxide dismutase (SOD1) is one of the common features caused by amyotrophic lateral sclerosis (ALS)-linked mutations. Although a large number of SOD1 variants have been reported in ALS patients, the detailed structural properties of each variant are not well summarized. We present SoDCoD, a database of superoxide dismutase conformational diversity, collecting our comprehensive biochemical analyses of the structural changes in SOD1 caused by ALS-linked gene mutations and other perturbations. SoDCoD version 1.0 contains information about the properties of 188 types of SOD1 mutants, including structural changes and their binding to Derlin-1, as well as a set of genes contributing to the proteostasis of mutant-like wild-type SOD1. This database provides valuable insights into the diagnosis and treatment of ALS, particularly by targeting conformational alterations in SOD1. Database URL: https://fujisawagroup.github.io/SoDCoDweb/.}, } @article {pmid39126144, year = {2024}, author = {Briones, MRS and Campos, JH and Ferreira, RC and Schneper, L and Santos, IM and Antoneli, FM and , and Broach, JR}, title = {Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {862-872}, pmid = {39126144}, issn = {1097-4598}, support = {//Tow Foundation/ ; //NIH/ ; 2013/07838-0//FAPESP/ ; 2014/25602-6//FAPESP/ ; //CAPES/ ; 303912/2017-0//CNPq/ ; T32 LM012415/LM/NLM NIH HHS/United States ; 19-SI-459//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genome, Mitochondrial/genetics ; Male ; Female ; *Genome-Wide Association Study ; Middle Aged ; Haplotypes ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease/genetics ; Aged ; Genetic Variation/genetics ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS.

METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls.

RESULTS: We identified 51 mitogenome variants with p values <10[-7], of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.

DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.}, } @article {pmid39126066, year = {2024}, author = {Mejzini, R and Caruthers, MH and Schafer, B and Kostov, O and Sudheendran, K and Ciba, M and Danielsen, M and Wilton, S and Akkari, PA and Flynn, LL}, title = {Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {15}, pages = {}, pmid = {39126066}, issn = {1422-0067}, support = {2322//Motor Neurone Disease Research Australia/ ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; *RNA-Binding Protein FUS/genetics ; *Alleles ; Fibroblasts/metabolism/drug effects ; Gene Knockdown Techniques ; Morpholinos/therapeutic use/genetics ; }, abstract = {Pathogenic variations in the fused in sarcoma (FUS) gene are associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS). As FUS-ALS is a dominant disease, a targeted, allele-selective approach to FUS knockdown is most suitable. Antisense oligonucleotides (AOs) are a promising therapeutic platform for treating such diseases. In this study, we have explored the potential for allele-selective knockdown of FUS. Gapmer-type AOs targeted to two common neutral polymorphisms in FUS were designed and evaluated in human fibroblasts. AOs had either methoxyethyl (MOE) or thiomorpholino (TMO) modifications. We found that the TMO modification improved allele selectivity and efficacy for the lead sequences when compared to the MOE counterparts. After TMO-modified gapmer knockdown of the target allele, up to 93% of FUS transcripts detected were from the non-target allele. Compared to MOE-modified AOs, the TMO-modified AOs also demonstrated reduced formation of structured nuclear inclusions and SFPQ aggregation that can be triggered by phosphorothioate-containing AOs. How overall length and gap length of the TMO-modified AOs affected allele selectivity, efficiency and off-target gene knockdown was also evaluated. We have shown that allele-selective knockdown of FUS may be a viable therapeutic strategy for treating FUS-ALS and demonstrated the benefits of the TMO modification for allele-selective applications.}, } @article {pmid39125740, year = {2024}, author = {Bernard, E and Cluse, F and Bohic, A and Hermier, M and Raoul, C and Leblanc, P and Guissart, C}, title = {A Novel De Novo Missense Mutation in KIF1A Associated with Young-Onset Upper-Limb Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {15}, pages = {}, pmid = {39125740}, issn = {1422-0067}, mesh = {Humans ; *Kinesins/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Female ; *Mutation, Missense ; Adult ; Upper Extremity/physiopathology/pathology ; Magnetic Resonance Imaging ; }, abstract = {We investigate the etiology of amyotrophic lateral sclerosis (ALS) in a 35-year-old woman presenting with progressive weakness in her left upper limb. Prior to sequencing, a comprehensive neurological work-up was performed, including neurological examination, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Six months before evaluation, the patient experienced weakness and atrophy in her left hand, accompanied by brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Trio genome sequencing identified a likely pathogenic de novo variant in the KIF1A gene (NM_001244008.2): c.574A>G, p.(Ile192Val). Pathogenic variants in KIF1A have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). This report describes a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS.}, } @article {pmid39124808, year = {2024}, author = {Miyaue, N and Yamanishi, Y and Ito, Y and Ando, R and Nagai, M}, title = {CSF Neopterin Levels Are Elevated in Various Neurological Diseases and Aging.}, journal = {Journal of clinical medicine}, volume = {13}, number = {15}, pages = {}, pmid = {39124808}, issn = {2077-0383}, abstract = {Background/Objectives: Cerebrospinal fluid (CSF) neopterin reflects inflammation of the central nervous system (CNS) and is a potentially useful biomarker for neuroinflammatory assessment and differential diagnosis. However, its optimal cut-off level in adult patients with neurological disease has not been established and it has not been adequately studied in controls. We aimed to determine its usefulness as a biomarker of neuroinflammation and the effect of age on its level. Methods: In this retrospective study, CSF neopterin was evaluated in 652 patients in 38 disease groups. Its levels were analyzed with high-performance liquid chromatography with fluorometric detection. Results: A receiver operating characteristic analysis revealed that the optimal cut-off value of 33.57 pmol/mL for CSF neopterin distinguished the control and meningitis/encephalitis groups with a sensitivity of 100.0% and specificity of 94.4%. In the control group, which consisted of 170 participants (99 men and 71 women; mean ± standard deviation age, 52.56 ± 17.99 years), age was significantly positively correlated with CSF protein (r = 0.474, p < 0.001) and CSF neopterin (r = 0.476, p < 0.001) levels but not with CSF cell count (r = 0.144, p = 0.061). Both male and female controls exhibited significant increases in CSF neopterin levels with age. Similarly, the CSF neopterin level was significantly positively correlated with age in patients with amyotrophic lateral sclerosis, independently of disease duration and respiratory function. Conclusions: CSF neopterin levels were elevated in patients with various CNS diseases, reflecting CNS inflammation; they were also elevated with age. Prospective studies are required to establish CSF neopterin as a sensitive biomarker of neuroinflammation.}, } @article {pmid39123212, year = {2024}, author = {Wang, X and Pan, W and Sun, C and Yang, H and Cheng, Z and Yan, F and Ma, G and Shang, Y and Zhang, R and Gao, C and Liu, L and Zhang, H}, title = {Creating large-scale genetic diversity in Arabidopsis via base editing-mediated deep artificial evolution.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {215}, pmid = {39123212}, issn = {1474-760X}, support = {TSQN202103160//Taishan Scholar Foundation of Shandong Province/ ; ZR202103010168//Excellent Youth Foundation of Shandong Scientific Committee/ ; 2022YFD1201700//National Key R&D Program of China/ ; }, mesh = {*Arabidopsis/genetics ; *Gene Editing/methods ; *Genetic Variation ; CRISPR-Cas Systems ; Directed Molecular Evolution ; Alleles ; Mutation ; Plant Breeding/methods ; Herbicide Resistance/genetics ; }, abstract = {BACKGROUND: Base editing is a powerful tool for artificial evolution to create allelic diversity and improve agronomic traits. However, the great evolutionary potential for every sgRNA target has been overlooked. And there is currently no high-throughput method for generating and characterizing as many changes in a single target as possible based on large mutant pools to permit rapid gene directed evolution in plants.

RESULTS: In this study, we establish an efficient germline-specific evolution system to screen beneficial alleles in Arabidopsis which could be applied for crop improvement. This system is based on a strong egg cell-specific cytosine base editor and the large seed production of Arabidopsis, which enables each T1 plant with unedited wild type alleles to produce thousands of independent T2 mutant lines. It has the ability of creating a wide range of mutant lines, including those containing atypical base substitutions, and as well providing a space- and labor-saving way to store and screen the resulting mutant libraries. Using this system, we efficiently generate herbicide-resistant EPSPS, ALS, and HPPD variants that could be used in crop breeding.

CONCLUSIONS: Here, we demonstrate the significant potential of base editing-mediated artificial evolution for each sgRNA target and devised an efficient system for conducting deep evolution to harness this potential.}, } @article {pmid39122743, year = {2024}, author = {Shin, B and Kwon, Y and Mittaz, M and Kim, H and Xu, X and Kim, E and Lee, YJ and Lee, J and Yeo, WH and Choo, HJ}, title = {All-in-one wearable drug efficacy assessment systems for bulbar muscle function using amyotrophic lateral sclerosis animal models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6803}, pmid = {39122743}, issn = {2041-1723}, support = {R21 EB031535/EB/NIBIB NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; R21EB031535//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy ; Animals ; *Disease Models, Animal ; *Wearable Electronic Devices ; *Electromyography/methods ; Drug Evaluation, Preclinical ; Deglutition Disorders/physiopathology/etiology ; Muscle, Skeletal/drug effects/physiopathology/innervation ; Humans ; Male ; Motor Neurons/drug effects/physiology ; Rats ; }, abstract = {Preclinical studies are crucial for developing amyotrophic lateral sclerosis drugs. Current FDA-approved drugs have been created by monitoring limb muscle function and histological analysis of amyotrophic lateral sclerosis model animals. Drug candidates for this disease have yet to be tested for bulbar-onset type due to the limitations of traditional preclinical tools: excessive animal use and discrete detection of disease progress. Here, our study introduces an all-in-one, wireless, integrated wearable system for facilitating continuous drug efficacy assessment of dysphagia-related muscles in animals during natural eating behaviors. By incorporating a kirigami-based strain-isolation mechanism, this device mounted on the skin of animals mitigates electromyography signal contamination caused by unpredictable animal movements. Our findings indicate this system, measuring the progression of motor neuron denervation, offers high precision in monitoring drug effects on dysphagia-responsible bulbar muscles. This study paves the way for more humane and efficient approaches to developing treatment solutions for degenerative neuromuscular diseases.}, } @article {pmid39122453, year = {2024}, author = {Khan, S and Bano, N and Ahamad, S and John, U and Dar, NJ and Bhat, SA}, title = {Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0125-1}, pmid = {39122453}, issn = {2152-5250}, abstract = {Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.}, } @article {pmid39122262, year = {2024}, author = {Wang, S and Jiang, Q and Zheng, X and Wei, Q and Lin, J and Yang, T and Xiao, Y and Li, C and Shang, H}, title = {Genotype-phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {61}, number = {10}, pages = {966-972}, doi = {10.1136/jmg-2023-109569}, pmid = {39122262}, issn = {1468-6244}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Frontotemporal Dementia/genetics/pathology ; Gene Frequency ; *Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Mutation ; Phenotype ; *Sequestosome-1 Protein/genetics ; Young Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Several variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear.

METHODS: We screened variants of SQSTM1 gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants of SQSTM1 gene in patients with ALS from our cohort and published studies.

RESULTS: In our cohort, we identified 32 patients with 25 different SQSTM1 variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency of SQSTM1 variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants in SQSTM1. Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget's disease of bone and FTD.

CONCLUSION: Our study established the largest cohort of patients with ALS with SQSTM1 variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of SQSTM1 variants.}, } @article {pmid39122006, year = {2024}, author = {Chen, X and Wei, Q and Yang, Z and Chen, X and Guo, S and Jiang, M and Wang, M}, title = {Structural basis for RNA recognition by the C-terminal RRM domain of human RBM45.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {9}, pages = {107640}, pmid = {39122006}, issn = {1083-351X}, mesh = {Humans ; *RNA-Binding Proteins/metabolism/chemistry/genetics ; *RNA/metabolism/chemistry ; Crystallography, X-Ray ; Protein Domains ; Protein Binding ; DNA, Single-Stranded/metabolism/chemistry/genetics ; Models, Molecular ; Nerve Tissue Proteins ; }, abstract = {RBM45 is an RNA-binding protein with roles in neural development by regulating RNA splicing. Its dysfunction and aggregation are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). RBM45 harbors three RRM domains that potentially bind RNA. While the recognitions of RNA by its N-terminal tandem RRM domains (RRM1 and RRM2) have been well understood, the RNA-binding property of its C-terminal RRM (RRM3) remains unclear. In this work, we identified that the RRM3 of the RBM45 sequence specifically binds RNA with a GACG sequence, similar but not identical to those recognized by the RRM1 and RRM2. Further, we determined the crystal structure of RBM45[RRM3] in complex with a GACG sequence-containing single-stranded DNA. Our structural results, together with the RNA-binding assays of mutants at key amino acid residues, revealed the molecular mechanism by which RBM45[RRM3] recognizes an RNA sequence. Our finding on the RNA-binding property of the individual RRM module of RBM45 provides the foundation for unraveling the RNA-binding characteristics of full-length RBM45 and for understanding the biological functions of RBM45.}, } @article {pmid39121134, year = {2024}, author = {Roos, A and Häusler, M and Kollipara, L and Topf, A and Preusse, C and Stucka, R and Nolte, K and Strom, T and Berutti, R and Jiang, X and Koll, R and Lochmüller, H and Schacht, SM and Zahedi, RP and Weis, J and Senderek, J}, title = {HNRNPA1 de novo Variant Associated with Early Childhood Onset, Rapidly Progressive Generalized Myopathy.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {5}, pages = {1131-1137}, pmid = {39121134}, issn = {2214-3602}, mesh = {Humans ; Female ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; *Muscular Diseases/genetics ; Disease Progression ; Age of Onset ; Muscle, Skeletal/pathology ; Phenotype ; Mutation ; Child ; }, abstract = {HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.}, } @article {pmid39120329, year = {2024}, author = {Steffke, C and Agarwal, S and Kabashi, E and Catanese, A}, title = {Overexpression of Toxic Poly(Glycine-Alanine) Aggregates in Primary Neuronal Cultures Induces Time-Dependent Autophagic and Synaptic Alterations but Subtle Activity Impairments.}, journal = {Cells}, volume = {13}, number = {15}, pages = {}, pmid = {39120329}, issn = {2073-4409}, mesh = {*Autophagy ; *Neurons/metabolism ; Animals ; *Synapses/metabolism ; *C9orf72 Protein/genetics/metabolism ; Cells, Cultured ; Peptides/metabolism ; Humans ; Protein Aggregates ; }, abstract = {The pathogenic expansion of the intronic GGGGCC hexanucleotide located in the non-coding region of the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the accumulation of toxic RNA foci and dipeptide repeats (DPRs), as well as reduced levels of the C9orf72 protein. Thus, both gain and loss of function are coexisting pathogenic aspects linked to C9orf72-ALS/FTD. Synaptic alterations have been largely described in C9orf72 models, but it is still not clear which aspect of the pathology mostly contributes to these impairments. To address this question, we investigated the dynamic changes occurring over time at the synapse upon accumulation of poly(GA), the most abundant DPR. Overexpression of this toxic form induced a drastic loss of synaptic proteins in primary neuron cultures, anticipating autophagic defects. Surprisingly, the dramatic impairment characterizing the synaptic proteome was not fully matched by changes in network properties. In fact, high-density multi-electrode array analysis highlighted only minor reductions in the spike number and firing rate of poly(GA) neurons. Our data show that the toxic gain of function linked to C9orf72 affects the synaptic proteome but exerts only minor effects on the network activity.}, } @article {pmid39119557, year = {2024}, author = {Fogarty, MJ and Drieberg-Thompson, JR and Bellingham, MC and Noakes, PG}, title = {Timeline of hypoglossal motor neuron death and intrinsic tongue muscle denervation in high-copy number SOD1[G93A] mice.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1422943}, pmid = {39119557}, issn = {1664-2295}, support = {R56 HL166204/HL/NHLBI NIH HHS/United States ; }, abstract = {In amyotrophic lateral sclerosis (ALS) postmortem tissue and the SOD1 mouse model at mid-disease, death of hypoglossal motor neurons (XII MNs) is evident. These XII MNs innervate the intrinsic and extrinsic tongue muscles, and despite their importance in many oral and lingual motor behaviours that are affected by ALS (e.g., swallowing, speech, and respiratory functions), little is known about the timing and extent of tongue muscle denervation. Here in the well-characterised SOD1[G93A] (high-copy) mouse model, we evaluated XII MN numbers and intrinsic tongue muscle innervation using standard histopathological approaches, which included stereological evaluation of Nissl-stained brainstem, and the presynaptic and postsynaptic evaluation of neuromuscular junctions (NMJs), using synapsin, neurofilament, and α-bungarotoxin immunolabelling, at presymptomatic, onset, mid-disease, and endstage timepoints. We found that reduction in XII MN size at onset preceded reduced XII MN survival, while the denervation of tongue muscle did not appear until the endstage. Our study suggests that denervation-induced weakness may not be the most pertinent feature of orolingual deficits in ALS. Efforts to preserve oral and respiratory functions of XII MNs are incredibly important if we are to influence patient outcomes.}, } @article {pmid39119436, year = {2024}, author = {Galeazzi, L and Holzman, J and Porporatti, A and Rochefort, J}, title = {Lingual Fasciculation as a Point of Call for the Diagnosis of Amyotrophic Lateral Sclerosis: A Literature Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64153}, pmid = {39119436}, issn = {2168-8184}, abstract = {BACKGROUND AND AIM: Dental surgeons often play a pivotal role in the initial detection of lingual fasciculations (LFs). These involuntary micro-movements of the tongue can serve as early clinical indicators of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most concerning. Therefore, it is imperative to educate dental surgeons on identifying LF and understanding the potential underlying pathologies.

OBJECTIVES: This study aimed to pinpoint the pathologies in which LFs could emerge as an early clinical marker. Our review focused on articles delineating patient populations exhibiting LF within broader pathological contexts, encompassing neurological and other conditions, with the aim of elucidating their etiologies.

METHODS: We conducted a comprehensive literature review across four databases (PubMed, Embase, Web of Science, and Scopus). Two authors independently extracted data, with consultation from a third author when necessary. Eligible articles included those describing patients with LFs, detailing the methods of detection, diagnosis, and associated pathologies.

RESULTS: Our review identified 22 articles encompassing 153 patients with LF, with an average age of 45.8 years and a female prevalence of 43%. Electromyography and ultrasound emerged as the predominant detection methods. ALS constituted the primary diagnosis in the majority of cases (91%). Additionally, other conditions diagnosed included Machado-Joseph disease (0.046%), familial transthyretin amyloid neuropathy (0.013%), Brown-Vialetto-Van-Laere syndrome (0.006%), chronic inflammatory demyelinating polyneuropathy (0.006%), bulbospinal amyotrophy or Kennedy's disease (0.006%), and osmotic demyelination syndrome (0.006%). LF secondary to organophosphate poisoning was also documented. Symptoms associated with LF encompassed taste alterations, dysphagia, difficulty swallowing, and slurred speech.

CONCLUSION: While primarily indicative of ALS, LFs may also signal diverse underlying pathologies. Healthcare practitioners should be vigilant in their detection and expedite patient referrals to facilitate early integration into care protocols.}, } @article {pmid39119372, year = {2024}, author = {Maristany, AJ and Sa, BC and Murray, C and Subramaniam, AB and Oldak, SE}, title = {Psychiatric Manifestations of Neurological Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64152}, pmid = {39119372}, issn = {2168-8184}, abstract = {Neurological diseases often manifest with psychiatric symptoms, profoundly impacting patients' well-being and treatment outcomes. This comprehensive review examines the psychiatric manifestations associated with Alzheimer's disease, frontotemporal dementia (FTD), Parkinson's disease, multiple sclerosis (MS), stroke, epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and multiple system atrophy (MSA). Key psychiatric symptoms include agitation, depression, anxiety, apathy, hallucinations, impulsivity, and aggression across these diseases. In addition, ethical considerations in treating these symptoms are paramount, particularly regarding genetic testing implications, end-of-life discussions, informed consent, and equitable access to innovative treatments. Effective management necessitates interdisciplinary collaboration, personalized interventions, and a focus on patient autonomy. Understanding the psychiatric burden of neurological diseases is crucial for enhancing patients' quality of life. Further research is needed to elucidate underlying mechanisms and develop targeted interventions. This review underscores the importance of comprehensive assessment and ethical treatment practices to address psychiatric manifestations effectively.}, } @article {pmid39118204, year = {2024}, author = {Fang, SY and Tsai, PC and Jih, KY and Hsu, FC and Liao, YC and Yang, CC and Lee, YC}, title = {TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {87}, number = {10}, pages = {920-926}, doi = {10.1097/JCMA.0000000000001147}, pmid = {39118204}, issn = {1728-7731}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; *Protein Serine-Threonine Kinases/genetics ; Adult ; *Haploinsufficiency ; *Age of Onset ; Disease Progression ; }, abstract = {BACKGROUND: TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS.

METHODS: The coding regions of TBK1 , SOD1 , TARDBP , and FUS were genetically analyzed using Sanger sequencing. Repeat-primed polymerase chain reaction (PCR) was used to survey the GGGGCC repeat in C9ORF72 . The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies.

RESULTS: We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization.

CONCLUSION: The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.}, } @article {pmid39117623, year = {2024}, author = {Hale, OJ and Wells, TR and Mead, RJ and Cooper, HJ}, title = {Mass spectrometry imaging of SOD1 protein-metal complexes in SOD1G93A transgenic mice implicates demetalation with pathology.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {6518}, pmid = {39117623}, issn = {2041-1723}, support = {EP/S002979/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; EP/S002979/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; BB/S019456/1//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Spinal Cord/metabolism/pathology ; *Mass Spectrometry/methods ; *Brain/metabolism/diagnostic imaging/pathology ; Copper/metabolism ; Zinc/metabolism ; Humans ; Superoxide Dismutase/metabolism/genetics/chemistry ; Mutation ; Protein Processing, Post-Translational ; Protein Multimerization ; Disease Models, Animal ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the central nervous system (CNS). Mutations in the metalloenzyme SOD1 are associated with inherited forms of ALS and cause a toxic gain of function thought to be mediated by dimer destabilization and misfolding. SOD1 binds two Cu and two Zn ions in its homodimeric form. We have applied native ambient mass spectrometry imaging to visualize the spatial distributions of intact metal-bound SOD1[G93A] complexes in SOD1[G93A] transgenic mouse spinal cord and brain sections and evaluated them against disease pathology. The molecular specificity of our approach reveals that metal-deficient SOD1[G93A] species are abundant in CNS structures correlating with ALS pathology whereas fully metalated SOD1[G93A] species are homogenously distributed. Monomer abundance did not correlate with pathology. We also show that the dimer-destabilizing post-translational modification, glutathionylation, has limited influence on the spatial distribution of SOD1 dimers.}, } @article {pmid39117616, year = {2024}, author = {Ramzan, F and Kumar, A and Abrar, F and Gray, RAV and Campbell, ZE and Liao, LMQ and Dang, A and Akanni, O and Guyn, C and Martin, DDO}, title = {Fatty links between multisystem proteinopathy and small VCP-interacting protein.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {358}, pmid = {39117616}, issn = {2058-7716}, abstract = {Multisystem proteinopathy (MSP) is a rare, dominantly inherited disorder that includes a cluster of diseases, including frontotemporal dementia, inclusion body myopathy, and Paget's disease of bone. MSP is caused by mutations in the gene encoding valosin-containing protein (VCP). Patients with the same mutation, even within the same family, can present with a different combination of any or all of the above diseases, along with amyotrophic lateral sclerosis (ALS). The pleiotropic effects may be linked to the greater than 50 VCP co-factors that direct VCP's many roles in the cell. Small VCP-interacting protein (SVIP) is a small protein that directs VCP to autophagosomes and lysosomes. We found that SVIP directs VCP localization to lysosomes in an acylation-dependent manner. We demonstrate that SVIP is myristoylated at Glycine 2 and palmitoylated at Cysteines 4 and 7. Acylation of SVIP is required to mediate cell death in the presence of the MSP-associated VCP variant (R155H-VCP), whereas blocking SVIP myristoylation prevents cytotoxicity. Therefore, SVIP acylation may present a novel target in MSP.}, } @article {pmid39117455, year = {2024}, author = {Lam, AYW and Tsuboyama, K and Tadakuma, H and Tomari, Y}, title = {DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43.}, journal = {RNA (New York, N.Y.)}, volume = {30}, number = {11}, pages = {1422-1436}, pmid = {39117455}, issn = {1469-9001}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; Fluorescence Resonance Energy Transfer ; Molecular Chaperones/metabolism/chemistry/genetics ; Protein Aggregates ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Conformation ; RNA-Binding Proteins/metabolism/genetics/chemistry ; }, abstract = {Many RNA-binding proteins (RBPs) contain low-complexity domains (LCDs) with prion-like compositions. These long intrinsically disordered regions regulate their solubility, contributing to their physiological roles in RNA processing and organization. However, this also makes these RBPs prone to pathological misfolding and aggregation that are characteristic of neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) forms pathological aggregates associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that highly disordered, hydrophilic, and charged heat-resistant obscure (Hero) proteins may have similar effects. Specifically, Hero proteins can maintain the activity of other proteins from denaturing conditions in vitro, while their overexpression can suppress cellular aggregation and toxicity associated with aggregation-prone proteins. However, it is unclear how these protective effects are achieved. Here, we used single-molecule FRET to monitor the conformations of the aggregation-prone prion-like LCD of TDP-43. While we observed high conformational heterogeneity in wild-type LCD, the ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, and a Hero protein, Hero11, stabilized extended states of the LCD, consistent with their ability to suppress the aggregation of TDP-43. Our results link single-molecule effects on conformation to macro effects on bulk aggregation, where a Hero protein, like a chaperone, can maintain the conformational integrity of a client protein to prevent its aggregation.}, } @article {pmid39117043, year = {2024}, author = {Curtisi, J and Ellis-Wittenhagen, J and Kokanovich, T and Volk-Craft, B}, title = {Compassionate Ventilator Release in Patients With Neuromuscular Disease: A Two-Case Comparison.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {5}, pages = {e392-e396}, doi = {10.1016/j.jpainsymman.2024.07.028}, pmid = {39117043}, issn = {1873-6513}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Respiration, Artificial ; Amyotrophic Lateral Sclerosis/complications/therapy ; Dyspnea/therapy/etiology ; Neuromuscular Diseases/complications/therapy ; Ventilator Weaning ; Terminal Care ; Aged ; Myasthenia Gravis/therapy/complications ; }, abstract = {Dyspnea, the subjective sensation of breathlessness, is a distressing and potentially traumatic symptom. Dyspnea associated with mechanical ventilation may contribute to intensive care unit (ICU) associated post-traumatic stress disorder and impaired quality of life. Dyspnea is both difficult to alleviate and a cause of significant distress to patients, their loved ones, and care providers People living with neuromuscular disease, such as amyotrophic lateral sclerosis (ALS) or myasthenia gravis (MG), often rely on a ventilator at late stages of illness due to complications of progressive respiratory muscle weakness and paralysis. When unable to wean from the ventilator, conversations turn towards goals of care and release from the ventilator for comfort and end of life (EOL). Patients with and without neuromuscular disease have high risk for dyspnea at EOL upon ventilator liberation. Although limited recommendations have been published specific to patients with ALS, no guidelines currently exist for the terminal liberation from mechanical ventilation in patients experiencing respiratory muscle insufficiency from a neuromuscular disease. Further research on this topic is needed, including creation of a protocol for ventilator release in patients with neuromuscular disease. The following case reports detail the dissimilar EOL experiences of two patients with different forms of neuromuscular disease.}, } @article {pmid39116956, year = {2024}, author = {Yang, N and Shi, L and Xu, P and Ren, F and Li, C and Qi, X}, title = {Identification of potential drug targets for amyotrophic lateral sclerosis by Mendelian randomization analysis based on brain and plasma proteomics.}, journal = {Experimental gerontology}, volume = {195}, number = {}, pages = {112538}, doi = {10.1016/j.exger.2024.112538}, pmid = {39116956}, issn = {1873-6815}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/drug therapy ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Proteomics/methods ; *Brain/metabolism ; *Protein Interaction Maps ; Anoctamins/genetics ; Bayes Theorem ; Blood Proteins/analysis/metabolism ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic lateral sclerosis as a fatal neurodegenerative disease currently lacks effective therapeutic agents. Thus, finding new therapeutic targets to drive disease treatment is necessary. In this study, we utilized brain and plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis to identify potential drug targets for amyotrophic lateral sclerosis. Additionally, we validated our results externally using other datasets. We also used Bayesian co-localization analysis and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets. Mendelian randomization analysis indicated that elevated levels of ANO5 (OR = 1.30; 95 % CI, 1.14-1.49; P = 1.52E-04), SCFD1 (OR = 3.82; 95 % CI, 2.39-6.10; P = 2.19E-08), and SIGLEC9 (OR = 1.05; 95% CI, 1.03-1.07; P = 4.71E-05) are associated with an increased risk of amyotrophic lateral sclerosis, with external validation supporting these findings. Co-localization analysis confirmed that ANO5, SCFD1, and SIGLEC9 (coloc.abf-PPH4 = 0.848, 0.984, and 0.945, respectively) shared the same variant with amyotrophic lateral sclerosis, further substantiating potential role of these proteins as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of amyotrophic lateral sclerosis. Our findings suggested that elevated levels of ANO5, SCFD1, and SIGLEC9 are connected with an increased risk of amyotrophic lateral sclerosis and might be promising therapeutic targets. However, further exploration is necessary to fully understand the underlying mechanisms involved.}, } @article {pmid39116527, year = {2024}, author = {Ceron-Codorniu, M and Torres, P and Fernàndez-Bernal, A and Rico-Rios, S and Serrano, JC and Miralles, MP and Beltran, M and Garcera, A and Soler, RM and Pamplona, R and Portero-Otín, M}, title = {TDP-43 dysfunction leads to bioenergetic failure and lipid metabolic rewiring in human cells.}, journal = {Redox biology}, volume = {75}, number = {}, pages = {103301}, pmid = {39116527}, issn = {2213-2317}, mesh = {Humans ; *Energy Metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Lipid Metabolism ; HeLa Cells ; *Adenosine Triphosphate/metabolism ; Induced Pluripotent Stem Cells/metabolism/cytology ; Coenzyme A Ligases/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Cell Survival ; Oxygen Consumption ; Ferroptosis ; }, abstract = {The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of TARDBP loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. TARDBP silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, TARDBP depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, TARDBP loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on TARDBP function.}, } @article {pmid39116263, year = {2024}, author = {Aguilar-Vázquez, CA and Aguilar-Castillo, SJ and Raymundo-Carrillo, AD}, title = {[Electrodiagnostic support in an atypical form of amyotrophic lateral sclerosis (Vulpian-Bernhardt syndrome)].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {1}, pages = {1-8}, doi = {10.5281/zenodo.10278187}, pmid = {39116263}, issn = {2448-5667}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; Male ; Electrodiagnosis ; Middle Aged ; }, abstract = {BACKGROUND: Vulpian-Bernhardt syndrome is an atypical form of the motor neuron disease described since the 19th century. The importance of a timely diagnosis lies in the increased survival present in this variant. Due to the clinical rarity and complex diagnosis we report a clinical case of this disease, which is why we describe the typical clinical presentation, the diagnostic approach, and we make a bibliographic review of this neurodegenerative disorder as well.

CLINICAL CASE: Latin American man whose clinical case onset was characterized by thoracic asymmetric and increasing limb weakness, showing affection from distal to proximal upper limbs area. Subsequently, symptoms worsened to the point of limiting day-to-day activities and conditioning patient's physical independence. Physical examination was consistent with motor neuron disease. Nerve conduction studies were performed and confirmed findings compatible with motor neuron involvement limited to thoracic limbs.

CONCLUSION: Vulpian-Bernhardt syndrome is an uncommon form of motor neuron disease. Due to the rarity of its presentation, it is frequent to confuse clinical profile even for trained physicians. The importance of electrodiagnosis relies in identifying the neurogenic origin of the disease, as well as the active denervation and reinnervation data. Considering that with this syndrome patients have a longer survival than with the classic form of amyotrophic lateral sclerosis, it is important to have a clear diagnosis approach in order to provide a better quality of life and supportive treatment.}, } @article {pmid39115673, year = {2024}, author = {Mishra, Y and Kumar, A and Kaundal, RK}, title = {Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39115673}, issn = {1559-1182}, support = {EEQ/2021/000875//Science & Engineering Research Board (SERB), Department of Science and Technology, Govt of India/ ; }, abstract = {Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.}, } @article {pmid39115327, year = {2024}, author = {Lescouzères, L and Patten, SA}, title = {Promising animal models for amyotrophic lateral sclerosis drug discovery: a comprehensive update.}, journal = {Expert opinion on drug discovery}, volume = {19}, number = {10}, pages = {1213-1233}, doi = {10.1080/17460441.2024.2387791}, pmid = {39115327}, issn = {1746-045X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Animals ; Humans ; *Disease Models, Animal ; *Drug Discovery/methods ; Mice ; Genetic Therapy/methods ; Translational Research, Biomedical/methods ; Induced Pluripotent Stem Cells ; Drug Development/methods ; Caenorhabditis elegans ; Motor Neurons/drug effects ; Zebrafish ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Several animal models have been generated to understand ALS pathogenesis. They have provided valuable insight into disease mechanisms and the development of therapeutic strategies.

AREAS COVERED: In this review, the authors provide a concise overview of simple genetic model organisms, including C. elegans, Drosophila, zebrafish, and mouse genetic models that have been generated to study ALS. They emphasize the benefits of each model and their application in translational research for discovering new chemicals, gene therapy approaches, and antibody-based strategies for treating ALS.

EXPERT OPINION: Significant progress is being made in identifying new therapeutic targets for ALS. This progress is being enabled by promising animal models of the disease using increasingly effective genetic and pharmacological strategies. There are still challenges to be overcome in order to achieve improved success rates for translating drugs from animal models to clinics for treating ALS. Several promising future directions include the establishment of novel preclinical protocol standards, as well as the combination of animal models with human induced pluripotent stem cells (iPSCs).}, } @article {pmid39114608, year = {2024}, author = {Koike, Y}, title = {Abnormal Splicing Events due to Loss of Nuclear Function of TDP-43: Pathophysiology and Perspectives.}, journal = {JMA journal}, volume = {7}, number = {3}, pages = {313-318}, pmid = {39114608}, issn = {2433-3298}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with a progressive and fatal course. They are often comorbid and share the same molecular spectrum. Their key pathological features are the formation of the aggregation of TDP-43, an RNA-binding protein, in the cytoplasm and its depletion from the nucleus in the central nervous system. In the nucleus, TDP-43 regulates several aspects of RNA metabolism, ranging from RNA transcription and alternative splicing to RNA transport. Suppressing the aberrant splicing events during RNA processing is one of the significant functions of TDP-43. This function is impaired when TDP-43 becomes depleted from the nucleus. Several critical cryptic splicing targets of TDP-43 have recently emerged, such as STMN2, UNC13A, and others. UNC13A is an important ALS/FTD risk gene, and the genetic variations, single nucleotide polymorphisms, cause disease via the increased susceptibility for cryptic exon inclusion under the TDP-43 dysfunction. Moreover, TDP-43 has an autoregulatory mechanism that regulates the splicing of its mRNA (TARDBP mRNA) in the healthy state. This study provides recent findings on the splicing regulatory function of TDP-43 and discusses the prospects of using these aberrant splicing events as efficient biomarkers.}, } @article {pmid39113924, year = {2024}, author = {Ueta, Y and Kanbayashi, T and Miyaji, Y and Hatanaka, Y and Tachiyama, K and Takahashi, K and Terashi, H and Aizawa, H and Sonoo, M}, title = {The speed of completion of the decremental responses on repetitive nerve stimulation.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {211-216}, pmid = {39113924}, issn = {2467-981X}, abstract = {OBJECTIVE: It is generally believed that the decremental response in repetitive nerve stimulation (RNS) stabilizes at the fourth or fifth response. We have a preliminary impression that the decremental response approaches a plateau earlier in proximal muscles than in distal muscles. We investigated the speed of the completion of the decremental response in different muscles.

METHODS: The "decrement completion ratio (DCR)" in the second or third response (DCR2 or DCR3) was defined as the ratio of the decremental percentage of the second or third response to that of the fourth response. Patients showing more than 10% decremental response both in the abductor pollicis (APB) and deltoid muscles were retrospectively extracted from our EMG database. The DCR2 and DCR3 were compared between two muscles in patients with myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS).

RESULTS: Identified subjects consisted of 11patients with MG and 11 patients with ALS. Multiple regression analysis revealed that only the difference of muscle influenced on DCR2 and DCR3, with no contribution from the different disorder (MG or ALS) or the initial amplitude of the compound muscle action potential (CMAP). Both DCR2 and DCR3 were significantly higher in deltoid than in APB. In ALS, the normalized CMAP amplitude was not different between APB and deltoid whereas the decremental percentage was significantly higher in deltoid, suggesting a lower safety factor of the neuromuscular transmission in proximal muscles.

CONCLUSIONS: The decremental response completed more rapidly in deltoid than in APB which may be related to the lower safety factor also documented by this study.

SIGNIFICANCE: Unexpected early completion of the decrement such as at the second response in RNS is not a technical error but may be an extreme of the rapid completion in deltoid, a proximal muscle.}, } @article {pmid39113457, year = {2024}, author = {Pervushina, EV and Kutlubaev, MA and Saifullina, EV and Gaisina, EV and Smakova, LA and Khidiyatova, IM}, title = {[Amyotrophic lateral sclerosis associated with a new pathogenic variant of the ERBB4 gene].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {7}, pages = {165-168}, doi = {10.17116/jnevro2024124071165}, pmid = {39113457}, issn = {1997-7298}, mesh = {Humans ; *Receptor, ErbB-4/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Male ; Middle Aged ; Disease Progression ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a sporadic disease in most of the cases; in 10-15% of cases genetic forms are recorded. A genetic form of ALS associated with the mutation in the ERBB4 gene (ALS19) has been reported in 2013. A protein encoded by the ERBB4 is probably involved in ubiquitous component of the pathogenesis of ALS. We present a case of ALS associated with a new pathogenic variant of the ERBB4 gene, with early bulbar onset and slow progression of the disease within 10 years.}, } @article {pmid39113334, year = {2024}, author = {Khadilkar, V and Lad, S and Mondkar, S and Yewale, S and Dange, N and Wagle, S and Khadilkar, A}, title = {Pediatric Advanced Life Support Tape for Indian Children.}, journal = {Indian pediatrics}, volume = {61}, number = {10}, pages = {961-965}, pmid = {39113334}, issn = {0974-7559}, mesh = {Humans ; India ; Male ; Female ; Child, Preschool ; Child ; *Body Height ; *Body Weight ; *Anthropometry/instrumentation ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To design a specific advanced life support (ALS) tape based on recent Indian multicenter height/length and weight data to accurately estimate the weight from the recumbent length.

METHODS: We designed the new ALS tape by matching the median weights to median heights/lengths from the recently published Indian multicenter growth data, maintaining the same color codes as the Broselow tape. The accuracy of weight estimation for the newly designed ALS tape was validated and compared with the Broselow estimated weights at a tertiary care hospital.

RESULTS: The color (weight) band matched median heights (cm) from the new ALS tape were higher (53.0 vs 53.9 for grey, 63.1 vs 67.4 for pink, 70.6 vs 76.4 for red, 79 vs 85.5 for purple, 89.6 vs 95.5 for yellow, 101.9 vs 107.5 for white, 126.1 vs 130.5 for orange and 137 vs 140.5 for green) than the Broselow tape. For every color band on the newly designed ALS tape, a sizable proportion of children (27% for grey, 78% for pink, 83% for red, 38% for purple, 63% for yellow, 41% for white, 35% for blue, 54% for orange) recorded a higher Broselow color band, suggesting overestimated weights at each color band. The percentage difference in the estimated weight from the actual weight was very small (-0.5% for under-5 years and 0.2% for older children) using the new ALS tape as compared to Broselow tape.

CONCLUSION: This Indianized ALS tape estimated Indian children's weights more accurately. Use of the newly designed ALS tape may reduce the errors in calculating emergency medications, fluids and equipment sizes. Further studies are required to validate this tape in pediatric emergency departments in India.}, } @article {pmid39112530, year = {2024}, author = {Tu, S and Li, T and Carroll, AS and Mahoney, CJ and Huynh, W and Park, SB and Henderson, R and Vucic, S and Kiernan, MC and Lin, CS}, title = {Central neurodegeneration in Kennedy's disease accompanies peripheral motor dysfunction.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18331}, pmid = {39112530}, issn = {2045-2322}, mesh = {Humans ; Male ; Middle Aged ; Female ; Aged ; *Bulbo-Spinal Atrophy, X-Linked/physiopathology/pathology ; Adult ; Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging ; Brain/diagnostic imaging/pathology/physiopathology ; Magnetic Resonance Imaging ; White Matter/diagnostic imaging/pathology/physiopathology ; }, abstract = {Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R[2] = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R[2] = 0.59, p < 0.01), motor (R[2] = 0.63, p < 0.01), and somatosensory (R[2] = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.}, } @article {pmid39111585, year = {2024}, author = {Bischoff, KE and Liera, D and Tang, J and Madugala, N and Cohen, E and Galea, MD and Lindenberger, E and Pantilat, SZ and Lomen-Hoerth, C}, title = {Development and Piloting of a Bereaved Care Partner Survey to Inform Quality Improvement in ALS Supportive Care.}, journal = {Journal of pain and symptom management}, volume = {68}, number = {5}, pages = {467-476.e2}, doi = {10.1016/j.jpainsymman.2024.07.031}, pmid = {39111585}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Quality Improvement ; Pilot Projects ; *Bereavement ; Female ; Male ; *Palliative Care ; Caregivers ; Middle Aged ; Aged ; Surveys and Questionnaires ; Adult ; }, abstract = {OBJECTIVES: Bereaved care partner surveys typically focus on the experience with care in the final days of life. We sought to develop and pilot a novel bereaved care partner survey to understand experiences with ALS supportive care provided throughout the illness and identify opportunities for quality improvement.

METHODS: We developed the survey using a multisite, interdisciplinary consensus process involving ALS and palliative care clinicians as well as patient advocates. We then piloted the survey at a single site via video interviews with care partners of patients who died from ALS between three and 15 months prior. Qualitative findings were analyzed using Rapid Qualitative Analysis.

RESULTS: The survey includes 17 core questions and nine demographic items. Questions inquire about whether the patient and care partner received adequate help with physical symptoms, emotional and practical needs, education about the illness and how to provide hands-on care, preparing for what was to come, and bereavement. They also query whether care was person-centered and consistent with the patient's values and preferences. During the pilot with 18 bereaved care partners, the tool generated detailed feedback about aspects of care to preserve as well as how to improve ALS supportive care.

DISCUSSION: We developed and piloted a bereaved care partner survey to understand and improve the quality of ALS supportive care, which was found to be feasible and acceptable. Next steps include testing it at additional centers in order to generate learnings that can advance ALS supportive care in ways that are meaningful to patients and care partners.}, } @article {pmid39111522, year = {2024}, author = {Li, Q and Zhu, W and Wen, X and Zang, Z and Da, Y and Lu, J}, title = {Different baseline functional patterns of the frontal cortex in amyotrophic lateral sclerosis patients with Corticospinal tract hyperintensity.}, journal = {Brain research}, volume = {1844}, number = {}, pages = {149140}, doi = {10.1016/j.brainres.2024.149140}, pmid = {39111522}, issn = {1872-6240}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Pyramidal Tracts/physiopathology/diagnostic imaging ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Frontal Lobe/physiopathology/diagnostic imaging ; Aged ; Adult ; Brain Mapping/methods ; }, abstract = {Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.}, } @article {pmid39111227, year = {2024}, author = {Torghabeh, FA and Moghadam, EA and Hosseini, SA}, title = {Simultaneous time-frequency analysis of gait signals of both legs in classifying neurodegenerative diseases.}, journal = {Gait & posture}, volume = {113}, number = {}, pages = {443-451}, doi = {10.1016/j.gaitpost.2024.07.302}, pmid = {39111227}, issn = {1879-2219}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/physiopathology ; *Gait Analysis/methods ; Gait Disorders, Neurologic/classification/diagnosis/physiopathology/etiology ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/classification ; Wavelet Analysis ; Male ; Female ; Middle Aged ; Parkinson Disease/diagnosis/physiopathology/classification ; Deep Learning ; Signal Processing, Computer-Assisted ; Case-Control Studies ; Huntington Disease/physiopathology/diagnosis/classification ; Aged ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) pose significant challenges due to their debilitating nature and limited therapeutic options. Accurate and timely diagnosis is crucial for optimizing patient care and treatment strategies. Gait analysis, utilizing wearable sensors, has shown promise in assessing motor abnormalities associated with NDDs.

RESEARCH QUESTION: Research Question 1 To what extent can analyzing the interaction of both limbs in the time-frequency domain serve as a suitable methodology for accurately classifying NDDs? Research Question 2 How effective is the utilization of color-coded images, in conjunction with deep transfer learning models, for the classification of NDDs?

METHODS: GaitNDD database was used, comprising recordings from patients with Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and healthy controls. The gait signals underwent signal preparation, wavelet coherence analysis, and principal component analysis for feature enhancement. Deep transfer learning models (AlexNet, GoogLeNet, SqueezeNet) were employed for classification. Performance metrics, including accuracy, sensitivity, specificity, precision, and F1 score, were evaluated using 5-fold cross-validation.

RESULTS: The classification performance of the models varied depending on the time window used. For 5-second gait signal segments, AlexNet achieved an accuracy of 95.91 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.49 % and 92.73 %, respectively. For 10-second segments, AlexNet outperformed other models with an accuracy of 99.20 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.75 % and 95.00 %, respectively. Statistical tests confirmed the significance of the extracted features, indicating their discriminative power for classification.

SIGNIFICANCE: The proposed method demonstrated superior performance compared to previous studies, offering a non-invasive and cost-effective approach for the automated diagnosis of NDDs. By analyzing the interaction between both legs during walking using wavelet coherence, and utilizing deep transfer learning models, accurate classification of NDDs was achieved.}, } @article {pmid39110593, year = {2024}, author = {Hoh, KL and Mu, B and See, T and Ng, AYE and Ng, AQE and Zhang, D}, title = {VAP-mediated membrane-tethering mechanisms implicate ER-PM contact function in pH homeostasis.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114592}, doi = {10.1016/j.celrep.2024.114592}, pmid = {39110593}, issn = {2211-1247}, mesh = {*Endoplasmic Reticulum/metabolism ; Hydrogen-Ion Concentration ; *Homeostasis ; *Cell Membrane/metabolism ; Humans ; *Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/metabolism ; Vesicular Transport Proteins/metabolism/genetics ; Protein Binding ; Membrane Proteins/metabolism ; Phospholipids/metabolism ; Mutation ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Vesicle-associated membrane protein (VAMP)-associated proteins (VAPs) are highly conserved endoplasmic reticulum (ER)-resident proteins that establish ER contacts with multiple membrane compartments in many eukaryotes. However, VAP-mediated membrane-tethering mechanisms remain ambiguous. Here, focusing on fission yeast ER-plasma membrane (PM) contact formation, using systematic interactome analyses and quantitative microscopy, we predict a non-VAP-protein direct binding-based ER-PM coupling. We further reveal that VAP-anionic phospholipid interactions may underlie ER-PM association and define the pH-responsive nature of VAP-tethered membrane contacts. Such conserved interactions with anionic phospholipids are generally defective in amyotrophic lateral sclerosis-associated human VAPB mutant. Moreover, we identify a conserved FFAT-like motif locating at the autoinhibitory hotspot of the essential PM proton pump Pma1. This modulatory VAP-Pma1 interaction appears crucial for pH homeostasis. We thus propose an ingenious strategy for maintaining intracellular pH by coupling Pma1 modulation with pH-sensory ER-PM contacts via VAP-mediated interactions.}, } @article {pmid39108340, year = {2024}, author = {Tröger, J and Dörr, F and Schwed, L and Linz, N and König, A and Thies, T and Barbe, MT and Orozco-Arroyave, JR and Rusz, J}, title = {An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1440986}, pmid = {39108340}, issn = {2673-253X}, abstract = {INTRODUCTION: Dysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework.

METHODS: The study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants' speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed.

RESULTS: Verification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability.

DISCUSSION: The ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.}, } @article {pmid39108272, year = {2024}, author = {De Federicis, D and Bassani, C and Chiarelli, RR and Montini, F and Giordano, A and Esposito, F and Riva, N and Quattrini, A and Martinelli, V and Filippi, M and Farina, C}, title = {Circulating MAIT cells in multiple sclerosis and amyotrophic lateral sclerosis.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1436717}, pmid = {39108272}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/blood ; *Mucosal-Associated Invariant T Cells/immunology/metabolism ; Male ; Middle Aged ; Female ; Adult ; Aged ; Multiple Sclerosis/immunology/blood ; CD8-Positive T-Lymphocytes/immunology/metabolism ; Biomarkers ; Flow Cytometry ; }, abstract = {Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8[+] T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8[+] MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.}, } @article {pmid39107374, year = {2024}, author = {Monselise, EB and Vyazmensky, M and Scherf, T and Batushansky, A and Fishov, I}, title = {D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18247}, pmid = {39107374}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/microbiology ; *Escherichia coli/metabolism ; *Glutamic Acid/metabolism ; Humans ; Stress, Physiological ; Complement C1q/metabolism ; Nitrogen/metabolism ; Carbon/metabolism ; }, abstract = {In the search for the origin of Amyotrophic Lateral Sclerosis disease (ALS), we hypothesized earlier (Monselise, 2019) that D-amino acids produced by stressed microbiome may serve as inducers of the disease development. Many examples of D-amino acid accumulation under various stress conditions were demonstrated in prokaryotic and eukaryotic cells. In this work, wild-type Escherichia coli, members of the digestive system, were subjected to carbon and nitrogen starvation stress. Using NMR and LC-MS techniques, we found for the first time that D-glutamate accumulated in the stressed bacteria but not in control cells. These results together with the existing knowledge, allow us to suggest a new insight into the pathway of ALS development: D-glutamate, produced by the stressed microbiome, induces neurobiochemical miscommunication setting on C1q of the complement system. Proving this insight may have great importance in preventive medicine of such MND modern-age diseases as ALS, Alzheimer, and Parkinson.}, } @article {pmid39107037, year = {2024}, author = {Jang, DG and Dou, JF and Koubek, EJ and Teener, S and Zhou, L and Bakulski, KM and Mukherjee, B and Batterman, SA and Feldman, EL and Goutman, SA}, title = {Multiple metal exposures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-333978}, pmid = {39107037}, issn = {1468-330X}, abstract = {BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources.

METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms.

RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20-1.58, p<0.001; urine, HR=1.44, CI=1.23-1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals.

CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.}, } @article {pmid39106320, year = {2024}, author = {Dong, D and Zhang, Z and Li, Y and Latallo, MJ and Wang, S and Nelson, B and Wu, R and Krishnan, G and Gao, FB and Wu, B and Sun, S}, title = {Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons.}, journal = {Science signaling}, volume = {17}, number = {848}, pages = {eadl1030}, pmid = {39106320}, issn = {1937-9145}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 AG072078/AG/NIA NIH HHS/United States ; T32 GM008403/GM/NIGMS NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Peptide Chain Elongation, Translational ; p38 Mitogen-Activated Protein Kinases/metabolism/genetics ; Stress, Physiological/genetics ; Ribosomes/metabolism/genetics ; }, abstract = {Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.}, } @article {pmid39106168, year = {2024}, author = {Glineburg, MR and Yildirim, E and Gomez, N and Rodriguez, G and Pak, J and Li, X and Altheim, C and Waksmacki, J and McInerney, GM and Barmada, SJ and Todd, PK}, title = {Stress granule formation helps to mitigate neurodegeneration.}, journal = {Nucleic acids research}, volume = {52}, number = {16}, pages = {9745-9759}, pmid = {39106168}, issn = {1362-4962}, support = {2018-03843//Swedish Research Council/ ; //Ann Arbor Active Against ALS/ ; T32 NS076401/NS/NINDS NIH HHS/United States ; BLRD BX004842//Veterans Affairs/ ; I01 BX004842/BX/BLRD VA/United States ; P50HD104463/NH/NIH HHS/United States ; }, mesh = {Animals ; *Stress Granules/metabolism ; *Neurodegenerative Diseases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Neurons/metabolism ; *Frontotemporal Dementia/metabolism/genetics ; RNA Recognition Motif Proteins/metabolism/genetics ; Drosophila Proteins/metabolism/genetics ; Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; Mice ; Drosophila melanogaster/metabolism/genetics ; RNA Helicases/metabolism/genetics ; Ataxia/genetics/metabolism ; DNA Helicases/metabolism/genetics ; Alphavirus/genetics/metabolism ; Rats ; Carrier Proteins/metabolism ; Drosophila/metabolism ; Cytoplasmic Granules/metabolism ; Stress, Physiological ; DNA-Binding Proteins ; }, abstract = {Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.}, } @article {pmid39106020, year = {2024}, author = {Mirmotahari, SA and Aliomrani, M and Hassanzadeh, F and Sirous, H and Rostami, M}, title = {Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico & in vivo study.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {32}, number = {2}, pages = {599-615}, pmid = {39106020}, issn = {2008-2231}, mesh = {*Dimethyl Fumarate/pharmacology/chemistry ; *Multiple Sclerosis/drug therapy ; Animals ; *Molecular Docking Simulation ; *Benzothiazoles/chemistry/pharmacology ; *Riluzole/pharmacology/chemistry ; Mice ; *Mice, Inbred C57BL ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Male ; Cuprizone ; Disease Models, Animal ; Computer Simulation ; Neuroprotective Agents/pharmacology/chemistry ; Remyelination/drug effects ; }, abstract = {BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways.

OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment.

METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model.

RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.}, } @article {pmid39105912, year = {2024}, author = {Andrysiak, K and Stępniewski, J and Spaczyńska-Boczar, M and Łapicka-Bodzioch, K and Słowik, A and Dulak, J}, title = {Generation of Human-Induced Pluripotent Stem Cells from Peripheral Blood Mononuclear Cells of C9ORF72-Associated Amyotrophic Lateral Sclerosis Patients.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2835}, number = {}, pages = {135-146}, pmid = {39105912}, issn = {1940-6029}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; Cell Culture Techniques/methods ; *Cell Differentiation ; Cellular Reprogramming ; DNA Repeat Expansion ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Leukocytes, Mononuclear/metabolism ; }, abstract = {Disease modeling of neuromuscular disorders, such as amyotrophic lateral sclerosis (ALS), is hindered by limited accessibility of affected cells. This problem can be overcome by generation of human induced pluripotent stem cells (hiPSC), which can be then differentiated into required cells. Here, we describe the detailed protocol of hiPSC establishment from peripheral blood mononuclear cells (PBMC) of two ALS patients with detected expansion of G4C2 (GGGGCC) repeats in the first intron of C9ORF72 gene, known to be linked with the most common form of familial ALS.Successful PBMC reprogramming with non-integrating Sendai vectors was confirmed by expression of pluripotency markers: OCT4, NANOG, SSEA4, and TRA-1-60 in obtained hiPSC and their ability to differentiate into cells of three germ layers.The generated ALS-patient-specific hiPSC create a possibility for deciphering molecular basis of this devastating neuromuscular disease.}, } @article {pmid39104673, year = {2024}, author = {Rezvani, S and Hosseini-Zahraei, SH and Tootchi, A and Guger, C and Chaibakhsh, Y and Saberi, A and Chaibakhsh, A}, title = {A review on the performance of brain-computer interface systems used for patients with locked-in and completely locked-in syndrome.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {4}, pages = {1419-1443}, pmid = {39104673}, issn = {1871-4080}, abstract = {Patients with locked-in syndrome (LIS) and complete locked-in syndrome (CLIS) own a fully functional brain restricted within a non-functional body. In order to help LIS patients stay connected with their surroundings, brain-computer interfaces (BCIs) and related technologies have emerged. BCIs translate brain activity into actions that can be performed by external devices enabling LIS patients to communicate, leading to an increase in their quality of life. The past decade has seen the rapid development of BCIs that have the potential to be used for patients with locked-in syndrome, from which a great deal is tested only on healthy subjects and not on actual patients. This study aims to (1) provide the readers with a comprehensive study that contributes to this growing area of research by exploring the performance of BCIs tested specifically on LIS and CLIS patients, (2) give an overview of different modalities and paradigms used in different stages of the locked-in syndrome, and (3) discuss the contributions and limitations of BCIs introduced for the LIS and CLIS patients in the state-of-the-art and lay a groundwork for researchers interested in this field.}, } @article {pmid39104562, year = {2024}, author = {Haikal, A and Ali, AR}, title = {Chemical composition and toxicity studies on Lantana camara L. flower essential oil and its in silico binding and pharmacokinetics to superoxide dismutase 1 for amyotrophic lateral sclerosis (ALS) therapy.}, journal = {RSC advances}, volume = {14}, number = {33}, pages = {24250-24264}, pmid = {39104562}, issn = {2046-2069}, abstract = {Using the gas chromatography mass spectrometry method, the chemical components of essential oil from flowers of Lantana camara growing in Egypt are analyzed. Through this investigation, 22 chemicals from floral oil were identified. Most of the oil is made up of sesquiterpene caryophyllene (15.51%) and monoterpene sabinene (14.90%). When the oil's composition was compared to oils extracted from the same plant on several continents, we observed that the essential components were largely the same with some difference in proportions and some compounds due to geographical differences. A molecular docking study of essential oil components was conducted with human superoxide dismutase 1, a target involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). Isospathulenol showed a comparable docking score to the reference ligand bound to the dismutase enzyme. Isospathulenol showed a reasonable drug score with some safety concerns. In addition, isospathulenol is predicted to have high GI absorption, good permeability through the blood-brain barrier and reasonable bioavailability score with ease access to synthetic modifications. In addition, the same compound is devoid from any violation to Lipinski rules or any PAINS alerts. This may establish the promising characteristics of such a compound to be optimized into potential drug candidates for treatment of ALS.}, } @article {pmid39104446, year = {2024}, author = {Higgins, S and Dlamini, S and Hattingh, M and Rambharose, S and Theron, E and Stassen, W}, title = {Views and perceptions of advanced life support practitioners on initiating, withholding and terminating resuscitation in out-of-hospital cardiac arrest in the Emergency Medical Services of South Africa.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100709}, pmid = {39104446}, issn = {2666-5204}, abstract = {INTRODUCTION: This study aimed to explore the views and perceptions of Advanced Life Support (ALS) practitioners in two South African provinces on initiating, withholding, and terminating resuscitation in OHCA.

METHODOLOGY: Semi-structured one-on-one interviews were conducted with operational ALS practitioners working within the prehospital setting in the Western Cape and Free State provinces. Recorded interviews were transcribed and subjected to inductive-dominant, manifest content analysis. After familiarisation with the data, meaning units were condensed, codes were applied and collated into categories that were then assessed, reviewed, and refined repeatedly.

RESULTS: A total of 18 ALS providers were interviewed. Five main categories were developed from the data analysis: 1) assessment of prognosis, 2) internal factors affecting decision-making, 3) external factors affecting decision-making, 4) system challenges, and 5) ideas for improvement. Factors influencing the assessment of prognosis were history, clinical presentation, and response to resuscitation. Internal factors affecting decision-making were driven by emotion and contemplation. External factors affecting decision-making included family, safety, and disposition. System challenges relating to bystander response and resources were identified. Ideas for improvement in training and support were brought forward.

CONCLUSION: Many factors influence OHCA decision-making in the Western Cape and Free State provinces, and numerous system challenges have been identified. The findings of this study can be used as a frame of reference for prehospital emergency care personnel and contribute to the development of context-specific guidelines.}, } @article {pmid39103661, year = {2024}, author = {Tomasicchio, G and Martines, G and Tartaglia, N and Buonfantino, M and Restini, E and Carlucci, B and Giove, C and Dezi, A and Ranieri, C and Logrieco, G and Vincenti, L and Ambrosi, A and Altomare, DF and De Fazio, M and Picciariello, A}, title = {Suture reinforcement using a modified cyanoacrylate glue to prevent anastomotic leak in colorectal surgery: a prospective multicentre randomized trial : The Rectal Anastomotic seaL (ReAL) trial.}, journal = {Techniques in coloproctology}, volume = {28}, number = {1}, pages = {95}, pmid = {39103661}, issn = {1128-045X}, mesh = {Humans ; *Anastomotic Leak/prevention & control/etiology ; Female ; Male ; Prospective Studies ; Aged ; Middle Aged ; *Cyanoacrylates/administration & dosage ; *Anastomosis, Surgical/adverse effects/methods ; *Rectum/surgery ; Tissue Adhesives/therapeutic use ; Suture Techniques ; Rectal Neoplasms/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Anastomotic leakage (AL) is the most frequent life-threating complication following colorectal surgery. Several attempts have been made to prevent AL. This prospective, randomized, multicentre trial aimed to evaluate the safety and efficacy of nebulised modified cyanoacrylate in preventing AL after rectal surgery.

METHODS: Patients submitted to colorectal surgery for carcinoma of the high-medium rectum across five high-volume centres between June 2021 and January 2023 entered the study and were randomized into group A (anastomotic reinforcement with cyanoacrylate) and group B (no reinforcement) and followed up for 30 days. Anastomotic reinforcement was performed via nebulisation of 1 mL of a modified cyanoacrylate glue. Preoperative features and intraoperative and postoperative results were recorded and compared. The study was registered at ClinicalTrials.gov (ID number NCT03941938).

RESULTS: Out of 152 patients, 133 (control group, n = 72; cyanoacrylate group, n = 61) completed the follow-up. ALs were detected in nine patients (12.5%) in the control group (four grade B and five grade C) and in four patients (6.6%), in the cyanoacrylate group (three grade B and one grade C); however, despite this trend, the differences were not statistically significant (p = 0.36). However, Clavien-Dindo complications grade > 2 were significantly higher in the control group (12.5% vs. 3.3%, p = 0.04). No adverse effects related to the glue application were reported.

CONCLUSION: The role of modified cyanoacrylate application in AL prevention remains unclear. However its use to seal colorectal anastomoses is safe and could help to reduce severe postoperative complications.}, } @article {pmid39103493, year = {2024}, author = {Talaia, G and Bentley-DeSousa, A and Ferguson, SM}, title = {Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.}, journal = {The EMBO journal}, volume = {43}, number = {18}, pages = {3948-3967}, pmid = {39103493}, issn = {1460-2075}, support = {R01 GM105718/GM/NIGMS NIH HHS/United States ; ASAP-000580//Michael J. Fox Foundation for Parkinson's Research (MJFF)/ ; ASAP-000580//Aligning Science Across Parkinson's (ASAP)/ ; GM105718//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Humans ; *Amino Acids/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Frontotemporal Dementia/metabolism/genetics/pathology ; HEK293 Cells ; *Lysosomes/metabolism ; *Mechanistic Target of Rapamycin Complex 1/metabolism/genetics ; Phosphorylation ; *Protein Serine-Threonine Kinases/metabolism/genetics ; rab GTP-Binding Proteins/metabolism/genetics ; *rab7 GTP-Binding Proteins ; Signal Transduction ; }, abstract = {Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.}, } @article {pmid39102937, year = {2024}, author = {Ali, F and Tang, Z and Mo, G and Zhang, B and Ling, X and Qiu, Z}, title = {Taxonomic and functional changes in wheat rhizosphere microbiome caused by imidazoline-based herbicide and genetic modification.}, journal = {Environmental research}, volume = {262}, number = {Pt 2}, pages = {119726}, doi = {10.1016/j.envres.2024.119726}, pmid = {39102937}, issn = {1096-0953}, mesh = {*Triticum/microbiology/genetics ; *Rhizosphere ; *Herbicides/toxicity ; *Microbiota/drug effects ; Soil Microbiology ; Plants, Genetically Modified/microbiology ; Imidazolines ; Imidazoles/toxicity ; Acetolactate Synthase/genetics ; Soil Pollutants/toxicity ; Bacteria/drug effects/genetics/classification ; }, abstract = {Genetically modified (GM) crop cultivation has received a lot of attention in recent years due to the substantial public debate. Consequently, an in-depth investigation of excessively used GM herbicide-tolerant crops is a vital step for the biosafety of genetically modified plants. Several studies have been conducted to study the impact of transgenic GM crops on soil microbial composition; however, research into the effects of non-transgenic GM crops is inadequate. In the current work, high-throughput sequencing was used to evaluate the impact of the acetolactate synthase (ALS)-mutant (WK170B), its control (YN19B), and the imazamox (IM) herbicide on the wheat rhizobiome. Under normal growth conditions, our work revealed a minimal impact of ALS-mutant WK170B on the rhizosphere microbiome compared to the control YN10B, except for some cyanobacterial microorganisms that showed a significant increase in abundance. This suggests that the gene mutation could potentially have a beneficial impact on the bacterial communities present in the rhizosphere. Following IM exposure, taxonomic analysis revealed a significant reduction in the relative abundance of Ralstonia pickettii and an unidentified member of the genus Ancylothrix 8 PC. Analyses of both alpha and beta diversity revealed a statistically significant increase in both microbial richness and species diversity. IM-induced relative abundance modulation was also evident through Linear discriminant analysis Effect Size (LEfSe), MetaStat, and heatmap analyses. The SIMPER analysis revealed that the microbial taxa Massilia, Limnobacter, Hydrogenophaga, Ralstonia, Nitrospira, and Ramlibacter exhibited the highest vulnerability to IM exposure. The functional attributes analysis revealed that the relative abundance of genes associated with the extracellular matrix-receptor interaction, which is responsible for structural support and stress response, increased significantly following IM exposure. Collectively, our study identifies key microbial taxa in the wheat rhizobiome that are sensitive to IM herbicides and provides a foundation for assessing the environmental risks associated with IM herbicide use.}, } @article {pmid39101689, year = {2024}, author = {Simão, S and Oliveira Santos, M and Gromicho, M and Pavão Martins, I and De Carvalho, M}, title = {Cognitive reserve as a modulator of cognitive decline and of behavioral symptoms in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {726-736}, doi = {10.1080/21678421.2024.2385684}, pmid = {39101689}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/psychology/complications/physiopathology ; Male ; Female ; *Cognitive Reserve/physiology ; Middle Aged ; *Cognitive Dysfunction/etiology/genetics/physiopathology/psychology ; Aged ; Neuropsychological Tests ; Behavioral Symptoms/etiology ; C9orf72 Protein/genetics ; Prospective Studies ; Adult ; Executive Function/physiology ; }, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (C9orf72) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (p < 0.001), 59.4% of executive functions (p < 0.001), and 55% of behavioral symptoms (p < 0.001). For controls, it accounted for 52.8% of variance in ECAS total (p < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (p < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (p = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom' predictor in patients (p = 0.009). Conclusion: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.}, } @article {pmid39101354, year = {2024}, author = {Faleco, FA and Machado, FM and Bobadilla, LK and Tranel, PJ and Stoltenberg, D and Werle, R}, title = {Resistance to protoporphyrinogen oxidase inhibitors in giant ragweed (Ambrosia trifida).}, journal = {Pest management science}, volume = {80}, number = {12}, pages = {6211-6221}, doi = {10.1002/ps.8349}, pmid = {39101354}, issn = {1526-4998}, mesh = {*Protoporphyrinogen Oxidase/genetics/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Ambrosia ; Plant Weeds/drug effects/genetics/enzymology ; Plant Proteins/genetics/metabolism ; Acetolactate Synthase/genetics/antagonists & inhibitors ; Enzyme Inhibitors/pharmacology ; Weed Control ; }, abstract = {BACKGROUND: Giant ragweed (Ambrosia trifida L.) is one of the most troublesome weed species in corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] cropping systems. Following numerous reports in 2018 of suspected herbicide resistance in several Ambrosia trifida populations from Wisconsin, our objective was to characterize the response of these accessions to acetolactate synthase (ALS), enolpyruvyl shikimate phosphate synthase (EPSPS), and protoporphyrinogen oxidase (PPO) inhibitors applied POST.

RESULTS: Four accessions (AT1, AT4, AT6, and AT10) exhibited ≥ 50% plant survival after exposure to the cloransulam 3× rate. Two accessions (AT8 and AT10) and one accession (AT2) exhibited ≥ 50% plant survival after exposure to glyphosate and fomesafen 1× rates, respectively. The AT10 accession exhibited multiple resistance to cloransulam and glyphosate. The AT12 accession was 28.8-fold resistant to fomesafen and 3.7-fold resistant to lactofen. A codon change in PPX2 conferring a R98L substitution was identified as the most likely mechanism conferring PPO-inhibitor resistance.

CONCLUSION: To our knowledge, this is the first confirmed case of PPO-inhibitor resistance in Ambrosia trifida globally and we identified the genetic mutation likely conferring resistance. Proactive and diversified integrated weed management strategies are of paramount importance for sustainable long-term Ambrosia trifida management. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39100390, year = {2024}, author = {Johnson, G and Tabner, A and Tilbury, N and Wesson, A and Hughes, GD and Elder, R and Bryson, P}, title = {Development of an algorithm to guide management of cardiorespiratory arrest in a diving bell.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100724}, pmid = {39100390}, issn = {2666-5204}, abstract = {AIM: The management of cardiorespiratory arrest in a diving bell presents multiple clinical, technical, and environmental considerations that standard resuscitation algorithms do not address, and no situation-specific algorithm exists. The development and testing of an algorithm to guide the management of cardiorespiratory arrest in a bell is described.

METHODS: An iterative approach to algorithm development was used. Phase 1 involved a small multidisciplinary group and took place in a simulation centre and a decommissioned diving bell. The algorithm was then refined in a purpose-build simulation complex with repeated simulation by a group of divers, and with input from industry experts. ALS principles were followed unless contextual or technical factors necessitated deviation.

RESULTS: Clinical and technical aspects of the resuscitation are addressed. Key priorities that conflict with standard ALS principles are: prioritisation of rescue breaths; use of mechanical CPR when available; and the provision of CPR with the casualty in a seated position where necessary.

CONCLUSION: This is the first algorithm to guide the delivery of resuscitation in a diving bell. It incorporates adapted ALS principles and available data concerning compression technique effectiveness, and was informed by industry and clinical expertise. It provides guiding principles that can be adapted to setting-specific needs, and we would encourage its industry-wide international adoption.}, } @article {pmid39099373, year = {2024}, author = {Serangeli, I and Diamanti, T and De Jaco, A and Miranda, E}, title = {Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions.}, journal = {The European journal of neuroscience}, volume = {60}, number = {5}, pages = {5040-5068}, doi = {10.1111/ejn.16485}, pmid = {39099373}, issn = {1460-9568}, support = {//Sapienza Università di Roma/ ; //Sapienza University of Rome/ ; }, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Endoplasmic Reticulum/metabolism ; Animals ; *Neurodevelopmental Disorders/metabolism ; *Mental Disorders/metabolism/physiopathology ; Mitochondria Associated Membranes ; }, abstract = {Mitochondria-endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention.}, } @article {pmid39099169, year = {2024}, author = {Wang, J and Qiu, Y and Yang, L and Wang, J and He, J and Tang, C and Yang, Z and Hong, W and Yang, B and He, Q and Weng, Q}, title = {Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.}, journal = {Autophagy}, volume = {20}, number = {12}, pages = {2677-2696}, pmid = {39099169}, issn = {1554-8635}, mesh = {*Mitophagy/drug effects/physiology ; *Homeostasis/drug effects ; *Membrane Transport Proteins/metabolism ; Animals ; *Cell Cycle Proteins/metabolism ; Humans ; *Valosin Containing Protein/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; *Hepatocytes/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Mice ; Transcription Factor TFIIIA/metabolism/genetics ; Mice, Inbred C57BL ; Beclin-1/metabolism ; Mitochondria, Liver/metabolism/drug effects ; }, abstract = {Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic - pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.}, } @article {pmid39098767, year = {2024}, author = {Endo, F}, title = {Deciphering the spectrum of astrocyte diversity: Insights into molecular, morphological, and functional dimensions in health and neurodegenerative diseases.}, journal = {Neuroscience research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neures.2024.07.008}, pmid = {39098767}, issn = {1872-8111}, abstract = {Astrocytes are the most abundant and morphologically complex glial cells that play active roles in the central nervous system (CNS). Recent research has identified shared and region-specific astrocytic genes and functions, elucidated the cellular origins of their regional diversity, and uncovered the molecular networks for astrocyte morphology, which are essential for their functional complexity. Reactive astrocytes exhibit a wide range of functional diversity in a context-specific manner in CNS disorders. This review discusses recent advances in understanding the molecular and morphological diversity of astrocytes in healthy individuals and those with neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.}, } @article {pmid39098618, year = {2024}, author = {Koehn, LM and Jalaldeen, R and Pelle, J and Nicolazzo, JA}, title = {Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis following oral administration.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {203}, number = {}, pages = {114434}, doi = {10.1016/j.ejpb.2024.114434}, pmid = {39098618}, issn = {1873-3441}, mesh = {Animals ; *Caffeine/administration & dosage/pharmacokinetics ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Spinal Cord/metabolism/drug effects ; Male ; Female ; Mice ; Administration, Oral ; *Brain/metabolism/drug effects ; *Disease Models, Animal ; *Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Digoxin/pharmacokinetics/administration & dosage ; Sulfasalazine/pharmacokinetics/administration & dosage ; Intestinal Absorption/drug effects/physiology ; }, abstract = {Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1[G93A] mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1[G93A] and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1[G93A] compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1[G93A] compared to WT mice, suggesting reduced gastric emptying in SOD1[G93A] mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1[G93A] compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1[G93A] mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.}, } @article {pmid39098187, year = {2024}, author = {R K Roy, A and Noohi, F and Morris, NA and Ljubenkov, P and Heuer, H and Fong, J and Hall, M and Lario Lago, A and Rankin, KP and Miller, BL and Boxer, AL and Rosen, HJ and Seeley, WW and Perry, DC and Yokoyama, JS and Lee, SE and Sturm, VE}, title = {Basal parasympathetic deficits in C9orf72 hexanucleotide repeat expansion carriers relate to smaller frontoinsula and thalamus volume and lower empathy.}, journal = {NeuroImage. Clinical}, volume = {43}, number = {}, pages = {103649}, pmid = {39098187}, issn = {2213-1582}, support = {R01 AG052496/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; *C9orf72 Protein/genetics ; Aged ; *Empathy/physiology ; *Frontotemporal Dementia/genetics/physiopathology/pathology/diagnostic imaging ; *DNA Repeat Expansion/genetics ; *Magnetic Resonance Imaging/methods ; *Parasympathetic Nervous System/physiopathology ; *Thalamus/diagnostic imaging/physiopathology/pathology ; *Cognitive Dysfunction/physiopathology/genetics/diagnostic imaging/etiology/pathology ; Heterozygote ; Respiratory Sinus Arrhythmia/physiology ; Cerebral Cortex/diagnostic imaging/physiopathology/pathology ; }, abstract = {Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9[+] asymp), 14 expansion carriers with mild cognitive impairment (C9[+] MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9[+] FTD), and 53 expansion-negative healthy controls (C9[-] HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9[+] FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9[+] FTD group had lower baseline respiratory sinus arrhythmia than the C9[+] MCI, C9[+] asymp, and C9[-] HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.}, } @article {pmid39097850, year = {2024}, author = {Luan, T and Li, Q and Huang, Z and Feng, Y and Xu, D and Zhou, Y and Hu, Y and Wang, T}, title = {Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.}, journal = {Neuroscience bulletin}, volume = {40}, number = {11}, pages = {1789-1810}, pmid = {39097850}, issn = {1995-8218}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Animals ; *Axons/pathology/metabolism ; Mitochondria/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive axonopathy, jointly leading to the dying back of the motor neuron, disrupting both nerve signaling and motor control. In this review, we highlight the roles of axonopathy in ALS progression, driven by the interplay of multiple factors including defective trafficking machinery, protein aggregation, and mitochondrial dysfunction. Dysfunctional intracellular transport, caused by disruptions in microtubules, molecular motors, and adaptors, has been identified as a key contributor to disease progression. Aberrant protein aggregation involving TDP-43, FUS, SOD1, and dipeptide repeat proteins further amplifies neuronal toxicity. Mitochondrial defects lead to ATP depletion, oxidative stress, and Ca[2+] imbalance, which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy. Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential. Collaborative research efforts aim to unravel ALS complexities, opening avenues for holistic interventions that target diverse pathological mechanisms.}, } @article {pmid39097602, year = {2024}, author = {Lehmann, J and Aly, A and Steffke, C and Fabbio, L and Mayer, V and Dikwella, N and Halablab, K and Roselli, F and Seiffert, S and Boeckers, TM and Brenner, D and Kabashi, E and Mulaw, M and Ho, R and Catanese, A}, title = {Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.}, journal = {Cell death & disease}, volume = {15}, number = {8}, pages = {560}, pmid = {39097602}, issn = {2041-4889}, support = {SFB 1506-Project 01//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 2019_A111//Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)/ ; }, mesh = {Humans ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Synaptotagmins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Heterozygote ; Phenotype ; Induced Pluripotent Stem Cells/metabolism/pathology ; Cell Differentiation/genetics ; Gene Knockout Techniques ; }, abstract = {Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13[+/-] hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13[+/-] transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.}, } @article {pmid39097310, year = {2024}, author = {Christian, CS and Nkonki, L and Desmond, C and Hoegfeldt, C and Dube, S and Rochat, T and Stein, A}, title = {Protocol of a cost-effectiveness analysis of a combined intervention for depression and parenting compared with enhanced standard of care for perinatally depressed, HIV-positive women and their infants in rural South Africa.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e082977}, pmid = {39097310}, issn = {2044-6055}, support = {/WT_/Wellcome Trust/United Kingdom ; MR/P006965/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Female ; Humans ; Infant ; Infant, Newborn ; Pregnancy ; *Cost-Effectiveness Analysis/methods ; Depression/therapy ; Depression, Postpartum/therapy/economics ; *HIV Infections ; Parenting ; Randomized Controlled Trials as Topic ; Rural Population ; South Africa ; Standard of Care ; Research Design ; }, abstract = {INTRODUCTION: Poverty, HIV and perinatal depression represent a triple threat to public health in sub-Saharan Africa because of their combined negative effects on parenting and child development. In the resource-constrained context of low-income and middle-income countries, a lay-counsellor-delivered intervention that combines a psychological and parenting intervention could offer the potential to mitigate the consequences of perinatal depression while also optimising scarce resources for healthcare.Measuring the cost-effectiveness of such a novel intervention will help decision-makers to better understand the relative costs and effects associated with replicating the intervention, thereby supporting evidence-based decision-making. This protocol sets out the methodological framework for analysing the cost-effectiveness of a cluster randomised controlled trial (RCT) that compares a combined intervention to enhanced standard of care when treating depressed, HIV-positive pregnant women and their infants in rural South Africa.

METHODS AND ANALYSIS: This cost-effectiveness analysis (CEA) protocol complies with the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. A societal perspective will be chosen.The proposed methods will determine the cost and efficiency of implementing the intervention as per the randomised control trial protocol, as well as the cost of replicating the intervention in a non-research setting. The costs will be calculated using an appropriately adjusted version of the Standardised Early Childhood Development Costing Tool.Primary health outcomes will be used in combination with costs to determine the cost per improvement in maternal perinatal depression at 12 months postnatal and the cost per improvement in child cognitive development at 24 months of age. To facilitate priority setting, the incremental cost-effectiveness ratios for improvements in child cognitive development will be ranked against six other child cognitive-development interventions according to Verguet et al's methodology (2022).A combination of activity-based and ingredient-based costing approaches will be used to identify, measure and value activities and inputs for all alternatives. Outcomes data will be sourced from the RCT team.

ETHICS AND DISSEMINATION: The University of Oxford is the sponsor of the CEA. Ethics approval has been obtained from the Human Sciences Research Council (HSRC, #REC 5/23/08/17), South Africa and the Oxford Tropical Research Ethics Committee (OxTREC #31-17), UK.Consent for publication is not applicable since no participant data are used in this protocol.We plan to disseminate the CEA results to key policymakers and researchers in the form of a policy brief, meetings and academic papers.

TRIAL REGISTRATION DETAILS: ISRCTN registry #11 284 870 (14/11/2017) and SANCTR DOH-27-102020-9097 (17/11/2017).}, } @article {pmid39096593, year = {2024}, author = {Ozeloglu, IG and Akman Aydin, E}, title = {Combining features on vertical ground reaction force signal analysis for multiclass diagnosing neurodegenerative diseases.}, journal = {International journal of medical informatics}, volume = {191}, number = {}, pages = {105542}, doi = {10.1016/j.ijmedinf.2024.105542}, pmid = {39096593}, issn = {1872-8243}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Support Vector Machine ; Parkinson Disease/diagnosis ; Neural Networks, Computer ; Huntington Disease/diagnosis/physiopathology ; Signal Processing, Computer-Assisted ; Gait/physiology ; Algorithms ; }, abstract = {Neurodegenerative diseases (NDDs), which are caused by the degeneration of neurons and their functions, affect a significant part of the world's population. Although gait disorders are one of the critical and common markers to determine the presence of NDDs, diagnosing which NDD the patients have among a group of NDDs using gait data is still a significant challenge to be addressed. In this study, we addressed the multi-class classification of NDDs and aim to diagnose Parkinson's disease (PD), Amyotrophic lateral sclerosis disease (AD), and Huntington's disease (HD) from a group containing NDDs and healthy control subjects. We also examined the impact of disease-specific identified features derived from VGRF signals. Detrended Fluctuation Analysis (DFA), Dynamic Time Warping (DTW) and Autocorrelation (AC) were used for feature extraction on Vertical Ground Reaction Force (VGRF) signals. To compare the performance of the features, we employed Support Vector Machines, K-Nearest Neighbors, and Neural Networks as classifiers. In three-class problem addressing the classification of AD, PD and HD 93.3% accuracy rate was achieved, while in the four classes case, in which NDDs and HC groups were considered together, 93.5% accuracy rate was yielded. Considering the disease-specific impact of features, it is revealed that while DFA based features diagnose patients with AD with the highest accuracy, DTW has been shown to be more successful in diagnosing PD. AC based features provided the highest accuracy in diagnosing HD. Although gait disorder is common for NDDs, each disease may have its own distinctive gait rhythms; therefore, it is important to identify disease-specific patterns and parameters for the diagnosis of each disease. To increase the diagnostic accuracy, it is necessary to use a combination of features, which were effective for each disease diagnosis. Determining a limited number of disease-specific features would provide NDD diagnostic systems suitable to be deployed in edge-computing environments.}, } @article {pmid39096334, year = {2024}, author = {Paterson, M and Doeltgen, S and Francis, R}, title = {Sensory Changes Related to Swallowing in Motor Neurone Disease.}, journal = {Dysphagia}, volume = {}, number = {}, pages = {}, pmid = {39096334}, issn = {1432-0460}, abstract = {Dysphagia is common in motor neurone disease (MND) and associated with negative health and psychosocial outcomes. Although largely considered a motor disease, a growing body of evidence suggests that MND can also affect the sensory system. As intact sensation is vital for safe swallowing, and sensory changes can influence the clinical management of dysphagia in people living with MND, this review evaluated and summarised the current evidence for sensory changes related to swallowing in MND. Of 3,481 articles originally identified, 29 met the inclusion criteria. Of these, 20 studies reported sensory changes, which included laryngeal sensation, taste, gag reflex, cough reflex, tongue sensation, smell, palatal and pharyngeal sensation, silent aspiration, and undefined sensation of the swallowing mechanism. Sensory changes were either described as decreased (n = 16) or heightened (n = 4). In the remaining nine studies, sensory function was reported as unaffected. The presence of changes to sensory function related to swallowing in MND remains inconclusive, although an increasing number of studies report sensory changes in some sensory domains. Future research is needed to evaluate the prevalence of sensory changes in MND and how such changes may influence dysphagia and its management.}, } @article {pmid39096043, year = {2024}, author = {Rabadi, MH and Russell, KA and Xu, C}, title = {Veterans with familial ALS and bulbar and respiratory presentations at onset had shorter survival.}, journal = {Science progress}, volume = {107}, number = {3}, pages = {368504241262902}, pmid = {39096043}, issn = {2047-7163}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology/genetics/diagnosis ; Middle Aged ; Male ; *Veterans/statistics & numerical data ; Female ; Aged ; Age of Onset ; Prognosis ; Kaplan-Meier Estimate ; }, abstract = {OBJECTIVE: We sought to characterize the clinical prognostic factors in veterans with amyotrophic lateral sclerosis (ALS) followed in our ALS clinic.

BACKGROUND: ALS is a rare, progressive neurodegenerative condition associated with decreased survival compared to that in the normal population.

METHOD: The electronic medical records of 105 veterans diagnosed with ALS who are followed in our ALS clinic between 2010 and 2021 were reviewed. Approval from the institutional review board was obtained from the study protocol. Demographic and clinical variables included age at symptom onset, age at initial evaluation, survival (from symptom onset to death), gender, site of onset (appendicular, bulbar, and respiratory), initial amyotrophic lateral sclerosis functional-related score-revised (ALSFRS-R), total functional independence measure (TFIM) scores, initial forced vital capacity (FVC), and interventions (Riluzole, gastrostomy, noninvasive ventilation [NIV], and tracheostomy). Normally distributed data was expressed as mean ± standard deviation. Fischer's exact analysis of the distribution differences of categorical data. The Kaplan-Meier plot analyzed the time-to-event.

RESULTS: The mean (SD) age at symptom onset was 62.0 (11.1) years, age at diagnosis was 65 (11) years, with 72% of the patients being over 60 years at diagnosis. The median survival time from symptom onset was 4.12 (3) years. Limb-onset ALS (appendicular) was the most frequent (52%) followed by bulbar-onset ALS (43%). The mean ALSFRS-R and TFIM scores were 31 (8) and 91 (25), respectively. Family history (familial), bulbar, and respiratory presentation at diagnosis were associated with shorter survival times.

CONCLUSION: This study suggests that of the clinical prognostic factors veterans with familial ALS, bulbar, and respiratory onset at presentations had shorter survival. The presence of Agent Orange, PEG placement, and NIV did not affect survival.}, } @article {pmid39095145, year = {2024}, author = {Sheers, NL and Andersen, T and Chatwin, M}, title = {Airway Clearance in Neuromuscular Disease.}, journal = {Sleep medicine clinics}, volume = {19}, number = {3}, pages = {485-496}, doi = {10.1016/j.jsmc.2024.04.009}, pmid = {39095145}, issn = {1556-4088}, mesh = {Humans ; *Neuromuscular Diseases/therapy/physiopathology ; Respiratory Therapy/methods ; Cough/therapy/physiopathology ; Airway Management/methods ; }, abstract = {High-quality respiratory care and airway clearance is essential for people with neuromuscular disease (pwNMD) as respiratory tract infections are a major cause of morbidity and mortality. This review expands on published guidelines by highlighting the role of cough peak flow along with other options for cough evaluation, and discusses recent key research findings which have influenced the practice of respiratory therapy for pwNMD.}, } @article {pmid39094561, year = {2024}, author = {Gomes, C and Huang, KC and Harkin, J and Baker, A and Hughes, JM and Pan, Y and Tutrow, K and VanderWall, KB and Lavekar, SS and Hernandez, M and Cummins, TR and Canfield, SG and Meyer, JS}, title = {Induction of astrocyte reactivity promotes neurodegeneration in human pluripotent stem cell models.}, journal = {Stem cell reports}, volume = {19}, number = {8}, pages = {1122-1136}, pmid = {39094561}, issn = {2213-6711}, support = {R01 EY033022/EY/NEI NIH HHS/United States ; T32 GM148382/GM/NIGMS NIH HHS/United States ; U24 EY033269/EY/NEI NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism ; Humans ; *Pluripotent Stem Cells/metabolism/cytology ; *Coculture Techniques ; Neurodegenerative Diseases/metabolism/pathology ; Complement C3/metabolism ; Cell Differentiation ; Neurons/metabolism ; Alzheimer Disease/pathology/metabolism ; Phagocytosis ; Blood-Brain Barrier/metabolism ; Glaucoma/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Calcium/metabolism ; Phenotype ; }, abstract = {Reactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression. Functionally, reactive astrocytes displayed decreased intracellular calcium, elevated phagocytic capacity, and decreased contribution to the blood-brain barrier. Subsequently, co-culture of reactive astrocytes with a variety of neuronal cell types promoted morphological and functional alterations. Furthermore, when reactivity was induced in astrocytes from patient-specific hPSCs (glaucoma, Alzheimer's disease, and amyotrophic lateral sclerosis), the reactive state exacerbated astrocytic disease-associated phenotypes. These results demonstrate how reactive astrocytes modulate neurodegeneration, significantly contributing to our understanding of a role for reactive astrocytes in neurodegenerative diseases.}, } @article {pmid39092466, year = {2024}, author = {Soubannier, V and Chaineau, M and Gursu, L and Lépine, S and Kalaydjian, D and Sirois, J and Haghi, G and Rouleau, G and Durcan, TM and Stifani, S}, title = {Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients with SOD1 mutations.}, journal = {Glia}, volume = {72}, number = {11}, pages = {2079-2094}, doi = {10.1002/glia.24598}, pmid = {39092466}, issn = {1098-1136}, support = {//ALS Canada/Brain Canada Hudson Translational Team Grant/ ; //Canada First Research Excellence Fund/ ; //ALS Canada/Brain Canada Discovery Grant/ ; }, mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Mutation ; *Phenotype ; Cells, Cultured ; Cell Nucleus/metabolism ; Motor Neurons/pathology/metabolism ; Oxidative Stress/physiology/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons (MNs). Glial cells play roles in MN degeneration in ALS. More specifically, astrocytes with mutations in the ALS-associated gene Cu/Zn superoxide dismutase 1 (SOD1) promote MN death. The mechanisms by which SOD1-mutated astrocytes reduce MN survival are incompletely understood. To characterize the impact of SOD1 mutations on astrocyte physiology, we generated astrocytes from human induced pluripotent stem cell (iPSC) derived from ALS patients carrying SOD1 mutations, together with control isogenic iPSCs. We report that astrocytes harboring SOD1(A4V) and SOD1(D90A) mutations exhibit molecular and morphological changes indicative of reactive astrogliosis when compared to isogenic astrocytes. We show further that a number of nuclear phenotypes precede, or coincide with, reactive transformation. These include increased nuclear oxidative stress and DNA damage, and accumulation of the SOD1 protein in the nucleus. These findings reveal early cell-autonomous phenotypes in SOD1-mutated astrocytes that may contribute to the acquisition of a reactive phenotype involved in alterations of astrocyte-MN communication in ALS.}, } @article {pmid39091724, year = {2024}, author = {Lv, G and Sayles, NM and Huang, Y and Mancinelli, CD and McAvoy, K and Shneider, NA and Manfredi, G and Kawamata, H and Eliezer, D}, title = {Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39091724}, issn = {2692-8205}, support = {P30 CA016087/CA/NCI NIH HHS/United States ; RF1 AG066493/AG/NIA NIH HHS/United States ; S10 OD028556/OD/NIH HHS/United States ; U01 NS134684/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; S10 OD016320/OD/NIH HHS/United States ; F31 HL154651/HL/NHLBI NIH HHS/United States ; F31 AG077836/AG/NIA NIH HHS/United States ; }, abstract = {CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.}, } @article {pmid39091345, year = {2024}, author = {Hernández, CA and Peikert, K and Qiao, M and Darras, A and de Wilde, JRA and Bos, J and Leibowitz, M and Galea, I and Wagner, C and Rab, MAE and Walker, RH and Hermann, A and van Beers, EJ and van Wijk, R and Kaestner, L}, title = {Osmotic gradient ektacytometry - a novel diagnostic approach for neuroacanthocytosis syndromes.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1406969}, pmid = {39091345}, issn = {1662-4548}, abstract = {INTRODUCTION: The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases.

METHODS: A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson's disease patients (n = 6), Huntington's disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients' characteristics.

RESULTS: Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width).

DISCUSSION: This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.}, } @article {pmid39091344, year = {2024}, author = {Goffin, L and Lemoine, D and Clotman, F}, title = {Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1434404}, pmid = {39091344}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) consists of a group of adult-onset fatal and incurable neurodegenerative disorders characterized by the progressive death of motor neurons (MNs) throughout the central nervous system (CNS). At first, ALS was considered to be an MN disease, caused by cell-autonomous mechanisms acting specifically in MNs. Accordingly, data from ALS patients and ALS animal models revealed alterations in excitability in multiple neuronal populations, including MNs, which were associated with a variety of cellular perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions. However, experimental evidence rapidly demonstrated the involvement of other types of cells, including glial cells, in the etiopathogenesis of ALS through non-cell autonomous mechanisms. Surprisingly, the contribution of pre-motor interneurons (INs), which regulate MN activity and could therefore critically modulate their excitability at the onset or during the progression of the disease, has to date been severely underestimated. In this article, we review in detail how spinal pre-motor INs are affected in ALS and their possible involvement in the etiopathogenesis of the disease.}, } @article {pmid39091255, year = {2024}, author = {Roggenbuck, J and Kaschalk, M and Eustace, R and Vicini, L and Gokun, Y and Harms, MB and Kolb, SJ}, title = {The Answer ALS return of results study: Answering the duty to disclose.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {743-750}, doi = {10.1080/21678421.2024.2385004}, pmid = {39091255}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/psychology ; Male ; Female ; Middle Aged ; *Genetic Testing/methods ; *Disclosure ; Aged ; Adult ; Prospective Studies ; }, abstract = {Objective: The Return of Answer ALS Results (RoAR) Study was designed to provide a mechanism for participants in Answer ALS, a large, prospectively designed natural history and biorepository study to receive select clinical genetic testing results and study participants' experience with the results disclosure. Methods: Participants consented to receive results of five ALS genes (C9orf72, SOD1, FUS, TARDP, TBK1) and/or 59 medically actionable genes as designated by the American College of Medical Genetics. Patient-reported genetic testing outcomes were measured via a post-disclosure survey. Results: Of 645 eligible Answer ALS enrollees, 143 (22%) enrolled and completed participation in RoAR. Pathogenic variants were identified in 22/143 (15.4%) participants, including 13/143 (9.0%) in ALS genes and 9/143 (6.3%) in ACMG genes. Participant-reported measures of result utility indicated the research result disclosure was as or more successful than published patient-reported outcomes of result disclosure the clinical setting. Conclusions: This study serves as a model of a "disclosure study" to share results from genomic research with participants who were not initially offered the option to receive results, and our findings can inform the design of future, large scale genomic projects to empower research participants to access their genetic information.}, } @article {pmid39091098, year = {2024}, author = {Annetta, MG and Barbato, G and Pisciaroli, E and Marche, B and Sabatelli, M and Pittiruti, M}, title = {Central venous catheter-related thrombosis in patients with amyotrophic lateral sclerosis.}, journal = {The journal of vascular access}, volume = {}, number = {}, pages = {11297298241262821}, doi = {10.1177/11297298241262821}, pmid = {39091098}, issn = {1724-6032}, abstract = {BACKGROUND: Central venous catheterization may be required in patients with amyotrophic lateral sclerosis (ALS) for parenteral nutrition, antibiotic treatment, or blood sampling. Different venous access devices can be taken into consideration-centrally inserted central catheters (CICC), peripherally inserted central catheters (PICC), and femorally inserted central catheters (FICCs)-depending on the clinical conditions of the patients. Regardless of the type of access, the presence of paraplegia or tetraplegia is commonly considered a risk factor for catheter-related thrombosis (CRT).

METHOD: This retrospective study analyzes the rate of CRT and other non-infectious complications associated with central venous access in a cohort of 115 patients with paraplegia or tetraplegia, most of them affected by ALS (n = 109).

RESULTS: In a period of 34 months, from January 2021 to October 2023, we inserted 75 FICCs, 29 CICCs, and 11 PICCs. PICCs were inserted only in patients with preserved motility of the upper limbs. All devices were inserted by trained operators adopting appropriate insertion bundles. We had no immediate or early complication. Though antithrombotic prophylaxis was adopted only in 61.7% of patients, we had no symptomatic CRT. Other non-infectious complications were infrequent (4 out of 115 patients).

CONCLUSION: These results suggest (a) that the presence of paraplegia or tetraplegia is not necessarily associated with an increased risk of CRT, (b) that the adoption of well-designed insertion bundles plays a key role in minimizing non-infectious complications, and (c) that the insertion of FICCs by direct cannulation of the superficial femoral vein at mid-thigh in paraplegic/tetraplegic patients may have the same advantages which have been described in the general population.}, } @article {pmid39088455, year = {2024}, author = {Bonthron, C and Burley, S and Broadhead, MJ and Metodieva, V and Grant, SGN and Chandran, S and Miles, GB}, title = {Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.}, journal = {PloS one}, volume = {19}, number = {8}, pages = {e0306423}, pmid = {39088455}, issn = {1932-6203}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/metabolism/genetics ; Animals ; *Astrocytes/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Coculture Techniques ; *Synapses/metabolism/physiology ; *Motor Neurons/metabolism/pathology/physiology ; *Spinal Cord/metabolism/pathology ; Humans ; Excitatory Postsynaptic Potentials ; Mice, Transgenic ; Cells, Cultured ; Synaptic Transmission ; }, abstract = {Hyperexcitability of motor neurons and spinal cord motor circuitry has been widely reported in the early stages of Amyotrophic Lateral Sclerosis (ALS). Changes in the relative amount of excitatory to inhibitory inputs onto a neuron (E:I synaptic ratio), possibly through a developmental shift in synapse formation in favour of excitatory transmission, could underlie pathological hyperexcitability. Given that astrocytes play a major role in early synaptogenesis and are implicated in ALS pathogenesis, their potential contribution to disease mechanisms involving synaptic imbalances and subsequent hyperexcitability is also of great interest. In order to assess E:I ratios in ALS, we utilised a novel primary spinal neuron / astrocyte co-culture system, derived from neonatal mice, in which synapses are formed in vitro. Using multiple ALS mouse models we found that no combination of astrocyte or neuron genotype produced alterations in E:I synaptic ratios assessed using pre- and post-synaptic anatomical markers. Similarly, we observed that ephrin-B1, a major contact-dependent astrocytic synaptogenic protein, was not differentially expressed by ALS primary astrocytes. Further to this, analysis of E:I ratios across the entire grey matter of the lumbar spinal cord in young (post-natal day 16-19) ALS mice revealed no differences versus controls. Finally, analysis in co-cultures of human iPSC-derived motor neurons and astrocytes harbouring the pathogenic C9orf72 hexanucleotide repeat expansion showed no evidence of a bias toward excitatory versus inhibitory synapse formation. We therefore conclude, utilising multiple ALS models, that we do not observe significant changes in the relative abundance of excitatory versus inhibitory synapses as would be expected if imbalances in synaptic inputs contribute to early hyperexcitability.}, } @article {pmid39088003, year = {2024}, author = {Lai, HJ and Kuo, YC and Ting, CH and Yang, CC and Kao, CH and Tsai, YC and Chao, CC and Hsueh, HW and Hsieh, PF and Chang, HY and Wang, IF and Tsai, LK}, title = {Increase of HCN current in SOD1-associated amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4240-4253}, doi = {10.1093/brain/awae248}, pmid = {39088003}, issn = {1460-2156}, support = {108-2314-B-002-082-MY3//Ministry of Science and Technology, ROC/ ; MQ999//National Taiwan University Hospital/ ; 112-BIH001//National Taiwan University Hospital Hsinchu branch/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Animals ; *Superoxide Dismutase-1/genetics ; Mice ; Male ; Female ; *Mice, Transgenic ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics/metabolism ; Middle Aged ; Aged ; Axons/metabolism ; Disease Models, Animal ; Potassium Channels/metabolism/genetics ; Adult ; }, abstract = {The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is based mainly on clinical presentations, and the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NETs) to investigate axonal membrane properties and chemical precipitation, followed by ELISA analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-voltage threshold curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the current-voltage threshold curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72 or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely to be associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the current-voltage threshold curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partly prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes to familial ALS patients and ALS mice with mutant SOD1, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the current-voltage threshold curve was attributable to an elevation in the HCN current in SOD1-associated ALS.}, } @article {pmid39087137, year = {2024}, author = {Chisthi, MM}, title = {Unveiling the potential of electrocautery-enhanced lumen-apposing metal stents in endoscopic ultrasound-guided biliary drainage.}, journal = {World journal of gastrointestinal surgery}, volume = {16}, number = {7}, pages = {1956-1959}, pmid = {39087137}, issn = {1948-9366}, abstract = {This editorial delves into Peng et al's article, published in the World Journal of Gastrointestinal Surgery. Peng et al's meta-analysis investigates the effectiveness of electrocautery-enhanced lumen-apposing metal stents (ECE-LAMS) in ultrasound-guided biliary drainage for alleviating malignant biliary obstruction. Examining 14 studies encompassing 620 participants, the research underscores a robust technical success rate of 96.7%, highlighting the efficacy of ECE-LAMS, particularly in challenging cases which have failed endoscopic retrograde cholangio pancreatography. A clinical success rate of 91.0% underscores its impact on symptom alleviation, while a reasonably tolerable adverse event rate of 17.5% is observed. However, the 7.3% re-intervention rate stresses the need for post-procedural monitoring. Subgroup analyses validate consistent outcomes, bolstering the applicability of ECE-LAMS. These findings advocate for the adoption of ECE-LAMS as an appropriate approach for biliary palliation, urging further exploration in real-world clinical contexts. They offer valuable insights for optimizing interventions targeting malignant biliary obstruction management.}, } @article {pmid39086926, year = {2024}, author = {Tilliole, P and Fix, S and Godin, JD}, title = {hnRNPs: roles in neurodevelopment and implication for brain disorders.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1411639}, pmid = {39086926}, issn = {1662-5099}, abstract = {Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a family of multifunctional RNA-binding proteins able to process nuclear pre-mRNAs into mature mRNAs and regulate gene expression in multiple ways. They comprise at least 20 different members in mammals, named from A (HNRNP A1) to U (HNRNP U). Many of these proteins are components of the spliceosome complex and can modulate alternative splicing in a tissue-specific manner. Notably, while genes encoding hnRNPs exhibit ubiquitous expression, increasing evidence associate these proteins to various neurodevelopmental and neurodegenerative disorders, such as intellectual disability, epilepsy, microcephaly, amyotrophic lateral sclerosis, or dementias, highlighting their crucial role in the central nervous system. This review explores the evolution of the hnRNPs family, highlighting the emergence of numerous new members within this family, and sheds light on their implications for brain development.}, } @article {pmid39086672, year = {2023}, author = {Pasinelli, P and Meyer, K and Ferraiuolo, L and Culibrk, RA and Sattler, R}, title = {Editorial: The role of glial cells in neurodegeneration.}, journal = {Frontiers in molecular medicine}, volume = {3}, number = {}, pages = {1337286}, doi = {10.3389/fmmed.2023.1337286}, pmid = {39086672}, issn = {2674-0095}, support = {T32 AG044402/AG/NIA NIH HHS/United States ; }, } @article {pmid39086635, year = {2024}, author = {Pérez-Holanda, S}, title = {Non-participation of asymptomatic candidates in screening protocols reduces early diagnosis and worsens prognosis of colorectal cancer.}, journal = {World journal of gastroenterology}, volume = {30}, number = {26}, pages = {3198-3200}, pmid = {39086635}, issn = {2219-2840}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/methods/statistics & numerical data ; Prognosis ; Asymptomatic Diseases ; Mass Screening/methods/statistics & numerical data ; Japan/epidemiology ; Neoplasm Staging ; Colonoscopy/statistics & numerical data ; }, abstract = {The Agatsuma et al's study shows that despite the evidence of the benefits of an early colorectal cancer (CRC) diagnosis, through screening in asymptomatic subjects, up to 50% of candidates reject this option and many of those affected are diagnosed later, in advanced stages. The efficacy of screening programs has been well-established for several years, which reduces the risk of CRC morbidity and mortality, without taking into account the test used for screening, or other tools. Nevertheless, a significant proportion of patients remain unscreened, so understanding the factors involved, as well as the barriers of the population to adherence is the first step to possibly modify the participation rate. These barriers could include a full range of social and political aspects, especially the type of financial provision of each health service. In Japan, health services are universal, and this advantageous situation makes it easier for citizens to access to these services, contributing to the detection of various diseases, including CRC. Interestingly, the symptomatic CRC group had a lower early-stage diagnosis rate than the patients detected during follow-up for other comorbidities, and symptomatic and cancer screening groups showed similar early-stage diagnosis.}, } @article {pmid39086545, year = {2024}, author = {Carrera-Juliá, S and Obrador, E and López-Blanch, R and Oriol-Caballo, M and Moreno-Murciano, P and Estrela, JM}, title = {Ketogenic effect of coconut oil in ALS patients.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1429498}, pmid = {39086545}, issn = {2296-861X}, abstract = {A recent pilot study in amyotrophic lateral sclerosis (ALS) patients analyzed the effect of a Mediterranean diet (MeDi) supplemented with nicotinamide riboside (NR, a NAD[+] promoter), pterostilbene (PTER, a natural antioxidant) and/or coconut oil on anthropometric variables in ALS patients. The results suggested that the MeDi supplemented with NR, PTER and coconut oil is the nutritional intervention showing the greatest benefits at anthropometric levels. Over the last 30 years, glucose intolerance has been reported in ALS patients. Thus, suggesting that an alternative source of energy may be preferential for motor neurons to survive. Ketone bodies (KBs), provided through a MeDi with a lower carbohydrate content but enriched with medium chain triglycerides, could be a therapeutic alternative to improve the neuromotor alterations associated with the disease. Nevertheless, the use of a coconut oil-supplemented diet, as potentially ketogenic, is a matter of controversy. In the present report we show that a MeDi supplemented with coconut oil increases the levels of circulating KBs in ALS patients.}, } @article {pmid39086006, year = {2024}, author = {An, TJ and Jang, S and Hering, K and Vazquez, R and Scalia, J and Berry, JD and Kalva, SP and Arellano, RS}, title = {Gastrostomy placement in patients with amyotrophic lateral sclerosis: assessment of risk factors for post-procedural respiratory failure.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {680-686}, doi = {10.1080/21678421.2024.2384994}, pmid = {39086006}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/surgery ; *Gastrostomy/methods ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; *Respiratory Insufficiency/etiology ; Risk Factors ; Adult ; Aged, 80 and over ; Deglutition Disorders/etiology/epidemiology ; }, abstract = {OBJECTIVE: Radiologically inserted gastrostomy placement may be performed in patients with dysphagia secondary to amyotrophic lateral sclerosis (ALS). This study assessed technical outcomes and complications related to gastrostomy placement in patients with ALS.

METHODS: A retrospective review of patients with ALS who underwent gastrostomy placement between 2021 and 2023 was performed. Patient demographics, medical history, ALS disease manifestations, survival, and post-procedural complications were obtained from the electronic medical record. Technical outcomes related to gastrostomy placement were obtained from operative notes and review of procedural imaging.

RESULTS: A total of 100 patients were included in the study. The mean duration of ALS diagnosis at time of gastrostomy placement was 1.3 +/-1.2 years. The mean slow vital capacity at time of gastrostomy placement was 54.0 +/-20.2% (range 10-155%). Technical success was 100%, with 91 placed using fluoroscopic guidance and 9 placed with computed tomography guidance. Eighty-three percent of gastrostomies were performed as outpatient procedures, while 17/100 patients were admitted following the procedure for monitoring. Post-procedural adverse events were noted in 21/100 patients (15 mild and 6 moderate or greater). Three patients developed respiratory failure after gastrostomy tube placement and died within 1-week post-procedure. Lower pre-procedural slow vital capacity was associated with higher risk of post-procedural respiratory failure (p = 0.0003*).

CONCLUSIONS: Gastrostomy placement in patients with ALS has a high technical success rate and may be performed safely in the outpatient setting in appropriate patients. Patients with low slow vital capacity related to ALS should be admitted post-procedurally for airway monitoring and support.}, } @article {pmid39085618, year = {2024}, author = {Müller, KJ and Schmidbauer, ML and Schönecker, S and Kamm, K and Pelz, JO and Holzapfel, K and Papadopoulou, M and Bakola, E and Tsivgoulis, G and Naumann, M and Hermann, A and Walter, U and Dimitriadis, K and Reilich, P and Schöberl, F}, title = {Diagnostic accuracy and confounders of vagus nerve ultrasound in amyotrophic lateral sclerosis-a single-center case series and pooled individual patient data meta-analysis.}, journal = {Journal of neurology}, volume = {271}, number = {9}, pages = {6255-6263}, pmid = {39085618}, issn = {1432-1459}, support = {DFG TRR 338//Deutsche Forschungsgemeinschaft/ ; DFG TRR 274//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Humans ; Male ; Aged ; Female ; Middle Aged ; *Ultrasonography ; *Vagus Nerve/diagnostic imaging ; }, abstract = {BACKGROUND: Several single-center studies proposed utility of vagus nerve (VN) ultrasound for detecting disease severity, autonomic dysfunction, and bulbar phenotype in amyotrophic lateral sclerosis (ALS). However, the resulting body of literature shows opposing results, leaving considerable uncertainty on the clinical benefits of VN ultrasound in ALS.

METHODS: Relevant studies were identified up to 04/2024 and individual patient data (IPD) obtained from the respective authors were pooled with a so far unpublished cohort (from Munich). An IPD meta-analysis of 109 patients with probable or definite ALS (El Escorial criteria) and available VN cross-sectional area (CSA) was performed, with age, sex, ALS Functional Rating Scale-revised (ALSFRS-R), disease duration, and bulbar phenotype as independent variables.

RESULTS: Mean age was 65 years (± 12) and 47% of patients (± 12) had bulbar ALS. Mean ALSFRS-R was 38 (± 7), and mean duration was 18 months (± 18). VN atrophy was highly prevalent [left: 67% (± 5), mean CSA 1.6mm[2] (± 0.6); right: 78% (± 21), mean CSA 1.8 mm[2] (± 0.7)]. VN CSA correlated with disease duration (mean slope: left - 0.01; right - 0.01), but not with ALSFRS-R (mean slope: left 0.004; mean slope: right - 0.002). Test accuracy for phenotyping bulbar vs. non-bulbar ALS was poor (summary receiver operating characteristic area under the curve: left 0.496; right 0.572).

CONCLUSION: VN atrophy in ALS is highly prevalent and correlates with disease duration, but not with ALSFRS-R. VN CSA is insufficient to differentiate bulbar from non-bulbar ALS phenotypes. Further studies are warranted to analyze the link between VN atrophy, autonomic impairment, and survival in ALS.}, } @article {pmid39084789, year = {2024}, author = {Wang, H and Zhang, Y and Ren, Y and Liu, Y and Feng, Z and Dong, L}, title = {Mechanism of multiple resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in Avena fatua L. from China.}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105985}, doi = {10.1016/j.pestbp.2024.105985}, pmid = {39084789}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Oxazoles/pharmacology ; China ; *Phenylurea Compounds/pharmacology ; *Acetyl-CoA Carboxylase/genetics/metabolism ; *Propionates/pharmacology ; *Acetolactate Synthase/genetics/metabolism ; Poaceae/drug effects ; Phenylpropionates/pharmacology ; Plant Proteins/genetics/metabolism ; Sulfonylurea Compounds ; }, abstract = {Avena fatua L. is one of the most damaging and malignant weeds in wheat fields in China. Fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon, which belong to Acetyl-CoA carboxylase- (ACCase), acetolactate synthase- (ALS), and photosystem II- (PS II) inhibitors, respectively, are commonly used in wheat fields and have a long history of use on A. fatua. An A. fatua population (R) resistant to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon was collected from a wheat field in 2020. This study explored the mechanisms of target site resistance (TSR) and non-target site resistance (NTSR) in the multi-resistant A. fatua. Whole-plant bioassays showed that the R population had evolved high resistance to fenoxaprop-P-ethyl and moderate resistance to mesosulfuron-methyl and isoproturon. However, no mutations were detected in the ACCase, ALS, or psbA genes in the R population. In addition, the ACCase and ALS gene expression levels in the R group were significantly higher than those in the susceptible population (S) after treatment with fenoxaprop-P-ethyl or mesosulfuron-methyl. In vitro ACCase and ALS activity assays showed that ACCase and ALS from the R population were insensitive to fenoxaprop and mesosulfuron-methyl, respectively, with resistance indices 6.12-fold and 17.46-fold higher than those of the S population. Furthermore, pretreatment with P450 inhibitors significantly (P < 0.05) reversed the multi-resistant A. fatua's resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon. Sethoxydim, flucarbazone‑sodium, chlortoluron, and cypyrafluone were effective in controlling multi-resistance A. fatua. Therefore, the overexpression of ACCase and ALS to synthesize sufficient herbicide-targeting proteins, along with P450-mediated metabolism, conferred resistance to fenoxaprop-P-ethyl, mesosulfuron-methyl, and isoproturon in the R population.}, } @article {pmid39084788, year = {2024}, author = {Ohta, K and Kawamata, E and Hori, T and Sada, Y}, title = {Connecting genes to whole plants in dilution effect of target-site ALS inhibitor resistance of Schoenoplectiella juncoides (Roxb.) Lye (Cyperaceae).}, journal = {Pesticide biochemistry and physiology}, volume = {203}, number = {}, pages = {105984}, doi = {10.1016/j.pestbp.2024.105984}, pmid = {39084788}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Cyperaceae/genetics/drug effects ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Mutation ; Genes, Plant ; }, abstract = {This study focuses on dilution effect of target-site resistance (TSR) to acetolactate synthase (ALS) inhibitors in Schoenoplectiella juncoides, which harbors two ALS genes, ALS1 and ALS2. We assessed gene expression, enzyme activity, and whole-plant resistance profiles across four S. juncoides lines: the susceptible line, the parental resistant lines with a homozygous mutation in either ALS1 or ALS2, and the bred progeny line with homozygous mutations in both ALS1 and ALS2. Gene expression and enzyme function showed a proportional relationship that the expression ratios of ALS1 to ALS2, approximately 70:30, were consistent with the functional ratio predicted by the double-sigmoidal plateau positions observed in enzyme assays. However, at the whole-plant level, resistance did not correlate to the putative abundance of susceptible enzyme, but the parental lines showed similar resistance to each other despite different enzyme-level resistances. This suggests a non-proportional mechanism in the reflection of physiological enzymatic profiles to whole-plant resistance profiles. These findings highlight the complexity of herbicide resistance and the need for further research to understand the mechanisms that influence resistance outcomes. Understanding these relationships is essential for developing strategies to manage herbicide resistance effectively.}, } @article {pmid39084570, year = {2024}, author = {Liu, J and Zhao, W and Guo, J and Kang, K and Li, H and Yang, X and Li, J and Wang, Q and Qiao, H}, title = {Electroacupuncture alleviates motor dysfunction by regulating neuromuscular junction disruption and neuronal degeneration in SOD1[G93A] mice.}, journal = {Brain research bulletin}, volume = {216}, number = {}, pages = {111036}, doi = {10.1016/j.brainresbull.2024.111036}, pmid = {39084570}, issn = {1873-2747}, mesh = {Animals ; *Electroacupuncture/methods ; *Neuromuscular Junction/pathology/metabolism ; *Motor Neurons/pathology/physiology ; *Mice, Transgenic ; Mice ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics ; Disease Models, Animal ; Male ; Nerve Degeneration/therapy/pathology ; Muscle, Skeletal/pathology ; Superoxide Dismutase-1/genetics/metabolism ; Sciatic Nerve/injuries/pathology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the progressive destruction of the neuromuscular junction (NMJ) and the degeneration of motor neurons, eventually leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. NMJs, synaptic connections between motor neurons and skeletal muscle fibers, are extremely fragile in ALS. To determine the effects of early electroacupuncture (EA) intervention on nerve reinnervation and regeneration following injury, a model of sciatic nerve injury (SNI) was first established using SOD1[G93A] mice, and early electroacupuncture (EA) intervention was conducted at Baihui (DU20), and bilateral Zusanli (ST36). The results revealed that EA increased the Sciatic nerve Functional Index, the structural integrity of the gastrocnemius muscles, and the cross-sectional area of muscle fibers, as well as up-regulated the expression of acetylcholinesterase and facilitated the co-location of α7 nicotinic acetate choline receptors and α-actinin. Overall, these results suggested that EA can promote the repair and regeneration of injured nerves and delay NMJ degeneration in SOD1[G93A]-SNI mice. Moreover, analysis of the cerebral cortex demonstrated that EA alleviated cortical motor neuron damage in SOD1[G93A] mice, potentially attributed to the inhibition of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and the release of interferon-β suppressing the activation of natural killer cells and the secretion of interferon-γ, thereby further inhibiting microglial activation and the expression of inflammatory factors. In summary, EA delayed the degeneration of NMJ and mitigated the loss of cortical motor neurons, thus delaying disease onset, accompanied by alleviation of muscle atrophy and improvements in motor function in SOD1[G93A] mice.}, } @article {pmid39084211, year = {2024}, author = {Sharma, S and Gilberto, VS and Rask, J and Chatterjee, A and Nagpal, P}, title = {Inflammasome-Inhibiting Nanoligomers Are Neuroprotective against Space-Induced Pathology in Healthy and Diseased Three-Dimensional Human Motor and Prefrontal Cortex Brain Organoids.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {16}, pages = {3009-3021}, doi = {10.1021/acschemneuro.4c00160}, pmid = {39084211}, issn = {1948-7193}, mesh = {Humans ; *Prefrontal Cortex/drug effects/metabolism ; *Organoids/drug effects ; *Inflammasomes/metabolism ; Neuroprotective Agents/pharmacology ; Space Flight ; Weightlessness ; Neurodegenerative Diseases ; Alzheimer Disease/pathology/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {The microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.}, } @article {pmid39083229, year = {2024}, author = {Kaji, R and Izumi, Y and Oki, R}, title = {Ultra-high dose methylcobalamin and other emerging therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {593-602}, doi = {10.1097/WCO.0000000000001311}, pmid = {39083229}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Vitamin B 12/analogs & derivatives/therapeutic use/administration & dosage ; Clinical Trials as Topic ; }, abstract = {PURPOSE OF REVIEW: Recent development in understanding the pathophysiology of amyotrophic lateral sclerosis (ALS) has led to increasing number of promising test drugs in the pipeline along with the existing ones. We will review these agents focusing on ultra-high dose methylcobalamin, which is pending approval in Japan. Clinical trial design best suited for ALS will also be discussed.

RECENT FINDINGS: The most recent phase 3 trial (JETALS) of ultra-high dose methylcobalamin demonstrated significant slowing of ALSFRSR changes (0.5/month), with marked reduction of serum homocysteine levels in the initial double-blind period. The post hoc analysis of the previous phase 2/3 study (E761 trial; Eisai) showed that it prolonged survival of ALS patients, if started within 1 year of onset, but the previous studies suggested its efficacy even in later stages, depending upon the rate of progression. Phase 3 trial of AMX0035 or Relyvrio on the other hand showed negative results despite the promising phase 2 data. The latter did not adjust the disease progression rate before entry.

SUMMARY: Ultra-high dose methylcobalamin is not a vitamin supplement but a novel disease-modifying therapy for ALS, and it emphasizes homocysteine as a key factor in the disease process. Clinical trial design must include entering patients early and with similar rates of progression using pretrial observation periods for meaningful results, since ALS is a chronologically heterogenous condition with similar phenotypes.}, } @article {pmid39080220, year = {2024}, author = {Han, M and Raymond, J and Larson, TC and Mehta, P and Horton, DK}, title = {Correction to: Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40615-024-02110-0}, pmid = {39080220}, issn = {2196-8837}, } @article {pmid39079696, year = {2024}, author = {Tress, F and Luecke, E and Stegemann-Koniszewski, S and Lux, A and Singla, A and Schreiber, J}, title = {Prediction of nocturnal ventilation by pulmonary function testing in patients with amyotrophic lateral sclerosis.}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {78}, number = {9}, pages = {626-633}, doi = {10.1055/a-2349-0936}, pmid = {39079696}, issn = {1438-8790}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy/diagnosis/complications ; Female ; Male ; Aged ; *Respiratory Function Tests ; Retrospective Studies ; Middle Aged ; Noninvasive Ventilation/methods ; Sensitivity and Specificity ; Reproducibility of Results ; Respiratory Insufficiency/therapy/physiopathology/etiology/diagnosis ; Polysomnography/methods ; Circadian Rhythm/physiology ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS) prognosis is poor due to progressive weakening of the respiratory muscles. Survival and quality of life can be improved by noninvasive ventilation (NIV), which is initially applied while sleeping. The indication for NIV is based on pulmonary function testing (PFT) and polysomnography (PSG) with capnography (tCO2). While it is desirable to predict nocturnal ventilation by waking PFT in ALS, the parameters suited for reliable predictions remain elusive.

METHODS: We retrospectively analyzed parameters derived from PFT (spirometry, body plethysmography, diffusion capacity, respiratory muscle testing) and blood gas analysis, PSG and tCO2 in 42 patients with ALS (27 men, 15 women, age 69 ± 12.1 years) and performed Spearman's correlation analysis of daytime waking parameters and nighttime sleep parameters.

RESULTS: 28 patients (66.7%) showed restrictive impairment of ventilation and 15 patients (48.3%) showed insufficiency of the respiratory musculature. There was no obstructive impairment of ventilation. We did not observe any significant correlations between any single daytime PFT parameter with nocturnal pCO2. However, there were significant correlations between the ratios PIF/PEF, MEF50/MIF50, DLCO/VA as well as FEV1/FVC and nocturnal pCO2. Highly normal FEV1/FVC and Krogh-Factor (DLCOc/VA) indicated nocturnal hypercapnia. Furthermore, waking hypercapnia, concentrations of bicarbonate and base excess were each positively correlated with nocturnal hypercapnia.

CONCLUSIONS: Waking PFT is not a good predictor of nocturnal ventilation. Inspiratory parameters as well as the ratios FEV1/FVC and DLCO/VA performed best and should be included in the interpretation. Our analyses confirm the relevance of inspiratory muscle weakness in ALS. PSG and tCO2 remain the gold standard for the assessment of nocturnal ventilation.}, } @article {pmid39079071, year = {2024}, author = {Crayle, JI and Rampersaud, E and Myers, JR and Wuu, J and Taylor, JP and Wu, G and Benatar, M and Bedlack, RS}, title = {Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {103}, number = {4}, pages = {e209696}, pmid = {39079071}, issn = {1526-632X}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; Cohort Studies ; *Genome-Wide Association Study ; *Phenotype ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Whole Genome Sequencing ; }, abstract = {BACKGROUND AND OBJECTIVES: The term "ALS Reversal" describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype.

METHODS: Participants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium's Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis.

RESULTS: WGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1, is uncertain given the absence of an associated effect on nearby gene transcription.

DISCUSSION: We found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS.

This study was registered with ClinicalTrials.gov (NCT03464903) on March 14, 2018. The first participant was enrolled on June 22, 2018.}, } @article {pmid39079069, year = {2024}, author = {Fournier, CN}, title = {Learning From the Exception and Not the Rule: Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.}, journal = {Neurology}, volume = {103}, number = {4}, pages = {e209780}, doi = {10.1212/WNL.0000000000209780}, pmid = {39079069}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Phenotype ; }, } @article {pmid39076845, year = {2024}, author = {Liu, X and Chen, L and Ye, S and Liu, X and Zhang, Y and Fan, D}, title = {Postural instability and lower extremity dysfunction in upper motor neuron-dominant amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1406109}, pmid = {39076845}, issn = {1664-2295}, abstract = {BACKGROUND: Upper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).

RESULTS: Among the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.

CONCLUSION: UMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.}, } @article {pmid39076207, year = {2024}, author = {Zheng, W and He, J and Chen, L and Yu, W and Zhang, N and Liu, X and Fan, D}, title = {Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1421841}, pmid = {39076207}, issn = {1663-4365}, abstract = {OBJECTIVES: Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.

METHODS: The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.

RESULTS: In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.

CONCLUSION: Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.}, } @article {pmid39075916, year = {2025}, author = {Wu, J and Ye, S and Liu, X and Xu, Y and Fan, D}, title = {The burden of upper motor neuron involvement is correlated with the bilateral limb involvement interval in patients with amyotrophic lateral sclerosis: a retrospective observational study.}, journal = {Neural regeneration research}, volume = {20}, number = {5}, pages = {1505-1512}, pmid = {39075916}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202505000-00032/figure1/v/2024-07-28T173839Z/r/image-tiff Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons. Early bilateral limb involvement significantly affects patients' daily lives and may lead them to be confined to bed. However, the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear. To address this issue, we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022. A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis. We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients. Multiple factor analyses revealed that higher upper motor neuron scores (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01-1.09, P = 0.018), onset in the left limb (HR = 0.72, 95% CI = 0.58-0.89, P = 0.002), and a horizontal pattern of progression (HR = 0.46, 95% CI = 0.37-0.58, P < 0.001) were risk factors for a shorter interval until bilateral limb involvement. The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients. These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.}, } @article {pmid39075908, year = {2025}, author = {Araúzo-Bravo, MJ and Gerovska, D and Schwab, M and Kretz, A}, title = {Small extrachromosomal circular DNA in amyotrophic lateral sclerosis matter.}, journal = {Neural regeneration research}, volume = {20}, number = {5}, pages = {1411-1413}, pmid = {39075908}, issn = {1673-5374}, } @article {pmid39075842, year = {2024}, author = {Lomnicka, I and Dubey, S and Waller, P and Vora, D and Dirikolu, L}, title = {Development and validation of general plasma screening method for performance enhancing drugs in racehorses utilizing liquid chromatography-high-resolution mass spectrometry (LC-HRMS).}, journal = {Drug testing and analysis}, volume = {}, number = {}, pages = {}, doi = {10.1002/dta.3774}, pmid = {39075842}, issn = {1942-7611}, support = {//Louisiana State Racing Commission, New Orleans, LA 70119/ ; }, abstract = {The screening of drugs in plasma and urine often requires initial extraction (such as liquid-liquid extraction and solid-phase extraction) before the samples are submitted to instrumental analyses. These extraction procedures are often laborious and time-consuming. In this manuscript, a high-throughput automated assay based on liquid chromatography-high-resolution mass spectrometry (LC-HRMS) suitable for use as an initial testing procedure covering multiple classes of compounds prohibited in horse racing is described. The assay requires a 600-μL plasma aliquot, which is subjected to solid phase extraction (SPE) using OASIS HLB 96-well SPE with Biotage Extrahera system, evaporation, and reconstitution in a 96-well collection plate. LC-HRMS analyses were carried out on a Thermo Q-Exactive Mass spectrometer coupled with Thermo UHPLC system equipped with Thermo Accela ALS 2.4.0 autosampler linked to ACE Excel column. Drug targets were detected by retention time and accurate mass, with a mass tolerance window of 5 ppm in positive and negative ionization mode. The screening method was validated for over 300 drug targets in a 13-min run. Validation data including sensitivity, specificity, extraction recovery, and precision are presented. As the method employs full-scan mass spectrometry, unlimited number of drug targets can theoretically be incorporated into this method.}, } @article {pmid39075493, year = {2024}, author = {Mangal, AL and Mücke, M and Rolke, R and Appelmann, I}, title = {Advance directives in amyotrophic lateral sclerosis - a systematic review and meta-analysis.}, journal = {BMC palliative care}, volume = {23}, number = {1}, pages = {191}, pmid = {39075493}, issn = {1472-684X}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy/complications ; Humans ; *Advance Directives/statistics & numerical data/psychology ; Advance Care Planning/statistics & numerical data/standards ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motoneuron. It is associated with a life expectancy of 2-4 years after diagnosis. Individuals experience paralysis, dysphagia, respiratory failure and loss of communicative function, rendering advance care planning (ACP) critically important. This systematic review primarily aimed to internationally compare the application of advance directives (AD) and ACP in ALS. Its secondary aim was to identify ACP preferences, identify fields for future research and to generate recommendations for improving patient care through ACP.

METHODS: We conducted a systematic literature review and meta-analysis. Five electronic databases (Embase, Medline, Scopus, PsycInfo and CENTRAL) were searched for qualitative and quantitative primary literature from 1999 to 2024. Cross-references were used to identify additional publications. Study selection was performed based on inclusion criteria. Number and content of AD were extracted systematically. After statistical analysis consecutive meta-analysis was performed for international differences and changes over time. Quality assessment of studies was performed using the MMAT (Mixed Methods Appraisal Tool). PROSPERO Registration (June 07, 2021) : CRD42021248040.

RESULTS: A total of 998 records was screened of which 26 were included in the synthesis. An increase in publication numbers of 88.9% was observed from 1999 to 2024. Results regarding use and content of AD were heterogeneous and international differences were detected. AD were signed in 60.4% of records (1,629 / 2,696 patients). The number of AD decreased over time when separating the review period in two decades (1st 1999-2011: 78% vs. 2nd 2012-2024: 42%). Study quality was superior in qualitative and mixed method designs compared to quantitative studies.

CONCLUSION: Further prospective studies should include detailed analyses on preferences regarding ventilation and artificial nutrition in ALS and should encompass countries of the global south. Despite the complexity of ACP with regard to individual patient needs, ACP should be part of each individual support plan for ALS patients and should specifically comprise a discussion on the preferred place of death. The available disease-specific AD documents should be preferred.}, } @article {pmid39073874, year = {2024}, author = {Gatch, AJ and Ding, F}, title = {TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {15}, pages = {2936-2953}, pmid = {39073874}, issn = {1948-7193}, support = {P20 GM121342/GM/NIGMS NIH HHS/United States ; R35 GM145409/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amyloid beta-Peptides/metabolism ; *DNA-Binding Proteins/metabolism ; Humans ; *Molecular Dynamics Simulation ; *Amyloid/metabolism ; Protein Binding ; Alzheimer Disease/metabolism ; }, abstract = {Amyloid-β (Aβ) is a peptide that undergoes self-assembly into amyloid fibrils, which compose the hallmark plaques observed in Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) is a protein with mislocalization and aggregation implicated in amyotrophic lateral sclerosis and other neurodegenerative diseases. Recent work suggests that TDP-43 may interact with Aβ, inhibiting the formation of amyloid fibrils and worsening AD pathology, but the molecular details of their interaction remain unknown. Using all-atom discrete molecular dynamics simulations, we systematically investigated the direct molecular interaction between Aβ and TDP-43. We found that Aβ monomers were able to bind near the flexible nuclear localization sequence of the N-terminal domain (NTD) of TDP-43, adopting β-sheet rich conformations that were promoted by the interaction. Furthermore, Aβ associated with the nucleic acid binding interface of the tandem RNA recognition motifs of TDP-43 via electrostatic interactions. Using the computational peptide array method, we found the strongest C-terminal domain interaction with Aβ to be within the amyloidogenic core region of TDP-43. With experimental evidence suggesting that the NTD is necessary for inhibiting Aβ fibril growth, we also simulated the NTD with an Aβ40 fibril seed. We found that the NTD was able to strongly bind the elongation surface of the fibril seed via extensive hydrogen bonding and could also diffuse along the lateral surface via electrostatic interactions. Our results suggest that TDP-43 binding to the elongation surface, thereby sterically blocking Aβ monomer addition, is responsible for the experimentally observed inhibition of fibril growth. We conclude that TDP-43 may promote Aβ toxicity by stabilizing the oligomeric state and kinetically delaying fibril maturation.}, } @article {pmid39073543, year = {2024}, author = {Litvinov, VV and Freynd, GG}, title = {[Clinical and morphologic characterization of Pick's dementia: case report and review of the literature].}, journal = {Arkhiv patologii}, volume = {86}, number = {4}, pages = {51-57}, doi = {10.17116/patol20248604151}, pmid = {39073543}, issn = {0004-1955}, mesh = {Humans ; *Pick Disease of the Brain/pathology/diagnosis ; Male ; tau Proteins/metabolism ; Female ; Middle Aged ; Cerebral Cortex/pathology ; }, abstract = {Diseases morphologically characterized by frontotemporal lobar degeneration have relatively recently been considered as a group of frontotemporal dementias. This group is characterized by a tendency to early clinical onset of dementia, common genetic and morphological features, as well as a possible association with diseases such as amyotrophic lateral sclerosis and atypical parkinsonism syndrome. Historically, Pick's dementia (Pick's disease) was described as the first of the frontotemporal dementias, which is morphologically characterized by the presence of argyrophilic Pick's bodies represented by 3R-tau protein in the neurons of the cerebral cortex. Despite the characteristic clinical and morphological picture due to the relative rarity, the diagnosis of Pick's dementia is infrequently made by both clinicians and pathologists. The article presents current data on frontotemporal dementia. A case of Pick's dementia with characteristic clinical manifestations in the form of early onset of behavioral and personality disorders, as well as specific morphological changes in the brain, is described.}, } @article {pmid39073531, year = {2024}, author = {Moglia, C and Palumbo, F and Botto, R and Iazzolino, B and Ticozzi, N and Calvo, A and Leombruni, P and , }, title = {Prognostic communication in amyotrophic lateral sclerosis: findings from a Nationwide Italian survey.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5787-5794}, pmid = {39073531}, issn = {1590-3478}, support = {RF-2016-02362405//Ministero della Salute/ ; 23C306//Ministero della Salute/ ; 101017598//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 2017SNW5MB//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 259867//Seventh Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Humans ; Italy ; Prognosis ; *Neurologists ; *Attitude of Health Personnel ; Communication ; Surveys and Questionnaires ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease with a highly variable prognosis. Among the proposed prognostic models, the European Network for the cure of ALS (ENCALS) survival model has demonstrated good predictive performance. However, few studies have examined prognostic communication and the diffusion of prognostic algorithms in ALS care.

OBJECTIVE: To investigate neurologists' attitudes toward prognostic communication and their knowledge and utilization of the ENCALS survival model in clinical practice.

METHODS: A web-based survey was administered between May 2021 and March 2022 to the 40 Italian ALS Centers members of the Motor Neuron Disease Study Group of the Italian Society of Neurology.

RESULTS: Twenty-two out of 40 (55.0%) Italian ALS Centers responded to the survey, totaling 37 responses. The model was known by 27 (73.0%) respondents. However, it was predominantly utilized for research (81.1%) rather than for clinical prognostic communication (7.4%). Major obstacles to prognostic communication included the unpredictability of disease course, fear of a negative impact on patients or caregivers, dysfunctional reaction to diagnosis, and cognitive impairment. Nonetheless, the model was viewed as potentially useful for improving clinical management, increasing disease awareness, and facilitating care planning, especially end-of-life planning.

CONCLUSIONS: Despite the widespread recognition and positive perceptions of the ENCALS survival model among Italian neurologists with expertise in ALS, its implementation in clinical practice remains limited. Addressing this disparity may require systematic investigations and targeted training to integrate tailored prognostic communication into ALS care protocols, aligning with the growing availability of prognostic tools for ALS.}, } @article {pmid39073225, year = {2024}, author = {Liu, X and Xue, H and Wirdefeldt, K and Song, H and Smedby, K and Fang, F and Liu, Q}, title = {Clonal hematopoiesis of indeterminate potential and risk of neurodegenerative diseases.}, journal = {Journal of internal medicine}, volume = {296}, number = {4}, pages = {327-335}, doi = {10.1111/joim.20001}, pmid = {39073225}, issn = {1365-2796}, support = {//Initial Founding for High Level Talented Scholars in Nanfang Hospital/ ; 2023G001//Southern Medical University/ ; 2021-00696//Swedish Research Council (JPND)/ ; P1030//Initial Founding for Postdoc in Greater Bay Area Institute of Precision Medicine (Guangzhou)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/genetics/epidemiology ; Female ; Male ; *Clonal Hematopoiesis/genetics ; Middle Aged ; Aged ; Risk Factors ; DNA Methyltransferase 3A ; United Kingdom/epidemiology ; Cohort Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics ; Repressor Proteins/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; DNA-Binding Proteins ; Dioxygenases ; }, abstract = {BACKGROUND: Little is known regarding the association between clonal hematopoiesis of indeterminate potential (CHIP) and risk of neurodegenerative diseases.

OBJECTIVE: To estimate the risk of neurodegenerative diseases among individuals with CHIP.

METHODS: We conducted a community-based cohort study based on UK Biobank and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of any neurodegenerative disease, subtypes of neurodegenerative diseases (including primary neurodegenerative diseases, vascular neurodegenerative diseases, and other neurodegenerative diseases), and specific diagnoses of neurodegenerative diseases (i.e., amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], and Parkinson's disease [PD]) associated with CHIP.

RESULTS: We identified 14,440 individuals with CHIP and 450,907 individuals without CHIP. Individuals with CHIP had an increased risk of any neurodegenerative disease (HR 1.10, 95% CI: 1.01-1.19). We also observed a statistically significantly increased risk for vascular neurodegenerative diseases (HR 1.31, 95% CI 1.05-1.63) and ALS (HR 1.50, 95% CI 1.05-2.15). An increased risk was also noted for other neurodegenerative diseases (HR 1.13, 95% CI 0.97-1.32), although not statistically significant. Null association was noted for primary neurodegenerative diseases (HR 1.06, 95% CI 0.96-1.17), AD (HR 1.04, 95% CI 0.88-1.23), and PD (HR 1.02, 95% CI 0.86-1.21). The risk increase in any neurodegenerative disease was mainly observed for DNMT3A-mutant CHIP, ASXL1-mutant CHIP, or SRSF2-mutant CHIP.

CONCLUSION: Individuals with CHIP were at an increased risk of neurodegenerative diseases, primarily vascular neurodegenerative diseases and ALS, but potentially also other neurodegenerative diseases. These findings suggest potential shared mechanisms between CHIP and neurodegenerative diseases.}, } @article {pmid39073146, year = {2024}, author = {Bublitz, SK and Eham, M and Ellrott, H and Littger, B and Richter, J and Lorenzl, S}, title = {Homecare amyotrophic lateral sclerosis (ALS): A multidisciplinary, home-based model of care for patients with ALS and their caregivers.}, journal = {Muscle & nerve}, volume = {70}, number = {5}, pages = {937-943}, doi = {10.1002/mus.28218}, pmid = {39073146}, issn = {1097-4598}, support = {//Bavarian Ministry of Health/ ; //Krankenhaus Agatharied/ ; //Dr. Mähler-Linke Stiftung/ ; //ALS Hilfe Bayern e.V./ ; //Marion von Tessin-Stiftung/ ; //Archdiocese München and Freising/ ; //Amylyx Pharmaceuticals Germany GmbH/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; *Caregivers/psychology ; Middle Aged ; Aged ; *Home Care Services ; Pilot Projects ; Longitudinal Studies ; Patient Satisfaction ; Patient Care Team ; Adult ; Palliative Care ; Cohort Studies ; Germany ; Terminal Care ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Multidisciplinary care for patients with amyotrophic lateral sclerosis (ALS) is recommended in international guidelines, but reaches its limits when immobility increases. This pilot project addresses this gap by delivering home-based, specialized, multiprofessional support to ALS patients who are not able to attend outpatient care. The study assessed the feasibility of this model of care and the satisfaction of both patients and caregivers.

METHODS: This was a longitudinal cohort study of patients with ALS and their caregivers in the surroundings of Munich, Germany. Patients were regularly visited at home by a multiprofessional team (neurologists/palliative care physicians, nurse, social worker, chaplain).

RESULTS: A total of 94 patients with ALS were included in the homecare project and 88 patients and 74 caregivers were enrolled in the accompanying study. The mean care duration was 221 days, enabling 61% of the 49 deceased patients to die at home. Notably, 20% of patients chose a way to hasten death. Patient satisfaction (ICECAP Supportive Care Measure [SCM]: 23.7/28, CollaboRATE: 10.6/12) and caregiver perception of the end-of-life phase (Caregiver Evaluation of the Quality of End-Of-Life Care [CEQUEL]: 24.9/26) were high.

DISCUSSION: This pilot project successfully implemented specialized, home-based multidisciplinary care for ALS patients and caregivers, demonstrating both feasibility and high satisfaction. The program enabled a large proportion of patients to remain in their homes, reducing the need for hospital care. The multiprofessional approach, including neuropalliative, psychosocial and spiritual support provided comprehensive care that addressed needs of patients and caregivers. Further research is warranted to explore cost-effectiveness.}, } @article {pmid39072769, year = {2024}, author = {Turner, J and Bruels, CC and Daugherty, AL and Estrella, EA and Stafki, S and Syeda, SB and Littel, HR and Pais, L and Ganesh, VS and Lidov, HGW and Paine, SML and Maddison, P and Harrison, RE and Straub, V and Ghosh, PS and Pacak, CA and Kunkel, LM and Draper, I and Topf, A and Kang, PB}, title = {Dominant stop-loss HNRNPA1 variants in juvenile-onset myopathy.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {843-850}, pmid = {39072769}, issn = {1097-4598}, support = {//Muscular Dystrophy UK/ ; //Ultragenyx/ ; R01 HG009141/HG/NHGRI NIH HHS/United States ; //Coalition to Cure Calpain 3/ ; //LGMD2I Research Fund/ ; R01HG009141/HG/NHGRI NIH HHS/United States ; //Kurt+Peter Foundation/ ; UM1HG008900//National Heart, Lung and Blood Institute/ ; //Sanofi Genzyme/ ; UM1 HG008900/HG/NHGRI NIH HHS/United States ; //Bernard F. and Alva B. Gimbel Foundation/ ; //LGMD2D Foundation/ ; //Samantha J. Brazzo Foundation/ ; /EY/NEI NIH HHS/United States ; R01HG009141/HG/NHGRI NIH HHS/United States ; /EY/NEI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Female ; Adolescent ; Muscular Diseases/genetics ; Muscle, Skeletal/pathology ; Young Adult ; Phenotype ; }, abstract = {INTRODUCTION/AIMS: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1.

METHODS: Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES).

RESULTS: The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon.

DISCUSSION: Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.}, } @article {pmid39072749, year = {2024}, author = {Stevenor, BA and Burgess, Y and Sampson, G and McBride, NL and Gugiu, MR and Copella, J and Davis, J and Wu, B and Panchal, AR}, title = {Examining the Reliability and Validity of the ALS Certification Examinations with the Inclusion of Clinical Judgment: An Update on the ALS Examination Redesign.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/10903127.2024.2379879}, pmid = {39072749}, issn = {1545-0066}, abstract = {OBJECTIVES: Clinical judgment describes the process an emergency medical service clinician uses to evaluate problems and make decisions in the out-of-hospital setting. As part of the redesign of the Advanced Life Support (ALS) certification examinations, the National Registry of Emergency Medical Technicians is developing and evaluating items that measure clinical judgment, with the intention of assessing these as a new domain in the ALS certification examinations. In this study, we provide evidence around the redesign by evaluating the reliability and validity of the advanced emergency medical technician (AEMT) and paramedic certification examinations when clinical judgment is included as a sixth domain along with the five current domains.

METHODS: Pretest (i.e., pilot, unscored) clinical judgment items were included as a new sixth clinical judgment domain. We then used the combination of operational (i.e., scored) and pretest items for all six domains and scored the redesigned AEMT and paramedic certification examinations. We evaluated the psychometric properties of these ALS examinations within the Rasch measurement framework with multiple assessments of reliability and validity including item-level statistics (e.g., mean-square infit and outfit, local dependence) and examination-level statistics (e.g., person reliability, item reliability, item separation, decision consistency, decision accuracy). Wright Maps were produced to evaluate whether the examination item difficulty statistics aligned with the candidate ability continuum.

RESULTS: The total population of all examination forms included were 20,136 (AEMT 4,983; paramedic 15,153). The Rasch-based statistics for the redesigned AEMT and paramedic examinations, for both item and examination-level statistics, were well within the psychometric standard values. Wright maps demonstrated that the developed items fall along the candidate ability continuum for both examinations. Further, the distribution of clinical judgment item difficulties fell within the current item distribution, providing evidence that these new items are of similar difficulty to the items measuring the five current domains.

CONCLUSION: We demonstrate strong reliability and validity evidence to support that the integrity of the examinations is upheld with the addition of clinical judgment items, while also providing a more robust candidate evaluation. Most importantly, the pass/fail decisions that candidates receive accurately reflect their level of ALS knowledge at the entry-level.}, } @article {pmid39072727, year = {2024}, author = {Defilippi, V and Petereit, J and Handlos, VJL and Notterpek, L}, title = {Quantitative proteomics unveils known and previously unrecognized alterations in neuropathic nerves.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {3154-3170}, pmid = {39072727}, issn = {1471-4159}, support = {P20 GM130459/GM/NIGMS NIH HHS/United States ; GM104944/NH/NIH HHS/United States ; P20 GM103440/GM/NIGMS NIH HHS/United States ; P20GM130459/NH/NIH HHS/United States ; GM103440/NH/NIH HHS/United States ; U54 GM104944/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Proteomics/methods ; Mice ; Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; Myelin Proteins/genetics/metabolism ; Peripheral Nerves/metabolism/pathology ; Mice, Inbred C57BL ; Male ; Peripheral Nervous System Diseases/genetics/metabolism/pathology ; Female ; }, abstract = {Charcot-Marie-Tooth disease type 1E (CMT1E) is an inherited autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. The identical leucine-to-proline (L16P) amino acid substitution in PMP22 is carried by the Trembler J (TrJ) mouse and is found in CMT1E patients presenting with early-onset disease. Peripheral nerves of patients diagnosed with CMT1E display a complex and varied histopathology, including Schwann cell hyperproliferation, abnormally thin myelin, axonal degeneration, and subaxonal morphological changes. Here, we have taken an unbiased data-independent analysis (DIA) mass spectrometry (MS) approach to quantify proteins from nerves of 3-week-old, age and genetic strain-matched wild-type (Wt) and heterozygous TrJ mice. Nerve proteins were dissolved in lysis buffer and digested into peptide fragments, and protein groups were quantified by liquid chromatography-mass spectrometry (LC-MS). A linear model determined statistically significant differences between the study groups, and proteins with an adjusted p-value of less than 0.05 were deemed significant. This untargeted proteomics approach identified 3759 quality-controlled protein groups, of which 884 demonstrated differential expression between the two genotypes. Gene ontology (GO) terms related to myelin and myelin maintenance confirm published data while revealing a previously undetected prominent decrease in peripheral myelin protein 2. The dataset corroborates the described pathophysiology of TrJ nerves, including elevated activity in the proteasome-lysosomal pathways, alterations in protein trafficking, and an increase in three macrophage-associated proteins. Previously unrecognized perturbations in RNA processing pathways and GO terms were also discovered. Proteomic abnormalities that overlap with other human neurological disorders besides CMT include Lafora Disease and Amyotrophic Lateral Sclerosis. Overall, this study confirms and extends current knowledge on the cellular pathophysiology in TrJ neuropathic nerves and provides novel insights for future examinations. Recognition of shared pathomechanisms across discrete neurological disorders offers opportunities for innovative disease-modifying therapeutics that could be effective for distinct neuropathies.}, } @article {pmid39072497, year = {2024}, author = {Alonso, JP and Ini, N and Villarejo, A and Belizán, M and Roberti, J}, title = {Amyotrophic lateral sclerosis in Argentina: unveiling the burden of treatment through patient and caregiver perspectives.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/09638288.2024.2385732}, pmid = {39072497}, issn = {1464-5165}, abstract = {PURPOSE: To examine the burden of treatment (BoT) experienced by people with Amyotrophic Lateral Sclerosis (ALS) in Argentina.

METHODS: Qualitative methodological design based on semi-structured interviews. Nineteen semi-structured interviews were conducted (PwALS = 7, informal caregivers= 12). The interview guides were designed based on the literature and BoT theory. Data were analysed following a framework analysis approach.

RESULTS: The research highlighted the arduous journey toward obtaining a diagnosis, marked by delays influenced by healthcare system inefficiencies, lack of disease awareness and pandemic-related anxiety. Receiving the diagnosis was a destabilising experience, triggering the need to reframe self-identity, a new reality. As the disease progressed, patients encountered significant challenges in their daily activities and basic tasks, affecting their ability to work, communicate, and manage personal care. The burden extended beyond the patients to their primary caregivers. Access to specialised care, bureaucratic complexities in securing treatment, and the financial impact of managing the disease posed substantial challenges.

CONCLUSION: The findings offer valuable insights into the experiences of PwALS and their caregivers in Argentina. They underscore the need for increased disease awareness, improved access to specialised care, and enhanced support networks to alleviate the burdens PwALS and their families face.}, } @article {pmid39071530, year = {2024}, author = {Gaspar, AD and Banayat, AC}, title = {Undergraduate Student Nurses' Satisfaction, Self-confidence, and Perception of High-fidelity Simulation-based Learning on Critically-ill Patients.}, journal = {Acta medica Philippina}, volume = {58}, number = {12}, pages = {110-117}, pmid = {39071530}, issn = {2094-9278}, abstract = {BACKGROUND AND OBJECTIVE: Replicating critical care practice settings in high-fidelity simulation (HFS) provides more learning opportunities to develop competencies, improve self-confidence, and learner satisfaction in a safe environment. Simulation is increasingly adopted globally as an alternative teaching strategy. Yet, data on the HFS experience of Filipino undergraduate nursing students is limited. This study describes the satisfaction, self-confidence, and perception of undergraduate nursing students on the use of HFS-based learning on critically-ill adult and pediatric patients requiring advanced life support (ALS).

METHODS: A quantitative, descriptive, correlational study was conducted using purposive sampling on all fourth-year BS Nursing students enrolled in Critical Care Nursing course in a state university. Data were collected through an online survey on demographic data, and the students' perceptions towards high-fidelity simulation-based learning (SBL) using three tools, namely: Simulation Design Scale, Educational Practices Questionnaire, and Student Satisfaction and Self-confidence in Learning. T-test and ANOVA were used to compare the means of the variables. Bivariate analysis (Pearson's product-moment correlation) was performed to find the relationship between variables.

RESULTS: A total of 86 students participated in the survey. Overall, the students were highly satisfied with the simulation experience (4.46 out of 5.0, SD=0.47), and had high ratings of self-confidence in SBL (4.44 out of 5.0, SD=0.42). Overall satisfaction level was positively related to student's perception on simulation design (r=0.61, p<0.01) and educational practices (r=0.59, p<0.01). Similarly, the students' overall self-confidence with SBL was also positively correlated with their perceptions of the simulation design (r=0.32, p<0.01), and educational practices (r=0.34, p<0.01).

CONCLUSION: Effective use of technology through HFS-based learning is useful in increasing satisfaction and self-confidence of Filipino undergraduate nursing students in caring for critically-ill patients needing ALS. Educators must highly consider all parameters of simulation design and educational practices in planning and implementing HFS-based learning to achieve meaningful learner experience.}, } @article {pmid39071309, year = {2024}, author = {Yousefian-Jazi, A and Kim, S and Choi, SH and Chu, J and Nguyen, PT and Park, U and Lim, K and Hwang, H and Lee, K and Kim, Y and Hyeon, SJ and Rhim, H and Ryu, HL and Lim, G and Stein, TD and Ryu, H and Lee, J}, title = {Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.15.603186}, pmid = {39071309}, issn = {2692-8205}, support = {R01 NS109537/NS/NINDS NIH HHS/United States ; }, abstract = {Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.}, } @article {pmid39071287, year = {2024}, author = {Tchounwou, C and Jobanputra, AJ and Lasher, D and Fletcher, BJ and Jacinto, J and Bhaduri, A and Best, RL and Fisher, WS and Ewert, KK and Li, Y and Feinstein, SC and Safinya, CR}, title = {Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase Separated Coacervates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39071287}, issn = {2692-8205}, support = {R01 NS035010/NS/NINDS NIH HHS/United States ; }, abstract = {Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein, which binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full length human protein tau and other negatively charged binding substrates, as revealed by differential-interference-contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes exhibited distinct types of morphologies. This included, large ≈20-30 micron tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles, and tau-mediated finite-size assemblies of small liposomes. As the ionic strength of the solution was increased to near and above physiological salt concentrations for 1:1 electrolytes (≈150 mM), AL-tau complexes remained stable while tau self-coacervate droplets were found to dissolve indicative of breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen facing monolayer of the axon plasma membrane suggesting the possibility of transient yet robust interactions at physiologically relevant ionic strengths.}, } @article {pmid39070547, year = {2024}, author = {Kannan, A and Gangadharan Leela, S and Branzei, D and Gangwani, L}, title = {Role of senataxin in R-loop-mediated neurodegeneration.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae239}, pmid = {39070547}, issn = {2632-1297}, support = {R01 NS115834/NS/NINDS NIH HHS/United States ; }, abstract = {Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic target to treat neurodegenerative diseases.}, } @article {pmid39069396, year = {2024}, author = {Codron, P and Millecamps, S and Corcia, P}, title = {EVolution in ALS diagnosis: molecular markers in extracellular vesicles.}, journal = {Trends in molecular medicine}, volume = {30}, number = {12}, pages = {1097-1099}, doi = {10.1016/j.molmed.2024.07.006}, pmid = {39069396}, issn = {1471-499X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/genetics ; Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {The identification of biomarkers for amyotrophic lateral sclerosis (ALS) is a central issue in disease research. In a recent article, Chatterjee et al. show that blood extracellular vesicles (EVs) with high levels of transactive response DNA-binding protein 43 (TDP-43) accurately discriminate patients with ALS from controls and correlate with disease severity, providing a promising biomarker for early diagnosis and monitoring.}, } @article {pmid39069095, year = {2024}, author = {Ho, PC and Hsieh, TC and Tsai, KJ}, title = {TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102441}, doi = {10.1016/j.arr.2024.102441}, pmid = {39069095}, issn = {1872-9649}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/therapy ; *Frontotemporal Lobar Degeneration/metabolism/pathology/therapy/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; Autophagy/physiology ; }, abstract = {Proteostasis failure is a common pathological characteristic in neurodegenerative diseases. Revitalizing clearance systems could effectively mitigate these diseases. The transactivation response (TAR) DNA-binding protein 43 (TDP-43) plays a critical role as an RNA/DNA-binding protein in RNA metabolism and synaptic function. Accumulation of TDP-43 aggregates in the central nervous system is a hallmark of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Autophagy, a major and highly conserved degradation pathway, holds the potential for degrading aggregated TDP-43 and alleviating FTLD/ALS. This review explores the causes of TDP-43 aggregation, FTLD/ALS-related genes, key autophagy factors, and autophagy-based therapeutic strategies targeting TDP-43 proteinopathy. Understanding the underlying pathological mechanisms of TDP-43 proteinopathy can facilitate therapeutic interventions.}, } @article {pmid39068922, year = {2024}, author = {Srivastava, K and Arshad, F and Mujawar, WJ and Cranberg, L and Rajeshwaran, J and Afsar, M and Thanissery, N and Desai, V and Keerthana, BS and Shubhangi, B and Vengalil, S and Nashi, S and Baskar, D and Polavarapu, K and Preethish-Kumar, V and Alladi, S and Nalini, A}, title = {Cognitive and Behavioral Profile of Patients with Amyotrophic Lateral Sclerosis Spectrum in the Indian Context.}, journal = {Dementia and geriatric cognitive disorders}, volume = {53}, number = {6}, pages = {310-320}, doi = {10.1159/000540018}, pmid = {39068922}, issn = {1421-9824}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; India/epidemiology ; *Frontotemporal Dementia/psychology ; *Neuropsychological Tests ; *Cognitive Dysfunction/psychology ; Aged ; Cognition/physiology ; Adult ; Executive Function ; Case-Control Studies ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is characterized by motor, cognitive, and behavioral impairment. There is a paucity of evidence about the cognitive/behavioral features of ALS patients from India. We aimed to investigate the cognitive/behavioral profile of ALS spectrum disorders in the Indian context.

METHODS: Sixty patients with ALS spectrum and 40 age-, gender-, and education-matched healthy controls were recruited. The scales used were Addenbrooke's Cognitive Examination (ACE-III), Clinical Dementia Rating (CDR) scale, and Frontal Systems Behavior (FrSBe) Scale.

RESULTS: The mean age of the overall cohort was 55 years, and male-to-female ratio was 2.5:1. The mean duration of illness of the cohort was 16 months. Patients were classified as ALS with normal cognition (ALS-cn, n = 21), mild cognitive or behavioral deficits (ALS-ci/-bi, n = 28), and frontotemporal dementia (ALS-FTD, n = 11). ALS-cn had poorer scores compared to healthy controls in global cognition, memory, and language (p < 0.05). ALS-ci/-bi performed poorer than healthy controls on all cognitive domains (p < 0.05). ALS-FTD had poorer scores than healthy controls and ALS-cn on all cognitive domains (p < 0.001). Behavioral assessment showed an increase in apathy among all subtypes. ALS-FTD showed significant worsening in disinhibition and executive function compared to ALS-cn and ALS-ci/-bi.

CONCLUSION: Our findings suggest that there are key cognitive and behavior characteristics in Indian patients with ALS spectrum. This further strengthens the evidence of a cognitive continuum in ALS and FTD in a diverse context and highlights the importance of meticulous evaluation and correct diagnosis that would assist in better management.}, } @article {pmid39067491, year = {2024}, author = {Cheung, SW and Willis, EF and Simmons, DG and Bellingham, MC and Noakes, PG}, title = {Phagocytosis of aggrecan-positive perineuronal nets surrounding motor neurons by reactive microglia expressing MMP-9 in TDP-43[Q331K] ALS model mice.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106614}, doi = {10.1016/j.nbd.2024.106614}, pmid = {39067491}, issn = {1095-953X}, mesh = {Animals ; Mice ; *Aggrecans/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Disease Models, Animal ; DNA-Binding Proteins/metabolism/genetics ; *Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; *Microglia/metabolism ; *Motor Neurons/metabolism/pathology ; *Phagocytosis/physiology ; Spinal Cord/metabolism/pathology ; }, abstract = {Perineuronal nets (PNNs) are extracellular matrix structures that surround excitable neurons and their proximal dendrites. PNNs play an important role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can act as a trigger for neuronal death, and this has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We therefore characterised PNNs around alpha motor neurons and the possible contributing cellular factors in the mutant TDP-43[Q331K] transgenic mouse, a slow onset ALS mouse model. PNNs around alpha motor neurons showed significant loss at mid-stage disease in TDP-43[Q331K] mice compared to wild type strain control mice. PNN loss coincided with an increased expression of matrix metallopeptidase-9 (MMP-9), an endopeptidase known to cleave PNNs, within the ventral horn. During mid-stage disease, increased numbers of microglia and astrocytes expressing MMP-9 were present in the ventral horn of TDP-43[Q331K] mice. In addition, TDP-43[Q331K] mice showed increased levels of aggrecan, a PNN component, in the ventral horn by microglia and astrocytes during this period. Elevated aggrecan levels within glia were accompanied by an increase in fractalkine expression, a chemotaxic protein responsible for the recruitment of microglia, in alpha motor neurons of onset and mid-stage TDP-43[Q331K] mice. Following PNN loss, alpha motor neurons in mid-stage TDP-43[Q331K] mice showed increased 3-nitrotyrosine expression, an indicator of protein oxidation. Together, our observations along with previous PNN research provide suggests a possible model whereby microglia and astrocytes expressing MMP-9 degrade PNNs surrounding alpha motor neurons in the TDP-43[Q331K] mouse. This loss of nets may expose alpha-motor neurons to oxidative damage leading to degeneration of the alpha motor neurons in the TDP-43[Q331K] ALS mouse model.}, } @article {pmid39066921, year = {2024}, author = {Guarnaccia, M and Morello, G and La Cognata, V and La Bella, V and Conforti, FL and Cavallaro, S}, title = {Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {316}, pmid = {39066921}, issn = {1420-9071}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *DNA Copy Number Variations/genetics ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Male ; Aged ; Risk Factors ; Polymorphism, Single Nucleotide ; Adult ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disease characterized by selective loss of motor neurons in the brainstem and spinal cord. Several genetic factors have been associated to ALS, ranging from causal genes and potential risk factors to disease modifiers. The search for pathogenic variants in these genes has mostly focused on single nucleotide variants (SNVs) while relatively understudied and not fully elucidated is the contribution of structural variants, such as copy number variations (CNVs). Here, we applied an exon-centric aCGH method to investigate, in sporadic ALS patients, the load of CNVs in 131 genes previously associated to ALS. Our approach revealed that CNV load, defined as the total number of CNVs or their size, was significantly higher in ALS cases than controls. About 87% of patients harbored multiple CNVs in ALS-related genes, and 75% structural variants compromised genes directly implicated in ALS pathogenesis (C9orf72, CHCHD10, EPHA4, FUS, HNRNPA1, KIF5A, NEK1, OPTN, PFN1, SOD1, TARDBP, TBK1, UBQLN2, UNC13A, VAPB, VCP). CNV load was also associated to higher onset age and disease progression rate. Although the contribution of individual CNVs in ALS is still unknown, their extensive load in disease-related genes may have relevant implications for the diagnostic, prognostic and therapeutical management of this devastating disorder.}, } @article {pmid39066735, year = {2024}, author = {Reis, PVM and Vargas, BS and Rebelo, RA and Massafera, MP and Prado, FM and Oreliana, H and de Oliveira, HV and Freitas, FP and Ronsein, GE and Miyamoto, S and Di Mascio, P and Medeiros, MHG}, title = {Quantitative Analysis of Glutathione and Carnosine Adducts with 4-Hydroxy-2-nonenal in Muscle in a hSOD1[G93A] ALS Rat Model.}, journal = {Chemical research in toxicology}, volume = {37}, number = {8}, pages = {1306-1314}, pmid = {39066735}, issn = {1520-5010}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Aldehydes/metabolism/chemistry ; *Carnosine/metabolism ; *Glutathione/metabolism ; Rats ; *Disease Models, Animal ; Muscle, Skeletal/metabolism ; Humans ; Superoxide Dismutase/metabolism ; Male ; Chromatography, High Pressure Liquid ; Rats, Transgenic ; Superoxide Dismutase-1/metabolism ; Rats, Sprague-Dawley ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects. 4-Hydroxy-2-nonenal (HNE) levels are elevated in the spinal cord motor neurons of ALS patients, and HNE-modified proteins have been identified in the spinal cord tissue of an ALS transgenic mice model, suggesting that reactive aldehydes can contribute to motor neuron degeneration in ALS. One biological pathway of aldehyde detoxification involves conjugation with glutathione (GSH) or carnosine (Car). Here, the detection and quantification of Car, GSH, GSSG (glutathione disulfide), and the corresponding adducts with HNE, Car-HNE, and GS-HNE, were performed in muscle and liver tissues of a hSOD1[G93A] ALS rat model by reverse-phase high-performance liquid chromatography coupled to electrospray ion trap tandem mass spectrometry in the selected reaction monitoring mode. A significant increase in the levels of GS-HNE and Car-HNE was observed in the muscle tissue of the end-stage ALS animals. Therefore, analyzing variations in the levels of these adducts in ALS animal tissue is crucial from a toxicological perspective and can contribute to the development of new therapeutic strategies.}, } @article {pmid39065892, year = {2024}, author = {Liu, K and Guan, X and Ren, X and Wu, J}, title = {Disciplining a Rubidium Atomic Clock Based on Adaptive Kalman Filter.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {14}, pages = {}, pmid = {39065892}, issn = {1424-8220}, abstract = {Rubidium atomic clocks have been used extensively in various fields, with applications such as a core component of Global Navigation Satellite Systems (GNSS). However, they exhibit inherently poor long-term stability. This paper presents the development of a control system for rubidium atomic clocks. It introduces an adaptive Kalman filtering algorithm for the disciplining of a rubidium atomic clock, utilizing autocovariance least squares (ALS) to estimate the clock's noise parameters. The experimental results demonstrate that the proposed algorithm achieves a high estimation accuracy. The standard deviation of the clock error between the steered rubidium atomic clock 1 Pulse Per Second (1PPS) and Coordinated Universal Time (UTC) provided by the National Time Service Center (NTSC) is better than 2.568 nanoseconds(ns), with peak-to-peak values improving to within 11.358 ns. Notably, its frequency stability is reduced to 3.06 × 10[-13] @100,000 s. The results for the rubidium atomic clock demonstrate that the adaptive Kalman filtering algorithm proposed herein constitutes an accurate and effective control strategy for the rubidium atomic clock discipline.}, } @article {pmid39063341, year = {2024}, author = {Lagrange, E and Vernoux, JP and Chambon, C and Camu, W and Spencer, PS}, title = {Cramp-Fasciculation Syndrome Associated with Natural and Added Chemicals in Popular Food Items.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {14}, pages = {}, pmid = {39063341}, issn = {2304-8158}, abstract = {Cramp-fasciculation syndrome (CFS) is a rare and benign neuromuscular disorder that may initially masquerade as motor neuron disease/amyotrophic lateral sclerosis. While CFS may have a familial disposition, we report on cases associated with high consumption of popular food items. One set of patients reversibly experienced acute onset of headache, flushing, muscle stiffness and fasciculations following the consumption of umami-flavored food containing a large concentration of monosodium glutamate. A second group of patients consuming food derived from lupin seed developed acute cholinergic toxicity, CFS, and, with chronic intake, significant, self-limiting, but incompletely reversible upper and lower motor neuron deficits. While these cases may improve our knowledge about the possible causes of CFS, our series also demonstrates that excessive consumption of some popular foods is not harmless. This warrants further research on their safety at all stages of human development from a neurological point of view.}, } @article {pmid39063053, year = {2024}, author = {Alanazi, N and Fitzgerald, M and Hume, P and Hellewell, S and Horncastle, A and Anyaegbu, C and Papini, MG and Hargreaves, N and Halicki, M and Entwistle, I and Hind, K and Chazot, P}, title = {Concussion-Related Biomarker Variations in Retired Rugby Players and Implications for Neurodegenerative Disease Risk: The UK Rugby Health Study.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39063053}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/blood ; Male ; *Brain Concussion/blood/epidemiology ; Middle Aged ; United Kingdom/epidemiology ; *Retirement ; *Football/injuries ; Adult ; *Athletes ; *Neurodegenerative Diseases/blood/epidemiology/etiology ; Rugby ; tau Proteins/blood ; Risk Factors ; Retinol-Binding Proteins, Plasma/metabolism ; Athletic Injuries/blood/epidemiology ; }, abstract = {The health and well-being of retired rugby union and league players, particularly regarding the long-term effects of concussions, are of major concern. Concussion has been identified as a major risk factor for neurodegenerative diseases, such as Alzheimer's and Amyotrophic Lateral Sclerosis (ALS), in athletes engaged in contact sports. This study aimed to assess differences in specific biomarkers between UK-based retired rugby players with a history of concussion and a non-contact sports group, focusing on biomarkers associated with Alzheimer's, ALS, and CTE. We randomly selected a sample of male retired rugby or non-contact sport athletes (n = 56). The mean age was 41.84 ± 6.44, and the mean years since retirement from the sport was 7.76 ± 6.69 for participants with a history of substantial concussions (>5 concussions in their career) (n = 30). The mean age was 45.75 ± 11.52, and the mean years since retirement was 6.75 ± 4.64 for the healthy controls (n = 26). Serum biomarkers (t-tau, RBP-4, SAA, Nf-L, and retinol), plasma cytokines, and biomarkers associated with serum-derived exosomes (Aβ42, p-tau181, p-tau217, and p-tau231) were analyzed using validated commercial ELISA assays. The results of the selected biomarkers were compared between the two groups. Biomarkers including t-tau and p-tau181 were significantly elevated in the history of the substantial concussion group compared to the non-contact sports group (t-tau: p < 0.01; p-tau181: p < 0.05). Although between-group differences in p-tau217, p-tau231, SAA, Nf-L, retinol, and Aβ42 were not significantly different, there was a trend for higher levels of Aβ42, p-tau217, and p-tau231 in the concussed group. Interestingly, the serum-derived exosome sizes were significantly larger (p < 0.01), and serum RBP-4 levels were significantly reduced (p < 0.05) in the highly concussed group. These findings indicate that retired athletes with a history of multiple concussions during their careers have altered serum measurements of exosome size, t-tau, p-tau181, and RBP-4. These biomarkers should be explored further for the prediction of future neurodegenerative outcomes, including ALS, in those with a history of concussion.}, } @article {pmid39062967, year = {2024}, author = {Kisielewska, M and Filipski, M and Sebastianka, K and Karaś, D and Molik, K and Choromańska, A}, title = {Investigation into the Neuroprotective and Therapeutic Potential of Plant-Derived Chk2 Inhibitors.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39062967}, issn = {1422-0067}, mesh = {*Checkpoint Kinase 2/metabolism/antagonists & inhibitors ; Humans ; Animals ; Protein Kinase Inhibitors/pharmacology/therapeutic use/chemistry ; Neuroprotective Agents/pharmacology/therapeutic use ; Neoplasms/drug therapy ; DNA Damage/drug effects ; DNA Repair/drug effects ; }, abstract = {Nature provides us with a rich source of compounds with a wide range of applications, including the creation of innovative drugs. Despite advancements in chemically synthesized therapeutics, natural compounds are increasingly significant, especially in cancer treatment, a leading cause of death globally. One promising approach involves the use of natural inhibitors of checkpoint kinase 2 (Chk2), a critical regulator of DNA repair, cell cycle arrest, and apoptosis. Chk2's activation in response to DNA damage can lead to apoptosis or DNA repair, influencing glycolysis and mitochondrial function. In cancer therapy, inhibiting Chk2 can disrupt DNA repair and cell cycle progression, promoting cancer cell death and enhancing the efficacy of radiotherapy and chemotherapy. Additionally, Chk2 inhibitors can safeguard non-cancerous cells during these treatments by inhibiting p53-dependent apoptosis. Beyond oncology, Chk2 inhibition shows potential in treating hepatitis C virus (HCV) infections, as the virus relies on Chk2 for RNA replication in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), in which DNA damage plays a crucial role. Plant-derived Chk2 inhibitors, such as artemetin, rhamnetin, and curcumin, offer a promising future for treating various diseases with potentially milder side effects and broader metabolic impacts compared to conventional therapies. The review aims to underscore the immense potential of natural Chk2 inhibitors in various therapeutic contexts, particularly in oncology and the treatment of other diseases involving DNA damage and repair mechanisms. These natural Chk2 inhibitors hold significant promise for revolutionizing the landscape of cancer treatment and other diseases. Further research into these compounds could lead to the development of innovative therapies that offer hope for the future with fewer side effects and enhanced efficacy.}, } @article {pmid39062592, year = {2024}, author = {Gao, J and Sterling, E and Hankin, R and Sikal, A and Yao, Y}, title = {Therapeutics Targeting Skeletal Muscle in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {7}, pages = {}, pmid = {39062592}, issn = {2218-273X}, support = {W81XWH2210261//United States Department of Defense/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/therapy ; Humans ; *Muscle, Skeletal/metabolism/pathology ; Animals ; Neuromuscular Junction/metabolism/pathology ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS.}, } @article {pmid39061876, year = {2024}, author = {Magalhães, RSS and Monteiro Neto, JR and Ribeiro, GD and Paranhos, LH and Eleutherio, ECA}, title = {Trehalose Protects against Superoxide Dismutase 1 Proteinopathy in an Amyotrophic Lateral Sclerosis Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061876}, issn = {2076-3921}, support = {PROBRAL 88881.371325/2019-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; CNE 201.174/2022 and Posdoc Nota 10 202.267/2019//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; Universal 401780/2023-6//National Council for Scientific and Technological Development/ ; }, abstract = {This work aimed to study the effect of trehalose in protecting cells against Sod1 proteinopathy associated with amyotrophic lateral sclerosis (ALS). Humanized yeast cells in which native Sod1 was replaced by wild-type human Sod1 or an ALS mutant (WT-A4V Sod1 heterodimer) were used as the experimental model. Cells were treated with 10% trehalose (p/v) before or after the appearance of hSod1 proteinopathy induced by oxidative stress. In both conditions, trehalose reduced the number of cells with Sod1 inclusions, increased Sod1 activity, and decreased the levels of intracellular oxidation, demonstrating that trehalose avoids Sod1 misfolding and loss of function in response to oxidative stress. The survival rates of ALS Sod1 cells stressed in the presence of trehalose were 60% higher than in their absence. Treatment with trehalose after the appearance of Sod1 inclusions in cells expressing WT Sod1 doubled longevity; after 5 days, non-treated cells did not survive, but 15% of cells treated with sugar were still alive. Altogether, our results emphasize the potential of trehalose as a novel therapy, which might be applied preventively in ALS patients with a family history of the disease or after diagnosis in ALS patients who discover the disease following the first symptoms.}, } @article {pmid39061402, year = {2024}, author = {Correia, JP and Gromicho, M and Pronto-Laborinho, AC and Oliveira Santos, M and de Carvalho, M}, title = {Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {7}, pages = {}, pmid = {39061402}, issn = {2076-3425}, abstract = {Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23-75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.}, } @article {pmid39060907, year = {2024}, author = {Asai, Y and Yano, K and Higashino, T and Yoshihara, D and Sakiyama, H and Eguchi, H and Fukushima, K and Suzuki, K and Fujiwara, N}, title = {The Ile35 Residue of the ALS-Associated Mutant SOD1 Plays a Crucial Role in the Intracellular Aggregation of the Molecule.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39060907}, issn = {1559-1182}, support = {22K11870//Japan Society for the Promotion of Science/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unknown pathogenesis. It has been reported that mutations in the gene for Cu/Zn superoxide dismutase (SOD1) cause familial ALS. Mutant SOD1 undergoes aggregation and forms amyloid more easily, and SOD1-immunopositive inclusions have been observed in the spinal cords of ALS patients. Because of this, SOD1 aggregation is thought to be related to the pathogenesis of ALS. Some core regions of amyloid have been identified, but the issue of whether these regions form aggregates in living cells remains unclear, and the mechanism responsible for intracellular SOD1 aggregation also remains unclear. The findings reported in this study indicate that the aggregation of the ALS-linked mutant SOD1-EGFP was significantly enhanced when the BioID2 gene was fused to the N-terminus of the mutant SOD1-EGFP plasmid for cellular expression. Expression of a series of BioID2-(C-terminal deletion peptides of SOD1)-EGFP permitted us to identify 1-35 as a minimal N-terminal sequence and Ile35 as an essential amino acid residue that contributes to the intracellular aggregation of SOD1. The findings also showed that an additional substitution of Ile35 with Ser into the ALS mutant SOD1 resulted in the significant suppression of aggregate formation. The fact that no Ile35 mutations have been reported to date in ALS patients indicates that all ALS mutant SOD1s contain Ile35. Taken together, we propose that Ile35 plays a pivotal role in the aggregation of the ALS-linked SOD1 and that this study will contribute to our understanding of the mechanism responsible for SOD1 aggregation.}, } @article {pmid39060854, year = {2024}, author = {Raymond, J and Nair, T and Gwathmey, KG and Larson, T and Horton, DK and Mehta, P}, title = {Racial Disparities in the Diagnosis and Prognosis of ALS Patients in the United States.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {39060854}, issn = {2196-8837}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease with largely unknown etiology. This study compares racial differences in clinical characteristics of ALS patients enrolled in the National ALS Registry (Registry).

METHODS: Data from ALS patients who completed the Registry's online clinical survey during 2013-2022 were analyzed to determine characteristics such as site of onset, associated symptoms, time of symptom onset to diagnosis, and pharmacological and non-pharmacological interventions for White, Black, and other race patients.

RESULTS: Surveys were completed by 4242 participants. Findings revealed that Black ALS patients were more likely to be diagnosed at a younger age, to have arm or hand initial site of onset, and to experience pneumonia than were White ALS patients. ALS patients of other races were more likely than White ALS patients to be diagnosed at a younger age and to experience twitching. The mean interval between the first sign of weakness and an ALS diagnosis for Black patients was almost 24 months, statistically greater than that of White (p = 0.0374; 16 months) and other race patients (p = 0.0518; 15.8 months). The mean interval between problems with speech until diagnosis was shorter for White patients (6.3 months) than for Black patients (17.7 months) and other race patients (14.8 months).

CONCLUSIONS AND RELEVANCE: Registry data shows racial disparities still exist in the diagnosis and clinical characteristics of ALS patients. Increased recruitment of non-White ALS patients and better characterization of symptom onset between races might aid clinicians in diagnosing ALS sooner, leading to earlier therapeutic interventions.}, } @article {pmid39060317, year = {2024}, author = {Wu, J and Zhang, G and Zhang, L and Ye, S and Huang, T and Fan, D}, title = {The integrity of the corticospinal tract and corpus callosum, and the risk of ALS: univariable and multivariable Mendelian randomization.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {17216}, pmid = {39060317}, issn = {2045-2322}, support = {81873784//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *Mendelian Randomization Analysis ; *Pyramidal Tracts/diagnostic imaging/pathology ; *Corpus Callosum/diagnostic imaging/pathology ; *Genome-Wide Association Study ; Risk Factors ; Male ; Female ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; White Matter/diagnostic imaging/pathology ; Diffusion Magnetic Resonance Imaging ; Anisotropy ; }, abstract = {Studies suggest that amyotrophic lateral sclerosis (ALS) compromises the integrity of white matter fiber tracts, primarily affecting motor fibers. However, it remains uncertain whether the integrity of these fibers influences the risk of ALS. We performed bidirectional two-sample Mendelian randomization (MR) and multivariable MR analyses to evaluate the associative relationships between the integrity of fiber tracts [including the corticospinal tract (CST) and corpus callosum (CC)] and the risk of ALS. Genetic instrumental variables for specific fiber tracts were obtained from published genome-wide association studies (GWASs), including 33,292 European individuals from five diffusion magnetic resonance imaging (dMRI) datasets. Summary-level GWAS data for ALS were derived from 27,205 ALS patients and 110,881 controls. The MR results suggested that an increase in the first principal component (PC1) of fractional anisotropy (FA) in the genu of the CC (GCC) was correlated with an increased risk of ALS (PFDR = 0.001, odds ratio = 1.363, 95% confidence interval 1.178-1.577). Although other neuroimaging phenotypes [mean diffusivity in the CST, radial diffusivity (RD) in the CST, FA in the GCC, PC1 in the body of the CC (BCC), PC1 in the CST, and RD in the GCC] did not pass correction, they were also considered to have suggestive associations with the risk of ALS. No evidence revealed that ALS caused changes in the integrity of fiber tracts. In summary, the results of this study provide genetic support for the potential association between the integrity of specific fiber tracts and the risk of ALS. Greater fiber integrity in the GCC and BCC may be a risk factor for ALS, while greater fiber integrity in the CST may have a protective effect on ALS. This study provides insights into ALS development.}, } @article {pmid39060265, year = {2024}, author = {Doi, H and Kageyama, I and Katoh-Fukui, Y and Hattori, A and Fukami, M and Shimura, N}, title = {Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature.}, journal = {Human genome variation}, volume = {11}, number = {1}, pages = {27}, pmid = {39060265}, issn = {2054-345X}, abstract = {Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty. Here, we report a prepubertal boy with a homozygous 2-amino acid deletion within the fourth N-glycosylation motif (c.1103_1108del, p.N368_S370delinsT) associated with parental consanguinity. He showed short stature consistent with ALS deficiency. This case expands the mutation spectrum of IGFALS to include the elimination of only one N-glycosylation motif of ALS.}, } @article {pmid39059442, year = {2024}, author = {Kilim, O and Báskay, J and Biricz, A and Bedőházi, Z and Pollner, P and Csabai, I}, title = {Transfer learning may explain pigeons' ability to detect cancer in histopathology.}, journal = {Bioinspiration & biomimetics}, volume = {19}, number = {5}, pages = {}, doi = {10.1088/1748-3190/ad6825}, pmid = {39059442}, issn = {1748-3190}, mesh = {Animals ; *Columbidae/physiology ; *Neoplasms/pathology/diagnostic imaging ; *Neural Networks, Computer ; Machine Learning ; Flight, Animal/physiology ; }, abstract = {Pigeons' unexpected competence in learning to categorize unseen histopathological images has remained an unexplained discovery for almost a decade (Levensonet al2015PLoS One10e0141357). Could it be that knowledge transferred from their bird's-eye views of the earth's surface gleaned during flight contributes to this ability? Employing a simulation-based verification strategy, we recapitulate this biological phenomenon with a machine-learning analog. We model pigeons' visual experience during flight with the self-supervised pre-training of a deep neural network on BirdsEyeViewNet; our large-scale aerial imagery dataset. As an analog of the differential food reinforcement performed in Levensonet al's study 2015PLoS One10e0141357), we apply transfer learning from this pre-trained model to the same Hematoxylin and Eosin (H&E) histopathology and radiology images and tasks that the pigeons were trained and tested on. The study demonstrates that pre-training neural networks with bird's-eye view data results in close agreement with pigeons' performance. These results support transfer learning as a reasonable computational model of pigeon representation learning. This is further validated with six large-scale downstream classification tasks using H&E stained whole slide image datasets representing diverse cancer types.}, } @article {pmid39059407, year = {2024}, author = {van den Berg, LH and Rothstein, JD and Shaw, PJ and Babu, S and Benatar, M and Bucelli, RC and Genge, A and Glass, JD and Hardiman, O and Libri, V and Mobach, T and Oskarsson, B and Pattee, GL and Ravits, J and Shaw, CE and Weber, M and Zinman, L and Jafar-Nejad, P and Rigo, F and Lin, L and Ferguson, TA and Gotter, AL and Graham, D and Monine, M and Inra, J and Sinks, S and Eraly, S and Garafalo, S and Fradette, S}, title = {Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {901-912}, doi = {10.1016/S1474-4422(24)00216-3}, pmid = {39059407}, issn = {1474-4465}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Double-Blind Method ; *C9orf72 Protein/genetics ; *Oligonucleotides, Antisense/pharmacokinetics/administration & dosage/adverse effects/pharmacology ; Aged ; Adult ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS.

METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed.

FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator.

INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.

FUNDING: Biogen.}, } @article {pmid39059406, year = {2024}, author = {Petri, S}, title = {Targeting C9orf72 in people with ALS.}, journal = {The Lancet. Neurology}, volume = {23}, number = {9}, pages = {850-852}, doi = {10.1016/S1474-4422(24)00284-9}, pmid = {39059406}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *C9orf72 Protein/genetics ; }, } @article {pmid39059260, year = {2024}, author = {Luo, L and Jiang, L and Chen, T and Zhao, Z and Kang, C and Chen, D and Long, Y}, title = {Analysis of spatiotemporal changes mechanism of cell wall biopolymers and monosaccharide components in kiwifruit during Botryosphaeria dothidea infection.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {322}, number = {}, pages = {124837}, doi = {10.1016/j.saa.2024.124837}, pmid = {39059260}, issn = {1873-3557}, mesh = {*Cell Wall/chemistry ; *Ascomycota/chemistry ; *Plant Diseases/microbiology ; *Monosaccharides/analysis ; *Actinidia/microbiology/chemistry ; *Spectrum Analysis, Raman/methods ; Fruit/microbiology/chemistry ; Biopolymers/chemistry/analysis ; Pectins/chemistry/metabolism ; Polysaccharides ; }, abstract = {To further reveal the interaction mechanism between plants and pathogens, this study used confocal Raman microscopy spectroscopy (CRM) combined with chemometrics to visualize the biopolymers distribution of kiwifruit cell walls at different infection stages at the cellular micro level. Simultaneously, the changes in the content of various monosaccharides in fruit were studied at the molecular level using high-performance liquid chromatography (HPLC). There were significant differences in the composition of various nutrient components in the cell wall structure of kiwifruit at different infection times after infection by Botryosphaeria dothidea. PCA could cluster samples with infection time of 0-9 d into different infection stages, and SVM was used to predict the PCA classification results, the accuracy >96 %. Multivariate curve resolution-alternating least squares (MCR-ALS) helped to identify single substance spectra and concentration signals from mixed spectral signals. The pure substance chemical imaging maps of low methylated pectin (LMP), high methylated pectin (HMP), cellulose, hemicellulose, and lignin were obtained by analyzing the resolved concentration data. The imaging results showed that the lignin content in the kiwifruit cell wall increased significantly to resist pathogens infection after the infection of B. dothidea. With the development of infection, B. dothidea decomposed various substances in the host cell walls, allowing them to penetrate the interior of fruit cells. This caused significant changes in the form, structure, and distribution of various chemicals on the fruit cell walls in time and space. HPLC showed that glucose was the main carbon source and energy substance obtained by pathogens from kiwifruit during infection. The contents of galactose and arabinose, which maintained the structure and function of the fruit cell walls, decreased significantly and the cell wall structure was destroyed in the late stage of pathogens infection. This study provided a new perspective on the cellular structure changes caused by pathogenic infection of fruit and the defense response process of fruit and provided effective references for further research on the mechanisms of host-pathogen interactions in fruit infected by pathogens.}, } @article {pmid39059072, year = {2024}, author = {Grieco, I and Bassani, D and Trevisan, L and Salmaso, V and Cescon, E and Prencipe, F and Da Ros, T and Martinez-Gonzalez, L and Martinez, A and Spalluto, G and Moro, S and Federico, S}, title = {7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions.}, journal = {Bioorganic chemistry}, volume = {151}, number = {}, pages = {107659}, doi = {10.1016/j.bioorg.2024.107659}, pmid = {39059072}, issn = {1090-2120}, mesh = {*Protein Kinase Inhibitors/pharmacology/chemistry/chemical synthesis ; Humans ; *Casein Kinase Idelta/antagonists & inhibitors/metabolism ; Structure-Activity Relationship ; Molecular Structure ; Triazines/chemistry/pharmacology/chemical synthesis ; Dose-Response Relationship, Drug ; Triazoles/chemistry/pharmacology/chemical synthesis ; Animals ; Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Molecular Docking Simulation ; }, abstract = {CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors. Both positions 2 and 5 have been explored leading to a total of ten compounds exhibiting IC50s comprised between 29.1 µM and 2.08 µM. Three of the four most potent compounds (IC50 < 3 µM) bear a thiophene ring at the 2 position. All compounds have been submitted to computational studies that identified the chain composed of at least 2 atoms (e.g., nitrogen and carbon atoms) at the 5 position as crucial to determine a key bidentate hydrogen bond with Leu85 of CK1δ. Most potent compounds have been tested in vitro, resulting passively permeable to the blood-brain barrier and, safe and slight neuroprotective on a neuronal cell model. These results encourage to further structural optimize the series to obtain more potent CK1δ inhibitors as possible neuroprotective agents to be tested on models of the above-mentioned neurodegenerative diseases.}, } @article {pmid39058450, year = {2024}, author = {Baumgartner, D and Mušová, Z and Zídková, J and Hedvičáková, P and Vlčková, E and Joppeková, L and Kramářová, T and Fajkusová, L and Stránecký, V and Geryk, J and Votýpka, P and Mazanec, R}, title = {Genetic Landscape of Amyotrophic Lateral Sclerosis in Czech Patients.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {5}, pages = {1035-1048}, pmid = {39058450}, issn = {2214-3602}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Czech Republic ; Male ; Middle Aged ; Female ; *C9orf72 Protein/genetics ; Aged ; *DNA Repeat Expansion ; Adult ; *Frontotemporal Dementia/genetics ; RNA-Binding Protein FUS/genetics ; Cohort Studies ; DNA-Binding Proteins/genetics ; Protein Serine-Threonine Kinases/genetics ; Age of Onset ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; }, abstract = {BACKGROUND: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far.

OBJECTIVE: We aimed to deliver pilot data on the genetic landscape of ALS in our country.

METHODS: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22).

RESULTS: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort.

CONCLUSION: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients.}, } @article {pmid39057679, year = {2024}, author = {Parvanovova, P and Hnilicova, P and Kolisek, M and Tatarkova, Z and Halasova, E and Kurca, E and Holubcikova, S and Koprusakova, MT and Baranovicova, E}, title = {Disturbances in Muscle Energy Metabolism in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Metabolites}, volume = {14}, number = {7}, pages = {}, pmid = {39057679}, issn = {2218-1989}, support = {1/0371/21//VEGA/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle atrophy and spasticity. It leads to death, mostly due to respiratory failure. Within the pathophysiology of the disease, muscle energy metabolism seems to be an important part. In our study, we used blood plasma from 25 patients with ALS diagnosed by definitive El Escorial criteria according to ALSFR-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) criteria and 25 age and sex-matched subjects. Aside from standard clinical biochemical parameters, we used the NMR (nuclear magnetic resonance) metabolomics approach to determine relative plasma levels of metabolites. We observed a decrease in total protein level in blood; however, despite accelerated skeletal muscle catabolism characteristic for ALS patients, we did not detect changes in plasma levels of essential amino acids. When focused on alterations in energy metabolism within muscle, compromised creatine uptake was accompanied by decreased plasma creatinine. We did not observe changes in plasma levels of BCAAs (branched chain amino acids; leucine, isoleucine, valine); however, the observed decrease in plasma levels of all three BCKAs (branched chain alpha-keto acids derived from BCAAs) suggests enhanced utilization of BCKAs as energy substrate. Glutamine, found to be increased in blood plasma in ALS patients, besides serving for ammonia detoxification, could also be considered a potential TCA (tricarboxylic acid) cycle contributor in times of decreased pyruvate utilization. When analyzing the data by using a cross-validated Random Forest algorithm, it finished with an AUC of 0.92, oob error of 8%, and an MCC (Matthew's correlation coefficient) of 0.84 when relative plasma levels of metabolites were used as input variables. Although the discriminatory power of the system used was promising, additional features are needed to create a robust discriminatory model.}, } @article {pmid39056697, year = {2024}, author = {Christidi, F and Kleinerova, J and Tan, EL and Delaney, S and Tacheva, A and Hengeveld, JC and Doherty, MA and McLaughlin, RL and Hardiman, O and Siah, WF and Chang, KM and Lope, J and Bede, P}, title = {Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients.}, journal = {Biology}, volume = {13}, number = {7}, pages = {}, pmid = {39056697}, issn = {2079-7737}, support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; }, abstract = {Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.}, } @article {pmid39056295, year = {2024}, author = {Lindamood, HL and Liu, TM and Read, TA and Vitriol, EA}, title = {Using ALS to understand profilin 1's diverse roles in cellular physiology.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/cm.21896}, pmid = {39056295}, issn = {1949-3592}, abstract = {Profilin is an actin monomer-binding protein whose role in actin polymerization has been studied for nearly 50 years. While its principal biochemical features are now well understood, many questions remain about how profilin controls diverse processes within the cell. Dysregulation of profilin has been implicated in a broad range of human diseases, including neurodegeneration, inflammatory disorders, cardiac disease, and cancer. For example, mutations in the profilin 1 gene (PFN1) can cause amyotrophic lateral sclerosis (ALS), although the precise mechanisms that drive neurodegeneration remain unclear. While initial work suggested proteostasis and actin cytoskeleton defects as the main pathological pathways, multiple novel functions for PFN1 have since been discovered that may also contribute to ALS, including the regulation of nucleocytoplasmic transport, stress granules, mitochondria, and microtubules. Here, we will review these newly discovered roles for PFN1, speculate on their contribution to ALS, and discuss how defects in actin can contribute to these processes. By understanding profilin 1's involvement in ALS pathogenesis, we hope to gain insight into this functionally complex protein with significant influence over cellular physiology.}, } @article {pmid39054893, year = {2024}, author = {Rajput, SS and Singh, SB and Subramanyam, D and Patil, S}, title = {Soft glassy rheology of single cells with pathogenic protein aggregates.}, journal = {Soft matter}, volume = {20}, number = {31}, pages = {6266-6274}, doi = {10.1039/d4sm00595c}, pmid = {39054893}, issn = {1744-6848}, mesh = {*Rheology ; Animals ; *Hemocytes/metabolism ; Protein Aggregates ; Viscosity ; Endocytosis ; Actins/metabolism/chemistry ; Single-Cell Analysis ; Microscopy, Atomic Force ; }, abstract = {A correlation between the mechanical properties of cells and various diseases has been emerging in recent years. Atomic force microscopy (AFM) has been widely used to measure a single cell's apparent Young's modulus by treating it as a fully elastic object. More recently, quantitative characterization of the complete viscoelasticity of single cells has become possible. We performed AFM-based nano-indentation experiments on hemocytes isolated from third instar larvae to determine their viscoelasticity and found that live hemocytes, like many other cells, follow a scale-free power-law rheology (PLR) akin to soft glasses. Further, we examined the changes in the rheological response of hemocytes in the presence of pathogenic protein aggregates known to cause neurodegenerative diseases such as Huntington's disorder and amyotrophic lateral sclerosis. Our results show that cells lose their fluidity and appear more solid-like in the presence of certain aggregates, in a manner correlated to actin reorganization. More solid-like cells also display reduced intracellular transport through clathrin-mediated endocytosis (CME). However, the cell's rheology remains largely unaffected and is similar to that of wild-type (WT) hemocytes, if aggregates do not perturb the actin organization and CME. Moreover, the fluid-like nature was significantly recovered when actin organization was rescued by overexpressing specific actin interacting proteins or chaperones. Our study, for the first time, underscores a direct correlation between parameters governing glassy dynamics, actin organization and CME.}, } @article {pmid39054501, year = {2024}, author = {Rahimi Darehbagh, R and Seyedoshohadaei, SA and Ramezani, R and Rezaei, N}, title = {Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives.}, journal = {European journal of medical research}, volume = {29}, number = {1}, pages = {386}, pmid = {39054501}, issn = {2047-783X}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Stem Cell Transplantation/methods/trends ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Neural Stem Cells/transplantation/physiology ; }, abstract = {Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.}, } @article {pmid39054363, year = {2024}, author = {Weishaupt, JH and Körtvélyessy, P and Schumann, P and Valkadinov, I and Weyen, U and Hesebeck-Brinckmann, J and Weishaupt, K and Endres, M and Andersen, PM and Regensburger, M and Dreger, M and Koch, JC and Conrad, J and Meyer, T}, title = {Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {150}, pmid = {39054363}, issn = {2730-664X}, abstract = {BACKGROUND: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1[D91A] in Europe, exceeding 1% in Finno-Scandinavia.

METHODS: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1[D91A] allele for up to 16 months with tofersen.

RESULTS: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1[D91A]. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1[D91A]. The results indicate that both mono- and bi-allelic SOD1[D91A] are causally relevant targets, with a possibly reduced effect size of SOD1[D91Ahet].

CONCLUSIONS: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1[D91A] patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.}, } @article {pmid39054069, year = {2024}, author = {Wong, HC and Lang, AE and Stein, C and Drerup, CM}, title = {ALS-Linked VapB P56S Mutation Alters Neuronal Mitochondrial Turnover at the Synapse.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {44}, number = {35}, pages = {}, pmid = {39054069}, issn = {1529-2401}, support = {R01 NS124692/NS/NINDS NIH HHS/United States ; T32 GM007133/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Zebrafish ; *Mitochondria/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Synapses/metabolism/genetics ; *Animals, Genetically Modified ; Vesicular Transport Proteins/genetics/metabolism ; Neurons/metabolism ; Humans ; Mutation ; Endoplasmic Reticulum/metabolism/genetics ; Mitophagy/genetics/physiology ; Zebrafish Proteins/genetics/metabolism ; }, abstract = {Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial dynamics. Vesicle-associated membrane protein-associated protein B (VapB) is an ER membrane protein present at a subset of ER-mitochondrial contact sites. A proline-to-serine mutation in VapB at amino acid 56 (P56S) correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrated that transgenic expression of VapB[P56S] in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild-type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapB[P56S] transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondrial tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.}, } @article {pmid39053342, year = {2024}, author = {Hideyama, T and Teramoto, S and Kato, H and Terashi, H and Kwak, S and Aizawa, H}, title = {Negative features of sporadic amyotrophic lateral sclerosis: Motor neurons of Onuf's nucleus survive in ADAR2-conditional knockout mice.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123142}, doi = {10.1016/j.jns.2024.123142}, pmid = {39053342}, issn = {1878-5883}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Adenosine Deaminase/genetics/deficiency/metabolism ; *Motor Neurons/pathology/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; Mice ; *Mice, Knockout ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Receptors, AMPA/genetics/metabolism ; Mice, Transgenic ; }, abstract = {Patients with amyotrophic lateral sclerosis (ALS) do not develop oculomotor disturbances and vesicorectal dysfunction until end-stage disease owing to the survival of certain motor neurons (MNs), including oculomotor neurons and MNs within Onuf's nucleus. In sporadic ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated editing of GluA2 mRNA at the Q/R site is compromised in lower MNs. We previously developed genetically modified mice with a conditional knockout of ADAR2 in cholinergic neurons (ADAR2[flox/flox]/VAChT-Cre, Fast; AR2). These mice displayed slow and progressive lower motor neuron death with TAR DNA-binding protein 43 (TDP-43) pathology, attributable to insufficient editing at the GluA2 Q/R site due to ADAR2 deficiency. MN death was more common in fast-fatigable MNs owing to differential vulnerability under conditions of ADAR2 deficiency. Although facial and hypoglossal nerves were impaired in AR2 mice, cell death did not occur within the oculomotor nerve nucleus, as observed in patients with sporadic ALS. Since the basis for avoiding cystorectal damage in ALS is unknown, we compared the features of Onuf's nucleus MNs in 12-month-old AR2 mice with those in age-matched wild-type mice. Although the number of MNs was not significantly lower in AR2 mice, the neurons exhibited a shrunken morphology and TDP-43 pathology. Onuf's nucleus MNs could survive in an ADAR2-deficient state and mainly included fast fatigue-resistant (FR) and slow (S) MNs. In summary, FR and S MNs show increased resilience to ADAR2 deficiency, potentially participating in an important neuronal death avoidance mechanism in ALS.}, } @article {pmid39050823, year = {2024}, author = {Min, JH and Sarlus, H and Harris, RA}, title = {Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1408159}, pmid = {39050823}, issn = {1662-5099}, abstract = {The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.}, } @article {pmid39050003, year = {2024}, author = {Özaydin Aksun, Z and Erdoğan, S and Kalkanci, A and Şahin, EA and Çuhadar, T and Şener, HÖ}, title = {Is gut microbiota of patients with ALS different from that of healthy individuals?.}, journal = {Turkish journal of medical sciences}, volume = {54}, number = {3}, pages = {579-587}, pmid = {39050003}, issn = {1303-6165}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology ; *Gastrointestinal Microbiome/genetics/physiology ; Female ; Male ; Middle Aged ; Adult ; Feces/microbiology ; RNA, Ribosomal, 16S/analysis/genetics ; Aged ; Case-Control Studies ; }, abstract = {BACKGROUND/AIM: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Several studies have shown that alterations of microbiota increase the risk of neurodegenerative disorders. We aimed to reveal whether there is a difference in the gut microbiota of patients with ALS.

MATERIALS AND METHODS: The participants are divided into three groups. Group 1 comprised patients with ALS. Healthy family members living in the same house of the patients formed Group 2. Lastly, sex- and age-matched healthy people were included in Group 3. Fecal samples were collected in 15-mL falcon tubes and stored at -80 °C. Genomic DNA isolation was performed on samples. Bacterial primers selected from the 16S rRNA region for the bacterial genome and ITS1 and ITS4 (internal transcribed spacer) were used for the identification of DNA. Next generation sequence analysis (NGS) and taxonomic analyses were performed at the level of bacterial phylum, class, order, family, genus, and species. Alpha and beta diversity indexes were used. The linear discriminant analysis (LDA) effect size method (LEfSe) was applied to identify a microbial taxon specific to ALS disease.

RESULTS: The relative abundances of the Succinivibrionaceae and Lachnospiraceae families were significantly lower in patients. The dominant families among patients were Streptococcaceae and Ruminococcaceae, while the dominant families among healthy controls were Bacteroidaceae and Succinivibrionaceae. The LEfSe analysis revealed that four families (Atopobiaceae, Actinomycetaceae, Erysipelatoclostridiaceae, Peptococcacceae) differed significantly between the patients and healthy controls (LDA values> 2.5, p < 0.05).

CONCLUSION: Comparison with family members living in the same house is the strength of this study. We found that there were changes in the microbiota of the patients, consistent with the literature. Studies that analyze the composition of the gut microbiota in the predisease period may be needed to understand whether dysbiosis is caused by the mechanisms inherent in the disease or whether it is dysbiosis that initiates the disease.}, } @article {pmid39047759, year = {2024}, author = {Schmid, G and Schneeweiss, P and Hirtl, R and Jhala, T and Samaras, T}, title = {Numerical assessment of induced electric fields in a worker's hand with commonly used metallic implants under exposure to low frequency magnetic fields.}, journal = {Journal of radiological protection : official journal of the Society for Radiological Protection}, volume = {44}, number = {3}, pages = {}, doi = {10.1088/1361-6498/ad66dc}, pmid = {39047759}, issn = {1361-6498}, mesh = {Humans ; *Occupational Exposure/analysis ; *Hand ; *Electromagnetic Fields ; Metals ; Magnetic Fields ; Prostheses and Implants ; Bone Screws ; Bone Plates ; }, abstract = {The European Union's Workers' Directive 2013/35/EU on the minimum health and safety requirements regarding the exposure of workers to electromagnetic fields specifies action levels (ALs) for external electric and magnetic fields, which should protect against induced tissue-internal electric field strengthEiabove the exposure limit values, the latter being defined in order to prevent tissue stimulation at low frequencies. However, although 2013/35/EU explicitly calls for the protection of 'workers at particular risk' (including workers with metallic implants), the AL specified in the Directive have been derived under the assumption that there are no metallic parts present inside the body. Therefore, in the present work, we analysed the situation of a worker's hand and forearm bearing metallic implants (Herbert screw and volar radius plate) used for osteosynthesis after the most common bone fractures of the hand/forearm, exposed to low frequency magnetic fields. The uniform exposure of the whole hand and forearm as well as the exposure to a specific and widely used device, a deactivator for single-use labels of acousto-magnetic electronic article surveillance systems, were considered based on numerical computations using a high-resolution anatomical hand and forearm model. The results obtained indicated that the maximum induced electric field strength averaged in a volume of 2 mm × 2 mm × 2 mm cube was higher in the presence of the metallic implants by a factor of up to 4.2 for bone tissue and 2.3 for soft tissue compared with the case without an implant. Hence, it is obvious that the local induced electric field strengths may be substantially increased by the implants. The extent of this increase, however, is highly dependent on the implant's position inside the body, the implant's geometry, and the field distribution and orientation with respect to the anatomical structure and the implant.}, } @article {pmid39046818, year = {2024}, author = {Brink, V and Kirkbride, J}, title = {Reply to Zhou et al's "Refining Psychosis Research: Insights on Cannabis Use and Data Accuracy".}, journal = {Schizophrenia bulletin}, volume = {50}, number = {5}, pages = {965-967}, pmid = {39046818}, issn = {1745-1701}, support = {//European Community's Seventh Framework/ ; 2012/0417-0//São Paulo Research Foundation/ ; MD-PhD 18-41//University Medical Centre Groningen/ ; //National Institute for Health and Care Research/ ; //University College London Hospitals NHS Foundation Trust/ ; //UK Research and Innovation/ ; MR/W030608/1//Clinical Academic Research Partnership/ ; }, mesh = {Humans ; *Psychotic Disorders ; Data Accuracy ; Biomedical Research/standards ; Marijuana Use/epidemiology ; Marijuana Abuse/epidemiology ; }, } @article {pmid39045865, year = {2024}, author = {Sanpei, Y and Yasuda, K and Takahashi, Y and Hanazono, A and Sugawara, M and Iijima, K}, title = {Evaluation of the applicability of weak shoulder and arm sparing signs in amyotrophic lateral sclerosis by multiple neurologists and neurology residents: A single-center study.}, journal = {Muscle & nerve}, volume = {70}, number = {4}, pages = {761-765}, doi = {10.1002/mus.28216}, pmid = {39045865}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Shoulder/physiopathology ; Retrospective Studies ; *Arm/physiopathology ; *Neurologists ; *Muscle Weakness/diagnosis/physiopathology ; Internship and Residency ; Neurology/education ; Muscle, Skeletal/physiopathology ; Adult ; Sensitivity and Specificity ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) exhibits selective muscle weakness. The weak shoulder and arm sparing signs, assessed by a single experienced neurologist, have been reported to be superior to previous signs in sensitivity and specificity. However, it is unknown whether the same results are observed when assessed by multiple neurologists.

METHODS: Subjects were retrospectively identified from our department's inpatient database from 2014 to 2023. Medical Research Council (MRC) scores of the deltoid (Del), biceps brachii (BB), triceps brachii (TB), and first dorsal interosseous (FDI) muscles were evaluated. The weak shoulder sign was defined as positive when Del was weaker than BB and TB. The arm sparing sign was defined as positive when both Del and FDI were weaker than BB and TB. Sensitivity was analyzed in all ALS patients and in subgroups based on the region of symptom onset, presence or absence of upper motor neuron (UMN) signs, and the Japanese ALS Severity Classification.

RESULTS: Seventy-one patients with ALS were identified. Eight neurologists and three neurology residents evaluated each patient's MRC scores. The weak shoulder and arm sparing signs were observed in 72% and 48% of patients, respectively, with no significant difference in sensitivity across patient subgroups.

DISCUSSION: The weak shoulder and arm sparing signs showed high and moderate sensitivity, respectively, consistent with a previous report, even when evaluated by multiple examiners. This expands the clinical utility and increases the reliability of these signs, potentially contributing to accurate ALS diagnosis when combined with other clinical features and objective assessments.}, } @article {pmid39044591, year = {2024}, author = {Wang, J and Feng, L and Zhang, Y and Xu, P}, title = {[Establishment of a stable THP-1 cell line expressing PSMB9-eGFP-His protein and detection of immunoproteasome activity].}, journal = {Sheng wu gong cheng xue bao = Chinese journal of biotechnology}, volume = {40}, number = {7}, pages = {2282-2293}, doi = {10.13345/j.cjb.240124}, pmid = {39044591}, issn = {1872-2075}, mesh = {Humans ; *Proteasome Endopeptidase Complex/genetics/metabolism ; *Green Fluorescent Proteins/genetics/metabolism ; THP-1 Cells ; Lentivirus/genetics ; Recombinant Fusion Proteins/genetics ; Cysteine Endopeptidases/genetics/metabolism ; }, abstract = {The ubiquitin/proteasome system (UPS) plays a crucial role in maintaining cellular protein homeostasis. The catalytic activity of proteasome in the UPS is regulated by β1 (PSMB6), β2 (PSMB7), and β5 (PSMB5) subunits. Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, inflammation, and oxidative stress can induce the replacement of β1, β2, and β5 with their respective immuno-subunits β1i (PSMB9), β2i (PSMB10), and β5i (PSMB8), which can be assembled into the immunoproteasome. Compared with the standard proteasome, the immunoproteasome exerts enhanced regulatory effects on immune responses, such as processing and presenting MHC class Ⅰ antigens, production of pro-inflammatory cytokines, and T cell differentiation and proliferation. Abnormal aggregation of immunoproteasomes can cause neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. To explore the function of PSMB9 after bacterial infection, we constructed a lentivirus plasmid overexpressing PSMB9-eGFP-His and transfected the plasmid into HEK293T cells for packaging by using a triple-plasmid system in this study. After screening with puromycin, we obtained a stable human leukemia monocytic THP-1 cell line expressing the fusion protein of PSMB9. Western blotting (WB) and fluorescence microscopy verified the expression of the fusion protein in the stable THP-1 cells. Quantitative PCR (qPCR) was employed to measure the copies of PSMB9-eGFP in THP-1 cells. Immunofluorescence results found that eGFP-His did not affect the subcellular localization of PSMB9. The purification with nickel affinity chromatography confirmed that the fusion protein could be assembled into the 20S immunoproteasome and exhibited cleaving activity for fluorescent peptide substrates. These results indicated that the PSMB9-eGFP fusion gene was integrated into the chromosome, and could be stably expressed in the constructed THP-1 cell line. This cell line can be utilized for the research on subcellular localization, dynamic expression, and activity of PSMB9 in live cells at different infection conditions and disease stages. It also provides a model for the stable cell lines construction of other immunoproteasome subunits PSMB8 and PSMB10.}, } @article {pmid39044379, year = {2024}, author = {Goutman, SA and Goyal, NA and Payne, K and Paisán-Ruiz, C and Kupelian, V and Kang, ML and Mitchell, AA and Fecteau, TE}, title = {ALS Identified: two-year findings from a sponsored ALS genetic testing program.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {8}, pages = {2201-2211}, pmid = {39044379}, issn = {2328-9503}, support = {//Biogen (Cambridge, MA, USA)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; *Genetic Testing ; Female ; Middle Aged ; Aged ; Adult ; United States ; }, abstract = {OBJECTIVE: To report initial results from the Amyotrophic Lateral Sclerosis (ALS) Identified genetic testing (GT) program on characteristics of individuals tested and frequency of reported disease-causing variants.

METHODS: ALS Identified used the Invitae Amyotrophic Lateral Sclerosis panel (Invitae, San Francisco, CA, USA) to assay 22 ALS-associated genes. Sponsored by Biogen (Cambridge, MA, USA), the program was launched in June 2021 and was available at no charge to individuals ≥18 years in the United States and Puerto Rico with an ALS diagnosis or a known family history of ALS. Deidentified data were available to Biogen.

RESULTS: As of 26 October 2023, 998 healthcare professionals ordered the panel at 681 unique care sites. Of 8054 individuals examined, 7483 (92.9%) were reported to have a clinical diagnosis of ALS, while 571 (7.1%) were asymptomatic relatives. Of the individuals with a clinical ALS diagnosis, 57.7% were male (n = 4319) and 42.3% female (n = 3164). Mean (SD) age at diagnosis is 62 (13) years. Out of the 7483 clinically diagnosed individuals, 1810 (24.2%) showed genetic variations in ALS-associated genes. Among these, 865 individuals (47.8%) carried pathogenic variants, and 44 (2.4%) had likely pathogenic variants, totaling 12.1% of the clinically diagnosed population.

INTERPRETATION: Since 2021 there has been robust uptake and sustained use of the ALS Identified program, one of the largest samples of people with ALS to date across the United States, demonstrating the interest and need for genetic ALS testing.}, } @article {pmid39044305, year = {2024}, author = {Chen, HH and Yeo, HT and Huang, YH and Tsai, LK and Lai, HJ and Tsao, YP and Chen, SL}, title = {AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice.}, journal = {Skeletal muscle}, volume = {14}, number = {1}, pages = {17}, pmid = {39044305}, issn = {2044-5040}, support = {NSTC 112-2320-B-002-004//National Science and Technology Council/ ; NSTC 112-2320-B-002-004//National Science and Technology Council/ ; 10R891903//National Taiwan University/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/pathology ; *Genetic Therapy/methods ; *Muscular Atrophy/genetics/therapy/metabolism/pathology ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; *Dependovirus/genetics ; Mice ; Humans ; Muscle, Skeletal/metabolism/pathology ; Neuromuscular Junction/metabolism/pathology ; Genetic Vectors/administration & dosage ; Nerve Degeneration/genetics/therapy ; Male ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.

METHODS: We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.

RESULTS: SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.

CONCLUSIONS: AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.}, } @article {pmid39042810, year = {2024}, author = {Haridevamuthu, B and Sathishkumar, K}, title = {Comment on Tsioti et al's "Systemic Lipopolysaccharide Exposure Exacerbates Choroidal Neovascularization in Mice".}, journal = {Ocular immunology and inflammation}, volume = {32}, number = {10}, pages = {2614-2615}, doi = {10.1080/09273948.2024.2377732}, pmid = {39042810}, issn = {1744-5078}, mesh = {*Choroidal Neovascularization/drug therapy ; Animals ; *Lipopolysaccharides ; Mice ; *Disease Models, Animal ; Macrophages/drug effects ; Fluorescein Angiography ; }, abstract = {The study "Systemic Lipopolysaccharide Exposure Exacerbates Choroidal Neovascularization in Mice" by Tsioti et al. explores the impact of systemic lipopolysaccharide (LPS) on choroidal neovascularization (CNV) progression. The findings reveal systemic LPS exposure significantly enhances fluorescein leakage, driven by increased pro-inflammatory monocyte-derived macrophages and microglia activation. The study underscores the importance of managing systemic inflammation to mitigate CNV progression, suggesting potential therapeutic strategies targeting CSF1R inhibition and Müller cell modulation. Future research should focus on elucidating the molecular pathways involved in LPS-induced CNV exacerbation and translating these findings into clinical interventions.}, } @article {pmid39042693, year = {2024}, author = {Celona, B and Salomonsson, SE and Wu, H and Dang, B and Kratochvil, HT and Clelland, CD and DeGrado, WF and Black, BL}, title = {Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {31}, pages = {e2220020121}, pmid = {39042693}, issn = {1091-6490}, support = {U01NS134062//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; HL146366//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; GM122603//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; K08 NS112330/NS/NINDS NIH HHS/United States ; U19 NS132303/NS/NINDS NIH HHS/United States ; R01 DK119621/DK/NIDDK NIH HHS/United States ; DK119621//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; NS126499//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM122603/GM/NIGMS NIH HHS/United States ; R01 NS126499/NS/NINDS NIH HHS/United States ; U01 NS134062/NS/NINDS NIH HHS/United States ; P01 HL146366/HL/NHLBI NIH HHS/United States ; AL210129//U.S. Department of Defense (DOD)/ ; U19NS132303//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; K99 GM138753/GM/NIGMS NIH HHS/United States ; K99GM138753//HHS | National Institutes of Health (NIH)/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics/metabolism ; DNA Repeat Expansion ; Frontotemporal Dementia/genetics/metabolism ; *G-Quadruplexes ; Nerve Tissue Proteins/metabolism/genetics ; Protein Binding ; Protein Biosynthesis ; *RNA/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Expansion of intronic GGGGCC repeats in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Transcription of the expanded repeats results in the formation of RNA-containing nuclear foci and altered RNA metabolism. In addition, repeat-associated non-AUG (RAN) translation of the expanded GGGGCC-repeat sequence results in the production of highly toxic dipeptide-repeat (DPR) proteins. GGGGCC repeat-containing transcripts form G-quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA-binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC repeats in cultured mammalian cells, and we demonstrate that Zfp106 coexpression reduces the levels of DPRs in C9orf72 patient-derived cells. Further, we show that Zfp106 binds to RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC repeats. Together, these data demonstrate that Zfp106 suppresses the formation of RNA foci and DPRs caused by GGGGCC repeats and suggest that the G-quadruplex RNA-binding function of Zfp106 contributes to its suppression of GGGGCC repeat-mediated cytotoxicity.}, } @article {pmid39039445, year = {2024}, author = {Jonsdottir, G and Haraldsdottir, E and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Tryggvadottir, GB and Jonsdottir, H}, title = {Transition to end-of-life care in patients with neurological diseases in an acute hospital ward.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {253}, pmid = {39039445}, issn = {1471-2377}, support = {71545//The Icelandic Nurses´ Association/ ; }, mesh = {Humans ; Male ; *Terminal Care/methods/statistics & numerical data ; Female ; Aged ; Middle Aged ; Retrospective Studies ; *Nervous System Diseases/therapy/diagnosis/epidemiology ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/therapy/diagnosis/mortality ; }, abstract = {BACKGROUND: Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously.

OBJECTIVE: To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting.

METHOD: All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson's disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status.

RESULTS: A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR = 1.02, 95% CI: 1.007-1.039, P = 0.005), ischaemic stroke (HR = 1.64, 95% CI: 1.034-2.618, P = 0.036) and haemorrhagic stroke (HR = 2.04, 95% CI: 1.219-3.423, P = 0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision.

CONCLUSIONS: Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients.}, } @article {pmid39039135, year = {2024}, author = {Tahir, M and Yude, B and Mehmood, T and Bashir, S and Zhenping, Y and Awais, M}, title = {Classification of LAMOST spectra of B-type and hot subdwarf stars using kernel support vector machine.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {16815}, pmid = {39039135}, issn = {2045-2322}, abstract = {Machine learning has emerged as a leading field in artificial intelligence, demonstrating expert-level performance in various domains. Astronomy has benefited from machine learning techniques, particularly in classifying and identifying stars based on their features. This study focuses on the spectra-based classification of 11,408 B-type and 2422 hot subdwarf stars. The study employs baseline correction using Asymmetric Least Squares (ALS) to enhance classification accuracy. It applies the Pan-Core concept to identify 500 unique patterns or ranges for both types of stars. These patterns are the foundation for creating Support Vector Machine (SVM) models, including the linear (L-SVM), polynomial (P-SVM), and radial basis (R-SVM) kernels. Parameter tuning for the SVM models is achieved through cross-validation. Evaluation of the SVM models on test data reveals that the linear kernel SVM achieves the highest accuracy (87.0%), surpassing the polynomial kernel SVM (84.1%) and radial kernel SVM (80.1%). The average calibrated accuracy falls within the range of 90-95%. These results demonstrate the potential of using spectrum-based classification to aid astronomers in improving and expanding their understanding of stars, with a specific focus on the identification of hot subdwarf stars. This study presents a valuable investigation for astronomers, as it enables the classification of stars based on their spectra, leveraging machine learning techniques to enhance their knowledge and insights in astronomy.}, } @article {pmid39039102, year = {2024}, author = {Acien, A and Calcagno, N and Burke, KM and Mondesire-Crump, I and Holmes, AA and Mruthik, S and Goldy, B and Syrotenko, JE and Scheier, Z and Iyer, A and Clark, A and Keegan, M and Ushirogawa, Y and Kato, A and Yasuda, T and Lahav, A and Iwasaki, S and Pascarella, M and Johnson, SA and Arroyo-Gallego, T and Berry, JD}, title = {A novel digital tool for detection and monitoring of amyotrophic lateral sclerosis motor impairment and progression via keystroke dynamics.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {16851}, pmid = {39039102}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Disease Progression ; Female ; Male ; Middle Aged ; Aged ; *Smartphone ; Machine Learning ; Case-Control Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition leading to progressive muscle weakness, atrophy, and ultimately death. Traditional ALS clinical evaluations often depend on subjective metrics, making accurate disease detection and monitoring disease trajectory challenging. To address these limitations, we developed the nQiALS toolkit, a machine learning-powered system that leverages smartphone typing dynamics to detect and track motor impairment in people with ALS. The study included 63 ALS patients and 30 age- and sex-matched healthy controls. We introduce the three core components of this toolkit: the nQiALS-Detection, which differentiated ALS from healthy typing patterns with an AUC of 0.89; the nQiALS-Progression, which separated slow and fast progression at specific thresholds with AUCs ranging between 0.65 and 0.8; and the nQiALS-Fine Motor, which identified subtle progression in fine motor dysfunction, suggesting earlier prediction than the state-of-the-art assessment. Together, these tools represent an innovative approach to ALS assessment, offering a complementary, objective metric to traditional clinical methods and which may reshape our understanding and monitoring of ALS progression.}, } @article {pmid39038319, year = {2024}, author = {Zhao, T and Huang, J and Chi, W}, title = {The Diagnostic Advantages of MRI in Cerebral Infarction: Multi-Sequence Imaging and Improved Sensitivity in Early Detection.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {39038319}, issn = {1078-6791}, abstract = {OBJECTIVE: The study aimed to investigate the diagnostic value of computed tomography (CT) and magnetic resonance imaging (MRI) in cerebral infarction (CI) in cerebrovascular diseases.

METHOD: 100 patients with acute ischemic cerebral infarction (AICI) were divided into a CT group and an MRI group. The diagnostic efficacy of the two diagnostic methods for CI was compared and analyzed.

RESULTS: Only 6 patients with acute early stage (AES) CI and 30 patients with acute late stage (ALS) CI were detected by CT, which was significantly less than those detected by MRI (P < .05); 5 patients with <5 mm infarction were detected by CT in ALS and 10 patients with 5-15 mm infarction were detected by CT in ALS, which were significantly less than those detected by MRI (P < .05); 3 patients were diagnosed with cerebral sulcus, fissure, and shallow and disappeared brain cistern, 4 patients with local gyrus swelling, and 31 patients with significant swelling by CT examination, which was significantly less than those detected by MRI (P < .05); the infarct area ratio measured by CT/ diffusion weighted imaging (DWI) was significantly lower than that measured by fluid attenuated inversion recovery (FLAIR)/DWI (P < .05); the diagnostic specificity (Sp), sensitivity (Se), Youden index, positive predictive value (PV), and negative PV of MRI were 0.82, 0.79, 0.58, 0.7, and 0.88, respectively, which were significantly better than those of CT (P < .05).

CONCLUSION: CT is not a sensitive technique for the diagnosis of early CI. Compared to CT, MRI has the characteristics of multi-sequence and multi-parameter imaging, is more sensitive to infarction within 2 hours after onset, and can more clearly and accurately diagnose CI.}, } @article {pmid39037980, year = {2024}, author = {Souza, AA and da Silva, ST and Macedo, LRD and Aires, DN and Pondofe, KM and Melo, LP and Valentim, RAM and Ribeiro, TS}, title = {Physical therapy for muscle strengthening in individuals with amyotrophic lateral sclerosis: A protocol for a systematic review and meta-analysis.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0307470}, pmid = {39037980}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Muscle Strength ; *Systematic Reviews as Topic ; *Meta-Analysis as Topic ; Physical Therapy Modalities ; Female ; Male ; }, abstract = {INTRODUCTION: People with Amyotrophic Lateral Sclerosis (ALS) can present initially muscle weakness, which is a debilitating symptom that may be improved by engaging in muscle strengthening activities. Currently, the effects of motor interventions for muscle strengthening in people with ALS are unclear. This review intends to analyze the effects of motor interventions for muscle strengthening in individuals with ALS.

METHODS AND ANALYSIS: Randomized, non-randomized, and quasi-experimental clinical trials assessing individuals with ALS of both sexes, aged 18 years or older, who have received motor interventions for muscle strengthening considering all practices that can lead to increased strength, endurance, power and muscular hypertrophy will be included. No restriction on language, location, or publication date will be applied. MEDLINE, EMBASE, Cochrane Library (CENTRAL), SPORTDiscus, and Physiotherapy Evidence Database (PEDro) databases will be searched. The US National Institutes of Health Ongoing, ClinicalTrials.gov, and the reference lists of included studies will also be searched. Two reviewers will independently screen titles and abstracts and extract data from included studies. The methodological quality of the included studies will be assessed by the PEDro scale and the certainty of the evidence by the GRADE approach. Disagreements will be resolved by a third researcher. Findings will be presented in text and table formats. A meta-analysis will compare the effects of motor interventions for muscle strengthening versus placebo or other interventions.}, } @article {pmid39037015, year = {2024}, author = {Timmins, HC and Thompson, AE and Kiernan, MC}, title = {Diagnostic criteria for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {570-576}, doi = {10.1097/WCO.0000000000001302}, pmid = {39037015}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/genetics ; Humans ; *Biomarkers/analysis ; }, abstract = {PURPOSE OF REVIEW: The present review will discuss the evolution of diagnostic criteria for amyotrophic lateral sclerosis (ALS) and biomarker considerations.

RECENT FINDINGS: To address the limitations of existing ALS diagnostic criteria, a consortium of key stakeholders developed the Gold Coast consensus criteria (GCC). The GCC has similar or greater sensitivity compared with the revised El Escorial (rEEC) and Awaji criteria (AC), particularly for atypical phenotypes, maintained across disease duration, severity, and site of onset. In addition to improving diagnostic sensitivity, using the GCC in clinical trials may promote an increased enrolment of up to 50% of ALS patients who do not currently meet the full diagnostic eligibility requirements of the rEEC. Future inclusion of genetic biomarkers may mitigate some limitations of the GCC, to further improve diagnostic utility. In advance of such a process, validation of these biomarkers will be required before inclusion as additional criteria.

SUMMARY: The GCC are simpler to use than previous consensus criteria, with demonstrated greater sensitivity and, enabling an earlier and more definitive ALS diagnosis, thereby facilitating wider enrolment into clinical trials. Broader implementation of the GCC in clinical trial settings is currently underway, globally.}, } @article {pmid39033904, year = {2024}, author = {Lu, XY and Li, MQ and Li, YT and Yao, JY and Zhang, LX and Zeng, ZH and Yu-Liu, and Chen, ZR and Li, CQ and Zhou, XF and Li, F}, title = {Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.}, journal = {Neuropharmacology}, volume = {258}, number = {}, pages = {110089}, doi = {10.1016/j.neuropharm.2024.110089}, pmid = {39033904}, issn = {1873-7064}, mesh = {Animals ; *Valproic Acid/pharmacology/administration & dosage ; *Edaravone/pharmacology ; *Autism Spectrum Disorder/drug therapy/chemically induced ; *Disease Models, Animal ; Female ; *Oxidative Stress/drug effects ; Male ; Administration, Oral ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Brain/drug effects/metabolism/pathology ; Prenatal Exposure Delayed Effects/chemically induced ; Free Radical Scavengers/pharmacology/administration & dosage/therapeutic use ; Dose-Response Relationship, Drug ; Stereotyped Behavior/drug effects ; Behavior, Animal/drug effects ; Social Interaction/drug effects ; }, abstract = {Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.}, } @article {pmid39032803, year = {2024}, author = {He, Q and Zhou, Y and Jin, J and Tian, Q and Li, H and Hou, B and Xie, A}, title = {Association between NEK1 gene polymorphisms and the potential risk of sporadic Parkinson's disease in the Chinese Northern Han population: A case-control study.}, journal = {Neuroscience letters}, volume = {837}, number = {}, pages = {137913}, doi = {10.1016/j.neulet.2024.137913}, pmid = {39032803}, issn = {1872-7972}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Case-Control Studies ; China/epidemiology ; East Asian People/genetics ; Genetic Association Studies ; *Genetic Predisposition to Disease ; Genotype ; *NIMA-Related Kinase 1/genetics ; *Parkinson Disease/genetics ; *Polymorphism, Single Nucleotide ; }, abstract = {OBJECTIVE: Parkinson's disease (PD) has been identified as a genetically influenced disease linked to various genetic loci. Previous studies have suggested that neurodegenerative illnesses, including PD, Alzheimer's disease, and Amyotrophic lateral sclerosis (ALS), may share certain genetic loci. Recently, the NEK1 gene was identified as overlapping between PD and ALS. We therefore wanted to explore the potential association between the NEK1 gene single nucleotide polymorphisms (SNPs) and the clinical features and pathophysiology of sporadic PD in a northern Chinese population.

METHODS: A total of 510 sporadic PD patients and 510 age- and sex-matched healthy controls (HCs) were included in this study. Two SNPs (rs4563461 and rs66509122) of the NEK1 gene were genotyped using polymerase chain reaction (PCR). And we analyzed the association between NEK1 gene polymorphisms and clinical manifestations.

RESULTS: Allele T (C vs. T, P = 0.018) and genotype TT (CC vs. TT: P = 0.021) of rs66509122 among PD group and HCs were significantly different. In addition, we discovered that the rs66509122 genotype TT was associated with depression in early-onset PD (EOPD) (P = 0.031) and diabetes in female PD (P = 0.032). Unfortunately, no distinct correlation of rs4563461 polymorphisms with sporadic PD susceptibility was found in either the overall group (C vs. T, P = 0.086) or other subgroups. However, the T allele of rs4563461 was significantly correlated with sleep disorders in the PD group, especially in the late-onset PD (LOPD) group and male PD group.

CONCLUSION: This study found that the NEK1 rs66509122 polymorphism was associated with a lower risk of sporadic PD, while T allele of rs66509122 may be a protective factor for PD. The NEK1 rs4563461 and rs66509122 polymorphisms both showed correlations with some non-motor symptoms in sporadic PD patients. Further research with a larger sample and varied ethnic groups is needed to investigate the role of NEK1 gene polymorphisms in the pathophysiology of PD.}, } @article {pmid39032788, year = {2024}, author = {Wu, KJ and Wei, KC}, title = {Response to Hasan et al's "Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {5}, pages = {e145-e146}, doi = {10.1016/j.jaad.2024.06.091}, pmid = {39032788}, issn = {1097-6787}, } @article {pmid39031772, year = {2024}, author = {Meyer, T and Schumann, P and Weydt, P and Petri, S and Weishaupt, JH and Weyen, U and Koch, JC and Günther, R and Regensburger, M and Boentert, M and Wiesenfarth, M and Koc, Y and Kolzarek, F and Kettemann, D and Norden, J and Bernsen, S and Elmas, Z and Conrad, J and Valkadinov, I and Vidovic, M and Dorst, J and Ludolph, AC and Hesebeck-Brinckmann, J and Spittel, S and Münch, C and Maier, A and Körtvélyessy, P}, title = {Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {333-345}, doi = {10.1002/mus.28182}, pmid = {39031772}, issn = {1097-4598}, support = {(H4017703513237604)//Boris Canessa ALS Stiftung (Düsseldorf, Germany) and Martin Herrenknecht Fonds for ALS Research/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Male ; Female ; *Patient Reported Outcome Measures ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; *Neurofilament Proteins/blood ; Treatment Outcome ; Disease Progression ; Adult ; Oligonucleotides/therapeutic use ; }, abstract = {INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany.

METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS).

RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80).

DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.}, } @article {pmid39030740, year = {2024}, author = {Jonson, C and Levine, KS and Lake, J and Hertslet, L and Jones, L and Patel, D and Kim, J and Bandres-Ciga, S and Terry, N and Mata, IF and Blauwendraat, C and Singleton, AB and Nalls, MA and Yokoyama, JS and Leonard, HL}, title = {Assessing the lack of diversity in genetics research across neurodegenerative diseases: A systematic review of the GWAS Catalog and literature.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20}, number = {8}, pages = {5740-5756}, pmid = {39030740}, issn = {1552-5279}, support = {U19AG079774/NS/NINDS NIH HHS/United States ; R01 AG062588/AG/NIA NIH HHS/United States ; ZO1AG000534/HH/HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; 75N95022C00031/NS/NINDS NIH HHS/United States ; //Intramural Research Program/ ; P01AG019724/NS/NINDS NIH HHS/United States ; P30AG062422/NS/NINDS NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; 75N95022C00031/DA/NIDA NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; R01AG057234/NS/NINDS NIH HHS/United States ; R01AG062588/NS/NINDS NIH HHS/United States ; //Global Brain Health Institute; and the Mary Oakley Foundation/ ; //Rainwater Charitable Foundation/ ; }, mesh = {Humans ; Genetic Predisposition to Disease/genetics ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; White People/genetics ; }, abstract = {The under-representation of non-European cohorts in neurodegenerative disease genome-wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non-European or multi-ancestry studies. Notably, only six of the loci have been replicated. The significant under-representation of non-European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. HIGHLIGHTS: Eighty-two percent of neurodegenerative genome-wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.}, } @article {pmid39030617, year = {2024}, author = {Chen, T and Dai, Y and Hu, C and Lin, Z and Wang, S and Yang, J and Zeng, L and Li, S and Li, W}, title = {Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {60}, pmid = {39030617}, issn = {2045-8118}, support = {LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; LGD21H250001 and LGD22H250001//Basic Public Welfare Research Program of Zhejiang Province/ ; No.X-202102//Scientific Research Foundation of Zhejiang University City College/ ; }, mesh = {*Blood-Brain Barrier/metabolism/physiopathology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; Animals ; }, abstract = {BACKGROUND: Maintaining the structural and functional integrity of the blood-brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases.

MAIN BODY: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions.

CONCLUSIONS: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.}, } @article {pmid39030200, year = {2024}, author = {Erb, ML and Sipple, K and Levine, N and Chen, X and Moore, DJ}, title = {Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities.}, journal = {NPJ Parkinson's disease}, volume = {10}, number = {1}, pages = {133}, pmid = {39030200}, issn = {2373-8057}, support = {PF-FBS-1894//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; PF-FBS-1894//Parkinson's Foundation (Parkinson's Foundation, Inc.)/ ; }, abstract = {Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.}, } @article {pmid39030186, year = {2024}, author = {Dubbioso, R and Spisto, M and Verde, L and Iuzzolino, VV and Senerchia, G and Salvatore, E and De Pietro, G and De Falco, I and Sannino, G}, title = {Voice signals database of ALS patients with different dysarthria severity and healthy controls.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {800}, pmid = {39030186}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Dysarthria/physiopathology ; Male ; Female ; Voice ; Databases, Factual ; Middle Aged ; Adult ; Aged ; Case-Control Studies ; }, abstract = {This paper describes a new publicly-available database of VOiCe signals acquired in Amyotrophic Lateral Sclerosis (ALS) patients (VOC-ALS) and healthy controls performing different speech tasks. This dataset consists of 1224 voice signals recorded from 153 participants: 51 healthy controls (32 males and 19 females) and 102 ALS patients (65 males and 37 females) with different severity of dysarthria. Each subject's voice was recorded using a smartphone application (Vox4Health) while performing several vocal tasks, including a sustained phonation of the vowels /a/, /e/, /i/, /o/, /u/ and /pa/, /ta/, /ka/ syllable repetition. Basic derived speech metrics such as harmonics-to-noise ratio, mean and standard deviation of fundamental frequency (F0), jitter and shimmer were calculated. The F0 standard deviation of vowels and syllables showed an excellent ability to identify people with ALS and to discriminate the different severity of dysarthria. These data represent the most comprehensive database of voice signals in ALS and form a solid basis for research on the recognition of voice impairment in ALS patients for use in clinical applications.}, } @article {pmid39030042, year = {2024}, author = {Haberkamp, M and Aislaitner, G and Martínez-Lapiscina, EH and Weise, M}, title = {Tofersen for SOD-1-associated amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {8}, pages = {772-773}, doi = {10.1016/S1474-4422(24)00259-X}, pmid = {39030042}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Superoxide Dismutase-1/genetics ; }, } @article {pmid39029959, year = {2024}, author = {}, title = {Erratum: Garbuzova-Davis et al., "Apolipoprotein A1 Enhances Endothelial Cell Survival in an In Vitro Model of ALS".}, journal = {eNeuro}, volume = {11}, number = {7}, pages = {}, doi = {10.1523/ENEURO.0280-24.2024}, pmid = {39029959}, issn = {2373-2822}, } @article {pmid39028002, year = {2024}, author = {Mercadante, S and Petronaci, A and Terranova, A and Casuccio, A}, title = {Characteristics of Patients With Amyotrophic Lateral Sclerosis Followed by a Home Palliative Care Team.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091241266985}, doi = {10.1177/10499091241266985}, pmid = {39028002}, issn = {1938-2715}, abstract = {BACKGROUND: Information about patients with amyothrophic lateral sclerosis (ALS) followed at home is limited.

OBJECTIVES: To assess patients's characteristics at admission to a home palliative care program based on a multidisciplinary team, and the temporal course along the trajectory of ALS disease.

DESIGN: Retrospective. Setting/subjects: Charts of a consecutive number of ALS patients who were referred to a specialistic home palliative care were reviewed.

MEASUREMENT: General data, referral, start of home palliative care, use of ventilator support and nutritional support, were recorded. The existence of advance directives and shared care planning was also collected.

RESULTS: 82 patients were examined; 31 patients died before the term of the study and 51 patients were still living. No patient anticipately expressed their will regarding their treatments. However, a certain number of patients shared a care planning with ALS team, generally after starting home care. Most patients did not have ventilatory support at the beginning of home care assistance, but progressively received ventilatory support by NIV or MV, particularly those who were still living. NIV at start of home care was negatively correlated to frontotemporal dementia. (P = 0.015), and directly correlated to referral from hospital and GP (P = 0.031) and awareness of disease (P = 0.034). Gastrostomy at start of home care was positively correlated to referral from hospital (P = 0.046). Gastrostomy during home care was correlated to bulbar SLA (P = 0.017). The use of NIV during home care was positively correlated to shared care planning (P = 0.001).

CONCLUSION: The continuous presence of a multi-specialist team may provide timely intervention, guarantee and trust on the part of the patient and family members.}, } @article {pmid39026758, year = {2024}, author = {Onwunma, J and Binsabaan, S and Allen, SP and Sankaran, B and Wohlever, ML}, title = {The structural and biophysical basis of substrate binding to the hydrophobic groove in Ubiquilin Sti1 domains.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39026758}, issn = {2692-8205}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R35 GM137904/GM/NIGMS NIH HHS/United States ; }, abstract = {Ubiquilins are a family of cytosolic proteins that ferry ubiquitinated substrates to the proteasome for degradation. Recent work has demonstrated that Ubiquilins can also act as molecular chaperones, utilizing internal Sti1 domains to directly bind to hydrophobic sequences. Ubiquilins are associated with several neurodegenerative diseases with point mutations in UBQLN2 causing dominant, X-linked Amyotrophic Lateral Sclerosis (ALS). The molecular basis of Ubiquilin chaperone activity and how ALS mutations in the Sti1 domains affect Ubiquilin activity are poorly understood. This study presents the first crystal structure of the Sti1 domain from a fungal Ubiquilin homolog bound to a transmembrane domain (TMD). The structure reveals that two Sti1 domains form a head-to-head dimer, creating a hydrophobic cavity that accommodates two TMDs. Mapping the UBQLN2 sequence onto the structure shows that several ALS mutations are predicted to disrupt the hydrophobic groove. Using a newly developed competitive binding assay, we show that Ubiquilins preferentially bind to hydrophobic substrates with low helical propensity, motifs that are enriched in both substrates and in Ubiquilins. This study provides insights into the molecular and structural basis for Ubiquilin substrate binding, with broad implications for the role of the Sti1 domain in phase separation and ALS.}, } @article {pmid39026010, year = {2024}, author = {Read, TA and Cisterna, BA and Skruber, K and Ahmadieh, S and Liu, TM and Vitriol, JA and Shi, Y and Black, JB and Butler, MT and Lindamood, HL and Lefebvre, AE and Cherezova, A and Ilatovskaya, DV and Bear, JE and Weintraub, NL and Vitriol, EA}, title = {The actin binding protein profilin 1 localizes inside mitochondria and is critical for their function.}, journal = {EMBO reports}, volume = {25}, number = {8}, pages = {3240-3262}, pmid = {39026010}, issn = {1469-3178}, support = {R35 GM137959/GM/NIGMS NIH HHS/United States ; R35GM137959//Foundation for the National Institutes of Health (FNIH)/ ; }, mesh = {*Profilins/metabolism/genetics ; *Mitochondria/metabolism/genetics ; Humans ; *Actins/metabolism ; Mitophagy/genetics ; Lysosomes/metabolism ; Cytosol/metabolism ; Gene Knockout Techniques ; Autophagosomes/metabolism ; HeLa Cells ; }, abstract = {The monomer-binding protein profilin 1 (PFN1) plays a crucial role in actin polymerization. However, mutations in PFN1 are also linked to hereditary amyotrophic lateral sclerosis, resulting in a broad range of cellular pathologies which cannot be explained by its primary function as a cytosolic actin assembly factor. This implies that there are important, undiscovered roles for PFN1 in cellular physiology. Here we screened knockout cells for novel phenotypes associated with PFN1 loss of function and discovered that mitophagy was significantly upregulated. Indeed, despite successful autophagosome formation, fusion with the lysosome, and activation of additional mitochondrial quality control pathways, PFN1 knockout cells accumulate depolarized, dysmorphic mitochondria with altered metabolic properties. Surprisingly, we also discovered that PFN1 is present inside mitochondria and provide evidence that mitochondrial defects associated with PFN1 loss are not caused by reduced actin polymerization in the cytosol. These findings suggest a previously unrecognized role for PFN1 in maintaining mitochondrial integrity and highlight new pathogenic mechanisms that can result from PFN1 dysregulation.}, } @article {pmid39025824, year = {2024}, author = {Lorenc, T and Khouja, C and Harden, M and Fulbright, H and Thomas, J}, title = {Defensive healthcare practice: systematic review of qualitative evidence.}, journal = {BMJ open}, volume = {14}, number = {7}, pages = {e085673}, pmid = {39025824}, issn = {2044-6055}, mesh = {Humans ; *Qualitative Research ; *Defensive Medicine ; Attitude of Health Personnel ; }, abstract = {OBJECTIVE: To synthesise qualitative evidence on clinicians' views and experiences of defensive practice.

DESIGN: Systematic review of qualitative data.

DATA SOURCES: MEDLINE, Embase, PsycINFO, AMED, Maternity and Infant Care, CINAHL, ASSIA, Sociological Abstracts, Proquest Dissertations & Theses and PROSPERO were searched from 2000 to October 2023.

ELIGIBILITY CRITERIA: We included English-language studies of clinicians which reported qualitative data on the impact of litigation or complaints on clinical practice.

DATA EXTRACTION AND SYNTHESIS: We coded findings data line by line using a grounded theory approach. We assessed quality using Hawker et al's tool and synthesised data thematically.

RESULTS: 17 studies were included. Participants identify a range of clinical decisions which may be defensively motivated, relating to diagnosis and documentation as well as to treatment. Defensive practice often relates to a diffuse sense of risk rather than the direct threat of litigation and may overlap with other motivations, such as perceived pressure from patients or the desire to avoid harm. Defensive practice is seen to be harmful in many ways, but again, these perceptions may gain force from broader narratives of mistrust and disempowerment, as much as from the risk of litigation.

CONCLUSIONS: The idea of defensive practice, as enacted, is more complex than some theoretical accounts suggest and may often function to express broader concerns about the work of clinical care. The qualitative evidence calls into question the view of defensive practice as a key mediator linking litigation risk to inappropriate treatment and excess costs.}, } @article {pmid39023312, year = {2024}, author = {Miceli, M and Cannariato, M and Tortarolo, R and Pallante, L and Zizzi, EA and Deriu, MA}, title = {Conformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies.}, journal = {Proteins}, volume = {92}, number = {11}, pages = {1343-1353}, doi = {10.1002/prot.26728}, pmid = {39023312}, issn = {1097-0134}, support = {GSP 20005_PAsIAHSP007//Fondazione Telethon/ ; //Associazione Help Olly Onlus-Italy/ ; }, mesh = {*Protein Multimerization ; Humans ; Molecular Dynamics Simulation ; Protein Conformation, alpha-Helical ; Protein Stability ; Protein Conformation, beta-Strand ; Protein Domains ; Amino Acid Sequence ; Models, Molecular ; Protein Interaction Domains and Motifs ; Protein Conformation ; Guanine Nucleotide Exchange Factors ; }, abstract = {Despite the ubiquity of membrane occupation recognition nexus (MORN) motifs across diverse species in both eukaryotic and prokaryotic organisms, these protein domains remain poorly characterized. Their significance is underscored in the context of the Alsin protein, implicated in the debilitating condition known as infantile-onset ascending hereditary spastic paralysis (IAHSP). Recent investigations have proposed that mutations within the Alsin MORN domain disrupt proper protein assembly, precluding the formation of the requisite tetrameric configuration essential for the protein's inherent biological activity. However, a comprehensive understanding of the relationship between the biological functions of Alsin and its three-dimensional molecular structure is hindered by the lack of available experimental structures. In this study, we employed and compared several protein structure prediction algorithms to identify a three-dimensional structure for the putative MORN of Alsin. Furthermore, inspired by experimental pieces of evidence from previous studies, we employed the developed models to predict and investigate two homo-dimeric assemblies, characterizing their stability. This study's insights into the three-dimensional structure of the Alsin MORN domain and the stability dynamics of its homo-dimeric assemblies suggest an antiparallel linear configuration stabilized by a noncovalent interaction network.}, } @article {pmid39023172, year = {2024}, author = {Zaky, MH and Shoorangiz, R and Poudel, GR and Yang, L and Innes, CRH and Jones, RD}, title = {Conscious but not thinking-Mind-blanks during visuomotor tracking: An fMRI study of endogenous attention lapses.}, journal = {Human brain mapping}, volume = {45}, number = {11}, pages = {e26781}, pmid = {39023172}, issn = {1097-0193}, support = {08-VDV-01 EHB//Marsden Fund, Royal Society of New Zealand/ ; //University of Canterbury/ ; //University of Otago/ ; 236930//Lottery Health Research/ ; }, mesh = {Humans ; Adult ; *Magnetic Resonance Imaging ; Female ; Male ; Young Adult ; *Attention/physiology ; *Psychomotor Performance/physiology ; Middle Aged ; Eye-Tracking Technology ; Thinking/physiology ; Nerve Net/diagnostic imaging/physiopathology/physiology ; Consciousness/physiology ; Visual Perception/physiology ; Motor Activity/physiology ; }, abstract = {Attention lapses (ALs) are complete lapses of responsiveness in which performance is briefly but completely disrupted and during which, as opposed to microsleeps, the eyes remain open. Although the phenomenon of ALs has been investigated by behavioural and physiological means, the underlying cause of an AL has largely remained elusive. This study aimed to investigate the underlying physiological substrates of behaviourally identified endogenous ALs during a continuous visuomotor task, primarily to answer the question: Were the ALs during this task due to extreme mind-wandering or mind-blanks? The data from two studies were combined, resulting in data from 40 healthy non-sleep-deprived subjects (20M/20F; mean age 27.1 years, 20-45). Only 17 of the 40 subjects were used in the analysis due to a need for a minimum of two ALs per subject. Subjects performed a random 2-D continuous visuomotor tracking task for 50 and 20 min in Studies 1 and 2, respectively. Tracking performance, eye-video, and functional magnetic resonance imaging (fMRI) were recorded simultaneously. A human expert visually inspected the tracking performance and eye-video recordings to identify and categorise lapses of responsiveness as microsleeps or ALs. Changes in neural activity during 85 ALs (17 subjects) relative to responsive tracking were estimated by whole-brain voxel-wise fMRI and by haemodynamic response (HR) analysis in regions of interest (ROIs) from seven key networks to reveal the neural signature of ALs. Changes in functional connectivity (FC) within and between the key ROIs were also estimated. Networks explored were the default mode network, dorsal attention network, frontoparietal network, sensorimotor network, salience network, visual network, and working memory network. Voxel-wise analysis revealed a significant increase in blood-oxygen-level-dependent activity in the overlapping dorsal anterior cingulate cortex and supplementary motor area region but no significant decreases in activity; the increased activity is considered to represent a recovery-of-responsiveness process following an AL. This increased activity was also seen in the HR of the corresponding ROI. Importantly, HR analysis revealed no trend of increased activity in the posterior cingulate of the default mode network, which has been repeatedly demonstrated to be a strong biomarker of mind-wandering. FC analysis showed decoupling of external attention, which supports the involuntary nature of ALs, in addition to the neural recovery processes. Other findings were a decrease in HR in the frontoparietal network before the onset of ALs, and a decrease in FC between default mode network and working memory network. These findings converge to our conclusion that the ALs observed during our task were involuntary mind-blanks. This is further supported behaviourally by the short duration of the ALs (mean 1.7 s), which is considered too brief to be instances of extreme mind-wandering. This is the first study to demonstrate that at least the majority of complete losses of responsiveness on a continuous visuomotor task are, if not due to microsleeps, due to involuntary mind-blanks.}, } @article {pmid39022351, year = {2024}, author = {Corvino, A and Caliendo, G and Fiorino, F and Frecentese, F and Valsecchi, V and Lombardi, G and Anzilotti, S and Andreozzi, G and Scognamiglio, A and Sparaco, R and Perissutti, E and Severino, B and Gargiulo, M and Santagada, V and Pignataro, G}, title = {Newly Synthesized Indolylacetic Derivatives Reduce Tumor Necrosis Factor-Mediated Neuroinflammation and Prolong Survival in Amyotrophic Lateral Sclerosis Mice.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {7}, pages = {1996-2005}, pmid = {39022351}, issn = {2575-9108}, abstract = {The debilitating neurodegenerative disease known as amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) in the brain, spinal cord, and motor cortex. The ALS neuroinflammatory component is being characterized and includes the overexpression of mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α). Currently, there are no effective treatments for ALS. Indeed, riluzole, an N-methyl-D-aspartate (NMDA) glutamate receptor blocker, and edaravone, a reactive oxygen species (ROS) scavenger, are currently the sole two medications approved for ALS treatment. However, their efficacy in extending life expectancy typically amounts to only a few months. In order to improve the medicaments for the treatment of neurodegenerative diseases, preferably ALS, novel substituted 2-methyl-3-indolylacetic derivatives (compounds II-IV) were developed by combining the essential parts of two small molecules, namely, the opioids containing a 4-piperidinyl ring with indomethacin, previously shown to be efficacious in different experimental models of neuroinflammation. The synthesized compounds were evaluated for their potential capability of slowing down neurodegeneration associated with ALS progression in preclinical models of the disease in vitro and in vivo. Notably, we produced data to demonstrate that the treatment with the newly synthesized compound III: (1) prevented the upregulation of TNF-α observed in BV-2 microglial cells exposed to the toxin lipopolysaccharides (LPS), (2) preserved SHSY-5Y cell survival exposed to β-N-methylamino-l-alanine (L-BMAA) neurotoxin, and (3) mitigated motor symptoms and improved survival rate of SOD1G93A ALS mice. In conclusion, the findings of the present work support the potential of the synthesized indolylacetic derivatives II-IV in ALS treatment. Indeed, in the attempt to realize an association between two active molecules, we assumed that the combination of the indispensable moieties of two small molecules (the opioids containing a 4-piperidinyl ring with the FANS indomethacin) might lead to new medicaments potentially useful for the treatment of amyotrophic lateral sclerosis.}, } @article {pmid39020237, year = {2024}, author = {Yuan, ZL and Ren, J and Huang, ML and Qi, YF and Gao, X and Sun, YY and He, YL and Zhu, L and Xue, HD}, title = {A new magnetic resonance imaging-based PUMCH classification system for congenital cervical malformations: devising a standardised diagnosis pathway.}, journal = {Insights into imaging}, volume = {15}, number = {1}, pages = {177}, pmid = {39020237}, issn = {1869-4101}, support = {2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; 2022-PUMCH-A-004//National High Level Hospital Clinical Research Funding/ ; }, abstract = {OBJECTIVES: To develop an innovative magnetic resonance imaging (MRI)-based PUMCH (Peking Union Medical College Hospital) classification system aimed at standardising the diagnosis of congenital cervical malformations (CCMs) by identifying their distinctive MRI features.

METHODS: Seventy-nine consecutive patients with CCM underwent pre-treatment pelvic MRI; three experienced gynaecological radiologists retrospectively analysed these images. Qualitative assessments included Rock et al's classification; PUMCH classification; haematometra; cervical signal features; ovarian endometriosis; haematosalpinx; and uterine, vaginal, urinary, and musculoskeletal malformations. Quantitative assessments involved the uterine volume, sagittal cervical length, and maximum ovarian cross-sectional area. The surgical treatment types were also recorded. Statistical methods were used to incorporate differences in clinical features and surgical methods into our classification.

RESULTS: Morphologically, CCMs were categorised into three types: type I (53%) was characterised by the presence of a cervix with visible cervical canals; type II (23%) featured an existing cervix with concealed cervical canals; and type III (24%) indicated cervical aplasia, which involves a blind end in the lower part of the uterine corpus. Haematometra was significantly more prevalent in patients with type I CCM than in those with type II (p < 0.001). There were three cervical signal patterns: no signal (27%), no evident layer differentiation (21%), and multi-layer differentiation with haematocele (52%). Most patients (94%) had complete vaginal atresia. Type I CCM patients had a higher likelihood of regaining normal uterovaginal anatomy compared to types II and III.

CONCLUSIONS: Our proposed PUMCH classification system has a high potential for enhancing the efficiency of clinical diagnosis among patients with CCM.

CRITICAL RELEVANCE STATEMENT: The proposed new PUMCH classification promised to elevate the conventional diagnostic trajectory for congenital cervical malformations, offering a valuable framework to refine the selection and planning of surgical interventions, thereby enhancing overall clinical efficacy.

KEY POINTS: Effective classification of congenital cervical malformations is desirable to optimise the diagnostic process. We presented a PUMCH classification of congenital cervical malformations using pelvic MRI. The new classification significantly aids clinical triage for congenital cervical malformations.}, } @article {pmid39019674, year = {2024}, author = {Georges, M and Perez, T and Rabec, C and Jacquin, L and Finet-Monnier, A and Ramos, C and Patout, M and Attali, V and Amador, M and Gonzalez-Bermejo, J and Salachas, F and Morelot-Panzini, C}, title = {[Proposals from a French expert panel for respiratory care in ALS patients].}, journal = {Revue des maladies respiratoires}, volume = {41}, number = {8}, pages = {620-637}, doi = {10.1016/j.rmr.2024.06.006}, pmid = {39019674}, issn = {1776-2588}, mesh = {*Amyotrophic Lateral Sclerosis/complications/therapy ; Humans ; France/epidemiology ; *Noninvasive Ventilation/methods/standards/instrumentation ; *Respiratory Insufficiency/therapy/etiology ; Respiratory Therapy/methods/standards ; Quality of Life ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres.

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

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

CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.}, } @article {pmid39019135, year = {2024}, author = {Cao, M and Yi, L and Xu, Y and Tian, Y and Li, Z and Bi, Y and Guo, M and Li, Y and Liu, Y and Xu, X and Sun, J and Li, C and Duan, W}, title = {Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.}, journal = {Brain research}, volume = {1843}, number = {}, pages = {149124}, doi = {10.1016/j.brainres.2024.149124}, pmid = {39019135}, issn = {1872-6240}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Disease Models, Animal ; Mice, Inbred C57BL ; *Mice, Transgenic ; *NF-kappa B/metabolism ; *NF-kappaB-Inducing Kinase ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear.

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

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

CONCLUSION: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.}, } @article {pmid39017978, year = {2024}, author = {Vinceti, M and Urbano, T and Filippini, T and Bedin, R and Simonini, C and Sorarù, G and Trojsi, F and Michalke, B and Mandrioli, J}, title = {Changes in Cerebrospinal Fluid Concentrations of Selenium Species Induced by Tofersen Administration in Subjects with Amyotrophic Lateral Sclerosis Carrying SOD1 Gene Mutations.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {39017978}, issn = {1559-0720}, support = {"PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022" (no. 2022MHMRPR)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; "PRIN 2022 PNRR" (no. P20229KSXB)//Ministero dell'Università e della Ricerca/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression.}, } @article {pmid39017652, year = {2024}, author = {Ranta-Aho, J and Johari, M and Udd, B}, title = {Current advance on distal myopathy genetics.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {515-522}, pmid = {39017652}, issn = {1473-6551}, mesh = {Humans ; *Distal Myopathies/genetics/pathology ; }, abstract = {PURPOSE OF REVIEW: Distal myopathies are a clinically heterogenous group of rare, genetic muscle diseases, that present with weakness in hands and/or feet at onset. Some of these diseases remain accentuated in the distal muscles whereas others may later progress to the proximal muscles. In this review, the latest findings related to genetic and clinical features of distal myopathies are summarized.

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

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

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

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

CONCLUSION: With proper instruction, ALS patients can effectively use the EyePhone to record their eye movements, potentially even in a home environment. These results demonstrate the potential for smartphone eye-tracking technology as a viable and self-administered tool for monitoring disease progression in ALS, reducing the need for frequent clinic visits.}, } @article {pmid39015316, year = {2024}, author = {Liu, Y and Chen, Y and Gao, M and Luo, J and Wang, Y and Wang, Y and Gao, Y and Yang, L and Wang, J and Wang, N}, title = {Association between glioma and neurodegenerative diseases risk: a two-sample bi-directional Mendelian randomization analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1413015}, pmid = {39015316}, issn = {1664-2295}, abstract = {BACKGROUND: Earlier observational studies have demonstrated a correlation between glioma and the risk of neurodegenerative diseases (NDs), but the causality and direction of their associations remain unclear. The objective of this study was to ascertain the causal link between glioma and NDs using Mendelian randomization (MR) methodology.

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

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

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

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

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

CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.}, } @article {pmid39009686, year = {2024}, author = {Neupane, K and Narayan, A and Sen Mojumdar, S and Adhikari, G and Garen, CR and Woodside, MT}, title = {Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants.}, journal = {Nature chemical biology}, volume = {20}, number = {9}, pages = {1220-1226}, pmid = {39009686}, issn = {1552-4469}, support = {N/A//Gouvernement du Canada | National Research Council Canada (Conseil national de recherches Canada)/ ; RGPIN-2018-04673//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; N/A//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; PJT-185931//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; N/A//Alberta Innovates | Alberta Innovates - Health Solutions (AIHS)/ ; }, mesh = {*Protein Folding ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; Humans ; *Mutation ; *Prions/metabolism/genetics/chemistry ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Optical Tweezers ; }, abstract = {Many neurodegenerative diseases feature misfolded proteins that propagate via templated conversion of natively folded molecules. However, crucial questions about how such prion-like conversion occurs and what drives it remain unsolved, partly because technical challenges have prevented direct observation of conversion for any protein. We observed prion-like conversion in single molecules of superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis. Tethering pathogenic misfolded SOD1 mutants to wild-type molecules held in optical tweezers, we found that the mutants vastly increased misfolding of the wild-type molecule, inducing multiple misfolded isoforms. Crucially, the pattern of misfolding was the same in the mutant and converted wild-type domains and varied when the misfolded mutant was changed, reflecting the templating effect expected for prion-like conversion. Ensemble measurements showed decreased enzymatic activity in tethered heterodimers as conversion progressed, mirroring the single-molecule results. Antibodies sensitive to disease-specific epitopes bound to the converted protein, implying that conversion produced disease-relevant misfolded conformers.}, } @article {pmid39009447, year = {2024}, author = {Akter, M and Sepehrimanesh, M and Xu, W and Ding, B}, title = {Assembling a Coculture System to Prepare Highly Pure Induced Pluripotent Stem Cell-Derived Neurons at Late Maturation Stages.}, journal = {eNeuro}, volume = {11}, number = {7}, pages = {}, pmid = {39009447}, issn = {2373-2822}, mesh = {*Induced Pluripotent Stem Cells/physiology ; *Coculture Techniques ; Animals ; *Motor Neurons/physiology ; Mice ; *Astrocytes/physiology ; Humans ; Cell Differentiation/physiology ; Cells, Cultured ; Neurogenesis/physiology ; }, abstract = {Generation of human induced pluripotent stem cell (hiPSC)-derived motor neurons (MNs) offers an unprecedented approach to modeling movement disorders such as dystonia and amyotrophic lateral sclerosis. However, achieving survival poses a significant challenge when culturing induced MNs, especially when aiming to reach late maturation stages. Utilizing hiPSC-derived motor neurons and primary mouse astrocytes, we assembled two types of coculture systems: direct coculturing of neurons with astrocytes and indirect coculture using culture inserts that physically separate neurons and astrocytes. Both systems significantly enhance neuron survival. Compared with these two systems, no significant differences in neurodevelopment, maturation, and survival within 3 weeks, allowing to prepare neurons at maturation stages. Using the indirect coculture system, we obtained highly pure MNs at the late mature stage from hiPSCs. Transcriptomic studies of hiPSC-derived MNs showed a typical neurodevelopmental switch in gene expression from the early immature stage to late maturation stages. Mature genes associated with neurodevelopment and synaptogenesis are highly enriched in MNs at late stages, demonstrating that these neurons achieve maturation. This study introduces a novel tool for the preparation of highly pure hiPSC-derived neurons, enabling the determination of neurological disease pathogenesis in neurons at late disease onset stages through biochemical approaches, which typically necessitate highly pure neurons. This advancement is particularly significant in modeling age-related neurodegeneration.}, } @article {pmid39009032, year = {2024}, author = {Scheithauer, S and Hoffmann, J and Lang, C and Fenz, D and Berens, MM and Köster, AM and Panchyrz, I and Harst, L and Adorjan, K and Apfelbacher, C and Ciesek, S and Denkinger, CM and Drosten, C and Geraedts, M and Hecker, R and Hoffmann, W and Karch, A and Koch, T and Krefting, D and Lieb, K and Meerpohl, JJ and Rehfuess, EA and Skoetz, N and Sopka, S and von Lengerke, T and Wiegand, H and Schmitt, J}, title = {Pandemic Preparedness - A Proposal for a Research Infrastructure and its Functionalities for a Resilient Health Research System.}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2365-9179}, pmid = {39009032}, issn = {1439-4421}, support = {01KX2121//Bundesministerium für Bildung und Forschung/ ; }, abstract = {Während einer Pandemie muss Resilienz nicht nur als Eigenschaft des Gesundheitssystems, sondern auch des umgebenden Forschungsumfelds betrachtet werden. Um verlässliche, evidenzbasierte Empfehlungen aus der Universitätsmedizin an die Gesundheitspolitik und die Entscheidungsträger bereitstellen zu können, müssen wissenschaftliche Erkenntnisse schnell, integrativ und multidisziplinär generiert, synthetisiert und kommuniziert werden. Die Resilienz der öffentlichen Gesundheitssysteme und der Gesundheitsforschungssysteme sind somit eng verknüpft. Die Reaktion auf die SARS-CoV-2-Pandemie in Deutschland wurde jedoch durch das Fehlen einer adäquat vernetzten Gesundheitsforschungsinfrastruktur erschwert. Das Netzwerk Universitätsmedizin (NUM) wurde zu Beginn der Pandemie mit dem Ziel gegründet, Deutschland auf zukünftige Pandemien vorzubereiten. Ziel des Projektes "PREparedness and PAndemic REsponse in Deutschland (PREPARED)" ist es, ein ganzheitliches Konzept für eine kooperative, adaptierbare und nachhaltige Gesundheitsforschungsinfrastruktur innerhalb des NUM zu entwickeln und damit einen Beitrag zu einer umfassenden Pandemiebereitschaft zu leisten. Das vorgeschlagene Konzept dieser Infrastruktur vereint vier Kern- und drei Unterstützungsfunktionalitäten in vier verschiedenen Handlungsfeldern. Die Funktionalitäten gewährleisten im Falle zukünftiger Gesundheitskrisen ein effizientes Funktionieren des Gesundheitsforschungssystems und eine rasche Übertragung entsprechender Implikationen in andere Systeme. Die vier Handlungsfelder sind (a) Monitoring und Surveillance, (b) Synthese und Transfer, (c) Koordination und Organisation sowie (d) Kapazitäten und Ressourcen. Die sieben Funktionalitäten umfassen 1) eine Monitoring- und Surveillance-Einheit, 2) eine Pathogenkompetenz-Plattform, 3) Evidenzsynthese und vertrauenswürdige Empfehlungen, 4) eine Einheit zur regionalen Vernetzung und Implementierung, 5) eine Strategische Kommunikationseinheit, 6) Human Resources Management und 7) ein Rapid Reaction & Response (R[3])-Cockpit. Die Governance wird als Kontroll- und Regulierungssystem eingerichtet, wobei agile Management-Methoden in interpandemischen Phasen trainiert werden, um die Reaktionsfähigkeit zu verbessern sowie die Eignung agiler Methoden für die wissenschaftliche Infrastruktur für die Pandemiebereitschaft zu untersuchen. Der Aufbau der PREPARED-Forschungsinfrastruktur muss vor der nächsten Pandemie erfolgen, da Training und regelmäßige Stresstests grundlegende Voraussetzungen für deren Funktionieren sind.During a pandemic, resilience must be considered not only as an attribute of the health care system, but also of the surrounding research environment. To provide reliable evidence-based advice from university medicine to health policy and decision makers, scientific evidence must be generated, synthesized and communicated in a rapid, integrative and multidisciplinary manner. The resilience of public health systems and the health research systems are thus closely linked. However, the response to the SARS-CoV-2 pandemic in Germany was hampered by the lack of an adequate health research infrastructure. The Network University Medicine (NUM) was founded at the beginning of the pandemic with the aim of preparing Germany for future pandemics. The aim of the project "PREparedness and PAndemic REsponse in Deutschland (PREPARED)" is to develop a holistic concept for a cooperative, adaptable and sustainable health research infrastructure within the NUM and thus contribute to pandemic preparedness and rapid response. The proposed concept for a health research infrastructure includes four core and three supporting functionalities in four different fields of action. The functionalities aim to ensure efficient functioning within the health research system and a rapid translation to other systems in future health crises. The four fields of action are (a) monitoring and surveillance, (b) synthesis and transfer, (c) coordination and organization, and (d) capacities and resources. The seven functionalities include 1) a monitoring and surveillance unit, 2) a pathogen competence platform, 3) evidence synthesis and trustworthy recommendations, 4) a regional networking and implementation unit, 5) a strategic communication unit, 6) human resources management, and 7) a rapid reaction and the response (R[3])-cockpit. A governance will be established as a control and regulatory system for all structures and processes, testing agile management in non-pandemic times to improve responsiveness and flexibility and to investigate the suitability of the methods for scientific pandemic preparedness. The establishment of the PREPARED health research infrastructure must take place before the next pandemic, as training and regular stress tests are its fundamental prerequisites.}, } @article {pmid39008674, year = {2024}, author = {Mason, AH and Motta, A and Kratish, Y and Marks, TJ}, title = {Demystifying group-4 polyolefin hydrogenolysis catalysis. Gaseous propane hydrogenolysis mechanism over the same catalysts.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {30}, pages = {e2406133121}, pmid = {39008674}, issn = {1091-6490}, support = {DE-FG02-03ER15457//DOE | Office of Science (SC)/ ; DOE DE-SC0024448//Dow Chemical Company (Dow)/ ; ECCS-2025633//National Science Foundation (NSF)/ ; NNA04CC36G//NASA | Ames Research Center (ARC)/ ; DOE DE-SC0001329//Dow Chemical Company (Dow)/ ; HP10CPXHA1 2023//CINECA HPC/ ; }, abstract = {A kinetic/mechanistic investigation of gaseous propane hydrogenolysis over the single-site heterogeneous polyolefin depolymerization catalysts AlS/ZrNp2 and AlS/HfNp2 (AlS = sulfated alumina, Np = neopentyl), is use to probe intrinsic catalyst properties without the complexities introduced by time- and viscosity-dependent polymer medium effects. In a polymer-free automated plug-flow catalytic reactor, propane hydrogenolysis turnover frequencies approach 3,000 h[-1] at 150 °C. Both catalysts exhibit approximately linear relationships between rate and [H2] at substoichiometric [H2] with rate law orders of 0.66 ± 0.09 and 0.48 ± 0.07 for Hf and Zr, respectively; at higher [H2], the rates approach zero-order in [H2]. Reaction orders in [C3H8] and [catalyst] are essentially zero-order under all conditions, with the former implying rapid, irreversible alkane binding/activation. This rate law, activation parameter, and DFT energy span analysis support a scenario in which [H2] is pivotal in one of two plausible and competing rate-determining transition states-bimolecular metal-alkyl bond hydrogenolysis vs. unimolecular β-alkyl elimination. The Zr and Hf catalyst activation parameters, ΔH[‡] = 16.8 ± 0.2 kcal mol[-1] and 18.2 ± 0.6 kcal mol[-1], respectively, track the relative turnover frequencies, while ΔS[‡] = -19.1 ± 0.8 and -16.7 ± 1.4 cal mol[-1] K[-1], respectively, imply highly organized transition states. These catalysts maintain activity up to 200 °C, while time-on-stream data indicate multiday activities with an extrapolated turnover number ~92,000 at 150 °C for the Zr catalyst. This methodology is attractive for depolymerization catalyst discovery and process optimization.}, } @article {pmid39008617, year = {2024}, author = {Tsitkanou, S and Lindsay, A and Abbott, G and Foletta, V and Walker, AK and Russell, AP and Della Gatta, PA}, title = {Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {137}, number = {3}, pages = {728-745}, doi = {10.1152/japplphysiol.00192.2023}, pmid = {39008617}, issn = {1522-1601}, support = {//Deakin University | Institute for Physical Activity and Nutrition (IPAN)/ ; //Onassis Foundation Greece/ ; //Deakin University, Alfread Deakin PostDoc Fellowship/ ; //Neurological Foundation of New Zealand/ ; 1124005//Australian National Health and Medical Research Council/ ; //Ross Maclean Fellowship/ ; //Bill Guest FightMND Mid-Career Development Fellowship/ ; //Brazil Family Program for Neurology/ ; }, mesh = {Animals ; *Disease Progression ; *Muscle, Skeletal/metabolism/physiopathology ; Mice ; *Physical Conditioning, Animal/physiology/methods ; *Adaptation, Physiological/physiology ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/physiopathology/metabolism/therapy ; Male ; Mice, Transgenic ; }, abstract = {Exercise training is considered a nonpharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete 4 wk of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial, and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimens need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.NEW & NOTEWORTHY This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3-4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.}, } @article {pmid39007704, year = {2024}, author = {Gandhi, P and Waito, AA and Peladeau-Pigeon, M and Plowman, EK and Steele, CM}, title = {How Do Quantitative Videofluoroscopy Measures Differ Between People With Amyotrophic Lateral Sclerosis and Age-Matched Healthy Adults?.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {8}, pages = {2512-2532}, pmid = {39007704}, issn = {1558-9102}, support = {R01 AG077481/AG/NIA NIH HHS/United States ; R01 DC011020/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/complications ; Male ; Female ; Aged ; Middle Aged ; Fluoroscopy/methods ; *Deglutition Disorders/physiopathology/etiology/diagnostic imaging ; Aged, 80 and over ; Retrospective Studies ; *Deglutition/physiology ; *Video Recording ; Case-Control Studies ; }, abstract = {PURPOSE: Dysphagia is a leading cause of morbidity in people with amyotrophic lateral sclerosis (PwALS). Previous videofluoroscopic swallowing studies (VFSS) in PwALS do not account for the influence of senescence. We aimed to compare swallowing in PwALS and an age- and sex-matched control group using healthy reference data to define typical and atypical values.

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

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

CONCLUSIONS: This analysis builds on previous descriptions of swallowing pathophysiology in amyotrophic lateral sclerosis (ALS) by clarifying the extent to which aging may account for some of the atypical findings seen in this patient population. Longitudinal studies are recommended to further differentiate the effects of ALS from age-related changes in swallowing over the course of disease progression.}, } @article {pmid39007446, year = {2024}, author = {Torra, J and Mora, G and Montull, JM and Royo-Esnal, A and Notter, JS and Salas, M}, title = {A 4-year field study monitoring the evolution of Trp574Leu-resistant plants in an Echinochloa crus-galli population under different crop rotation and herbicide programs in maize.}, journal = {Pest management science}, volume = {80}, number = {11}, pages = {5843-5851}, doi = {10.1002/ps.8315}, pmid = {39007446}, issn = {1526-4998}, support = {//Corteva Agriscience/ ; RYC2018-023866-I//Spanish Ministry of Science, Innovation, and Universities/ ; //Spanish State Research Agency/ ; PID2020-113229RB-C42//European Regional Development Fund (ERDF)/ ; }, mesh = {*Echinochloa/drug effects/genetics ; *Zea mays/growth & development ; *Herbicide Resistance ; *Herbicides/pharmacology ; *Weed Control/methods ; *Plant Weeds/drug effects ; *Acetolactate Synthase/antagonists & inhibitors/metabolism ; Agriculture/methods ; }, abstract = {BACKGROUND: A 4-year experiment evaluated the effects of different integrated weed management (IWM) programs on the evolution of a Echinochloa crus-galli population resistant to acetolactate synthase (ALS) inhibitors in a maize cropping system. The programs included the continued use of ALS inhibitors, mixing them with alternative herbicides, or without ALS-inhibitors, in all cases under maize monocrop or a biennial crop rotation.

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

CONCLUSION: At the end of the experiment, the only IWM programs that reduced infestation levels were the one without ALS-inhibitors under soybean rotation, and the one with standard pre-emergence treatments. These findings highlight the effectiveness of crop rotation and alternative herbicides both pre- or post-emergence in controlling E. crus-galli. ALS-inhibitors, while challenged by resistance in E. crus-galli, remain valuable tools for managing other grass weed species in maize. It is crucial to adapt IWM strategies for herbicide-resistant E. crus-galli and other grass weed populations to mitigate the further evolution of resistance. © 2024 Corteva Agriscience. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid39007083, year = {2024}, author = {Chidambaram, SB and Anand, N and Varma, SR and Ramamurthy, S and Vichitra, C and Sharma, A and Mahalakshmi, AM and Essa, MM}, title = {Superoxide dismutase and neurological disorders.}, journal = {IBRO neuroscience reports}, volume = {16}, number = {}, pages = {373-394}, pmid = {39007083}, issn = {2667-2421}, abstract = {Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.}, } @article {pmid39006832, year = {2023}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Combining Multiple Multimodal Speech Features into an Interpretable Index Score for Capturing Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {2353-2357}, pmid = {39006832}, issn = {2308-457X}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {Multiple speech biomarkers have been shown to carry useful information regarding Amyotrophic Lateral Sclerosis (ALS) pathology. We propose a two-step framework to compute optimal linear combinations (indexes) of these biomarkers that are more discriminative and noise-robust than the individual markers, which is important for clinical care and pharmaceutical trial applications. First, we use a hierarchical clustering based method to select representative speech metrics from a dataset comprising 143 people with ALS and 135 age- and sex-matched healthy controls. Second, we analyze three methods of index computation that optimize linear discriminability, Youden Index, and sparsity of logistic regression model weights, respectively, and evaluate their performance with 5-fold cross validation. We find that the proposed indexes are generally more discriminative of bulbar vs non-bulbar onset in ALS than their individual component metrics as well as an equally-weighted baseline.}, } @article {pmid39006831, year = {2023}, author = {Kothare, H and Neumann, M and Liscombe, J and Green, J and Ramanarayanan, V}, title = {Responsiveness, Sensitivity and Clinical Utility of Timing-Related Speech Biomarkers for Remote Monitoring of ALS Disease Progression.}, journal = {Interspeech}, volume = {2023}, number = {}, pages = {2323-2327}, pmid = {39006831}, issn = {2308-457X}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {In this study, we describe the responsiveness of timing-related measures extracted from read speech in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We found that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt is the most responsive measure, of the ones considered in this study, at detecting such change in both pALS with bulbar (n = 35) and non-bulbar onset (n = 94). We further evaluated the sensitivity of speech metrics in tracking disease progression in pALS while their ALSFRS-R speech score remained unchanged at 3 out of a total possible score of 4. We observed that timing-related speech metrics showed significant longitudinal changes even after accounting for learning effects. The findings of this study have the potential to inform disease prognosis and functional outcomes of clinical trials.}, } @article {pmid39006764, year = {2024}, author = {Yang, C and Liu, G and Chen, X and Le, W}, title = {Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier.}, journal = {MedComm}, volume = {5}, number = {7}, pages = {e638}, pmid = {39006764}, issn = {2688-2663}, abstract = {The cerebellum is crucial for both motor and nonmotor functions. Alzheimer's disease (AD), alongside other dementias such as vascular dementia (VaD), Lewy body dementia (DLB), and frontotemporal dementia (FTD), as well as other neurodegenerative diseases (NDs) like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias (SCA), are characterized by specific and non-specific neurodegenerations in central nervous system. Previously, the cerebellum's significance in these conditions was underestimated. However, advancing research has elevated its profile as a critical node in disease pathology. We comprehensively review the existing evidence to elucidate the relationship between cerebellum and the aforementioned diseases. Our findings reveal a growing body of research unequivocally establishing a link between the cerebellum and AD, other forms of dementia, and other NDs, supported by clinical evidence, pathological and biochemical profiles, structural and functional neuroimaging data, and electrophysiological findings. By contrasting cerebellar observations with those from the cerebral cortex and hippocampus, we highlight the cerebellum's distinct role in the disease processes. Furthermore, we also explore the emerging therapeutic potential of targeting cerebellum for the treatment of these diseases. This review underscores the importance of the cerebellum in these diseases, offering new insights into the disease mechanisms and novel therapeutic strategies.}, } @article {pmid39006715, year = {2024}, author = {Suleiman Khoury, Z and Sohail, F and Wang, J and Mendoza, M and Raake, M and Tahoor Silat, M and Reddy Bathinapatta, M and Sadeghzadegan, A and Meghana, P and Paul, J}, title = {Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62310}, pmid = {39006715}, issn = {2168-8184}, abstract = {This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.}, } @article {pmid39006307, year = {2023}, author = {Ayoubi, R and Alshafie, W and Shlaifer, I and Southern, K and McPherson, PS and Laflamme, C and , }, title = {The identification of high-performing antibodies for Sequestosome-1 for use in Western blot, immunoprecipitation and immunofluorescence.}, journal = {F1000Research}, volume = {12}, number = {}, pages = {324}, pmid = {39006307}, issn = {2046-1402}, mesh = {*Sequestosome-1 Protein/immunology/metabolism ; Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western ; Antibodies/immunology ; }, abstract = {Sequestosome-1, encoded by the gene SQSTM1, functions as a bridge between ubiquitinated proteins and the proteasome or autophagosome, thereby regulating protein degradation pathways. Loss of Sequestosome-1 is hypothesized to enhance neurodegeneration progression in several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal disorders (FTD). Sequestosome-1 reproducible research would be facilitated with the availability of well-characterized anti-Sequestosome-1 antibodies. In this study, we characterized seventeen Sequestosome-1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.}, } @article {pmid39005475, year = {2024}, author = {Xie, M and Miller, AS and Pallegar, PN and Umpierre, A and Liang, Y and Wang, N and Zhang, S and Nagaraj, NK and Fogarty, ZC and Ghayal, NB and Oskarsson, B and Zhao, S and Zheng, J and Qi, F and Nguyen, A and Dickson, DW and Wu, LJ}, title = {Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.30.601396}, pmid = {39005475}, issn = {2692-8205}, abstract = {Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.}, } @article {pmid39005384, year = {2024}, author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Bai, J and Shahzad, S and Nedumaran, J and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, P and Ward, M and Todd, P and Barmada, SJ}, title = {TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005384}, issn = {2692-8205}, support = {F31 NS134123/NS/NINDS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS115257/NS/NINDS NIH HHS/United States ; T32 GM145470/GM/NIGMS NIH HHS/United States ; }, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, highly prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a byproduct of TDP43 autoregulation and cleared by nonsense mediated RNA decay (NMD). The sTDP43-encoding transcripts that escape NMD can lead to toxicity but are rapidly degraded post-translationally. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration in vitro and in vivo via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and provide insight into the consequences of aberrant sTDP43 accumulation in disease.}, } @article {pmid39005345, year = {2024}, author = {Rizuan, A and Shenoy, J and Mohanty, P and Dos Passos, PMS and Mercado Ortiz, JF and Bai, L and Viswanathan, R and Wang, SH and Johnson, V and Mamede, LD and Ayala, YM and Ghirlando, R and Mittal, J and Fawzi, NL}, title = {Structural details of helix-mediated TDP-43 C-terminal domain multimerization.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005345}, issn = {2692-8205}, support = {R01 NS116176/NS/NINDS NIH HHS/United States ; }, abstract = {The primarily disordered C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43), a key nuclear protein in RNA metabolism, forms neuronal inclusions in several neurodegenerative diseases. A conserved region (CR, spanning residues 319-341) in CTD forms transient helix-helix contacts important for its higher-order oligomerization and function that are disrupted by ALS-associated mutations. However, the structural details of CR assembly and the explanation for several ALS-associated variants' impact on phase separation and function remain unclear due to challenges in analyzing the dynamic association of TDP-43 CTD using traditional structural biology approaches. By employing an integrative approach, combining biophysical experiments, biochemical assays, AlphaFold2-Multimer (AF2-Multimer), and atomistic simulations, we generated structural models of helical oligomerization of TDP-43 CR. Using NMR, we first established that the native state of TDP-43 CR under physiological conditions is α-helical. Next, alanine scanning mutagenesis revealed that while hydrophobic residues in the CR are important for CR assembly, phase separation and TDP-43 nuclear retention function, polar residues down regulate these processes. Finally, pairing AF2-Multimer modeling with AAMD simulations indicated that dynamic, oligomeric assemblies of TDP-43 that are stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. In conclusion, our results advance the structural understanding of the mechanisms driving TDP-43 function and provide a window into the initial stages of its conversion into pathogenic aggregates.}, } @article {pmid39005286, year = {2024}, author = {Krattli, RP and Do, AH and El-Khatib, SM and Alikhani, L and Markarian, M and Vagadia, AR and Usmani, MT and Madan, S and Baulch, JE and Clark, RJ and Woodruff, TM and Tenner, AJ and Acharya, MM}, title = {Complement C5a receptor 1 blockade reverses cognitive deficits following cranial radiation therapy for brain cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.02.601806}, pmid = {39005286}, issn = {2692-8205}, abstract = {Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are particularly a pressing problem for the survivors of pediatric and low grade glioma (LGG) patients who often live long post-RT. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205, to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. C5aR1 inhibition reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 inhibition in the syngeneic, orthotopic astrocytoma, and glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 is currently in clinical trials for amyotrophic lateral sclerosis (ALS). Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.}, } @article {pmid39005258, year = {2024}, author = {Feringa, FM and Hertog, SJK and Wang, L and Derks, RJE and Kruijff, I and Erlebach, L and Heijneman, J and Miramontes, R and Pömpner, N and Blomberg, N and Olivier-Jimenez, D and Johansen, LE and Cammack, AJ and Giblin, A and Toomey, CE and Rose, IVL and Yuan, H and Ward, M and Isaacs, AM and Kampmann, M and Kronenberg-Versteeg, D and Lashley, T and Thompson, LM and Ori, A and Mohammed, Y and Giera, M and van der Kant, R}, title = {The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39005258}, issn = {2692-8205}, support = {P01 NS084974/NS/NINDS NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; T32 NS115706/NS/NINDS NIH HHS/United States ; }, abstract = {Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.}, } @article {pmid39004530, year = {2024}, author = {Vacchiano, V and Di Stasi, V and Bruni, S and Rizzo, G and Liguori, R}, title = {Thoracic paraspinal muscles denervation assessment in amyotrophic lateral sclerosis: Clinical-neurophysiological correlations and prognostic value.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123133}, doi = {10.1016/j.jns.2024.123133}, pmid = {39004530}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Paraspinal Muscles/physiopathology ; Male ; Middle Aged ; Female ; Prognosis ; Aged ; Electromyography/methods ; Muscle Denervation/methods ; Adult ; }, } @article {pmid39004370, year = {2024}, author = {Hajdukiewicz, H and Hajdukiewicz, M and Ruiz-Villanueva, V and Radecki-Pawlik, A and Zawiejska, J}, title = {Exploring historical changes in mountain river hydrodynamics induced by human impact.}, journal = {The Science of the total environment}, volume = {948}, number = {}, pages = {174742}, doi = {10.1016/j.scitotenv.2024.174742}, pmid = {39004370}, issn = {1879-1026}, abstract = {During the 20th-century many mountain rivers in Europe were subjected to intensive human impacts which substantially modified their channel morphology. How these changes affected river hydrodynamics and response to floods remains uncertain. In this work, we perform hydraulic modelling using data from archival aerial photos to explore relations between hydraulic parameters of floods and human-induced channel incision occurring on the Czarny Dunajec River (Polish Carpathians) between 1964 and 2012. Data on vertical position of the channel used for two-dimensional modelling of flood flows were extracted (as Digital Elevation Models DEMs) from archival aerial photos from 1964 and 1983 and ALS (Airborne Laser Skanning)-derived DEM from 2012. Water depth, flow velocity, bed shear stress, and sediment critical diameter were modelled for four flood scenarios (2-year, 5-year, 20-year, and 50-year floods) as well as the extent of flooded area and additionally the grain size of channel sediment was calculated. The values of water depth, flow velocity, bed shear stress and sediment critical diameter increased significantly between 1964 and 1983, especially for 20-year and 50-year floods. Only the flow velocity within the floodplain zone did not increase for the two largest flood scenarios due to the expansion of riparian forest in the second half of the twentieth century. The increase in flow rate was accompanied by a progressive reduction of the extent of flooded area, especially between 1964 and 1983, as well as by increase in mean grain size of channel sediment. Between 1983 and 2012 changes in hydraulic parameters were less pronounced, and coarser and well packed channel sediment dominated on the river bed. Our work demonstrates that reconstruction of past river hydrodynamics, rather than river state at time horizons, can give essential insights into functioning of the river channel and floodplain during the intensification of human impacts after 1950s.}, } @article {pmid39003629, year = {2024}, author = {Yao, S and Yin, H and Li, Y and Yang, Q and Yuan, S and Deng, W}, title = {Cytochrome P450 CYP81A104 in Eleusine indica confers resistance to multiherbicide with different modes of action.}, journal = {Pest management science}, volume = {80}, number = {11}, pages = {5791-5798}, doi = {10.1002/ps.8310}, pmid = {39003629}, issn = {1526-4998}, support = {32372569//National Natural Science Foundation of China/ ; 137050535//Qing Lan Project of Yangzhou University/ ; }, mesh = {*Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; *Eleusine/genetics/drug effects/enzymology ; Acetolactate Synthase/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Arabidopsis/genetics/drug effects/enzymology ; Plant Weeds/drug effects/genetics ; Imidazoles ; }, abstract = {BACKGROUND: Developing herbicide-resistant (HR) crop cultivars is an efficient way to control weeds and minimize crop yield losses. However, widespread and long-term herbicide application has led to the evolution of resistant weeds. Here, we established a resistant (R) E. indica population, collected from imidazolinone-resistant rice cultivar fields.

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

CONCLUSION: This study confirmed that the CYP81A104 gene endowed resistance to multiherbicides with different modes-of-action. Our findings provide an insight into the molecular characteristics of resistance and contribute to formulating an appropriate strategy for weed management in HR crops. © 2024 Society of Chemical Industry.}, } @article {pmid39002811, year = {2024}, author = {Huin, V and Blum, D and Delforge, V and Cailliau, E and Djeziri, S and Dujardin, K and Genet, A and Viard, R and Attarian, S and Bruneteau, G and Cassereau, J and Genestet, S and Kaminsky, AL and Soriani, MH and Lefilliatre, M and Couratier, P and Pittion-Vouyovitch, S and Esselin, F and De La Cruz, E and Guy, N and Kolev, I and Corcia, P and Cintas, P and Desnuelle, C and Buée, L and Danel-Brunaud, V and Devos, D and Rolland, AS}, title = {Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106603}, doi = {10.1016/j.nbd.2024.106603}, pmid = {39002811}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Female ; Male ; Middle Aged ; *Caffeine ; *Disease Progression ; *Polymorphism, Single Nucleotide ; Aged ; *Receptor, Adenosine A2A/genetics ; *Cytochrome P-450 CYP1A2/genetics ; Cognition/physiology/drug effects ; Prospective Studies ; Cytochrome P-450 CYP1A1/genetics ; Receptors, Aryl Hydrocarbon/genetics ; Adult ; Cognitive Dysfunction/genetics ; Riluzole/therapeutic use ; Central Nervous System Stimulants/therapeutic use ; Basic Helix-Loop-Helix Transcription Factors ; }, abstract = {Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.}, } @article {pmid39002563, year = {2024}, author = {Shih, PC and Wei, JCC}, title = {Response to Hasan et al's "Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {5}, pages = {e137-e138}, doi = {10.1016/j.jaad.2024.06.076}, pmid = {39002563}, issn = {1097-6787}, } @article {pmid39001793, year = {2024}, author = {Gao, J and Okolo, O and Siedlak, SL and Friedland, RP and Wang, X}, title = {Ferritin is closely associated with microglia in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {11}, pages = {917-926}, pmid = {39001793}, issn = {1554-6578}, support = {HHSN275200900011C/HD/NICHD NIH HHS/United States ; RF1AG066578/NH/NIH HHS/United States ; AARG-22-923849/ALZ/Alzheimer's Association/United States ; //Brain and Tissue Bank for Developmental Disorders/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; RF1 AG065342/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Microglia/metabolism/pathology ; *Ferritins/metabolism ; Humans ; *Mice, Transgenic ; Animals ; Female ; Male ; Mice ; Middle Aged ; *Spinal Cord/pathology/metabolism ; Aged ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase/metabolism/genetics ; }, abstract = {Iron deposition is a hallmark of amyotrophic lateral sclerosis (ALS) and has been strongly implicated in its pathogenesis. As a byproduct of cellular oxidative stress, iron dysregulation modifies basal levels of the regulatory iron-binding protein ferritin. Examination of thoracic and lumbar spinal cord tissues found increased ferritin immunostaining in white matter axons that corresponded to areas of increased microgliosis in 8 ALS patients versus 8 normal subjects. Gray matter areas containing the motor neurons also demonstrated increased ferritin and microglia in ALS compared to controls but at lower levels than in the white matter. Motor neurons with or without TDP-43 inclusions did not demonstrate either increased ferritin or associated microglial activation. We also observed an association of ferritin with microglia in cerebral cortical tissue samples of ALS cases and in the spinal cord tissues of transgenic mice expressing the SOD1G93A mutation. Elevated ferritin levels were detected in the insoluble fraction from spinal cord tissues of individuals with ALS. These findings suggest that activated microglia and increased ferritin may play significant roles in ALS progression since they are found closely associated in areas of axonal and cortical degeneration.}, } @article {pmid39000814, year = {2024}, author = {Fan, S and Jing, S and Xu, W and Wu, B and Li, M and Jing, H}, title = {Extraction of Moso Bamboo Parameters Based on the Combination of ALS and TLS Point Cloud Data.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {13}, pages = {}, pmid = {39000814}, issn = {1424-8220}, support = {LTGC23C160002//Zhejiang Provincial Natural Science Foundation of China/ ; 2021LFR057//Research Fund of Zhejiang A&F University/ ; 2023LFK141//Research Fund of Zhejiang A&F University/ ; }, mesh = {*Algorithms ; Sasa ; Lasers ; Poaceae ; }, abstract = {Extracting moso bamboo parameters from single-source point cloud data has limitations. In this article, a new approach for extracting moso bamboo parameters using airborne laser scanning (ALS) and terrestrial laser scanning (TLS) point cloud data is proposed. Using the field-surveyed coordinates of plot corner points and the Iterative Closest Point (ICP) algorithm, the ALS and TLS point clouds were aligned. Considering the difference in point distribution of ALS, TLS, and the merged point cloud, individual bamboo plants were segmented from the ALS point cloud using the point cloud segmentation (PCS) algorithm, and individual bamboo plants were segmented from the TLS and the merged point cloud using the comparative shortest-path (CSP) method. The cylinder fitting method was used to estimate the diameter at breast height (DBH) of the segmented bamboo plants. The accuracy was calculated by comparing the bamboo parameter values extracted by the above methods with reference data in three sample plots. The comparison results showed that by using the merged data, the detection rate of moso bamboo plants could reach up to 97.30%; the R[2] of the estimated bamboo height was increased to above 0.96, and the root mean square error (RMSE) decreased from 1.14 m at most to a range of 0.35-0.48 m, while the R[2] of the DBH fit was increased to a range of 0.97-0.99, and the RMSE decreased from 0.004 m at most to a range of 0.001-0.003 m. The accuracy of moso bamboo parameter extraction was significantly improved by using the merged point cloud data.}, } @article {pmid39000336, year = {2024}, author = {Bodai, L and Borosta, R and Ferencz, Á and Kovács, M and Zsindely, N}, title = {The Role of miR-137 in Neurodegenerative Disorders.}, journal = {International journal of molecular sciences}, volume = {25}, number = {13}, pages = {}, pmid = {39000336}, issn = {1422-0067}, support = {OTKA 145898//National Research, Development and Innovation Office [Hungary]/ ; }, mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; Gene Expression Regulation ; }, abstract = {Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.}, } @article {pmid39000168, year = {2024}, author = {Ciuro, M and Sangiorgio, M and Cacciato, V and Cantone, G and Fichera, C and Salvatorelli, L and Magro, G and Leanza, G and Vecchio, M and Valle, MS and Gulino, R}, title = {Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.}, journal = {International journal of molecular sciences}, volume = {25}, number = {13}, pages = {}, pmid = {39000168}, issn = {1422-0067}, support = {2015MJBEM2_006//the Italian "Ministero dell'Istruzione, dell'Università e della Ricerca"/ ; }, mesh = {Animals ; *Motor Neurons/drug effects/metabolism/pathology ; *Mitochondrial Dynamics/drug effects ; Mice ; *Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Cholera Toxin/metabolism ; Saporins ; Quinazolinones/pharmacology ; Neuronal Plasticity/drug effects ; Male ; Mitochondria/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.}, } @article {pmid38999600, year = {2024}, author = {Chakraborty, N and Das, A and Pal, S and Roy, S and Sil, SK and Adak, MK and Hassanzamman, M}, title = {Exploring Aluminum Tolerance Mechanisms in Plants with Reference to Rice and Arabidopsis: A Comprehensive Review of Genetic, Metabolic, and Physiological Adaptations in Acidic Soils.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999600}, issn = {2223-7747}, abstract = {Aluminum (Al) makes up a third of the Earth's crust and is a widespread toxic contaminant, particularly in acidic soils. It impacts crops at multiple levels, from cellular to whole plant systems. This review delves into Al's reactivity, including its cellular transport, involvement in oxidative redox reactions, and development of specific metabolites, as well as the influence of genes on the production of membrane channels and transporters, alongside its role in triggering senescence. It discusses the involvement of channel proteins in calcium influx, vacuolar proton pumping, the suppression of mitochondrial respiration, and the initiation of programmed cell death. At the cellular nucleus level, the effects of Al on gene regulation through alterations in nucleic acid modifications, such as methylation and histone acetylation, are examined. In addition, this review outlines the pathways of Al-induced metabolic disruption, specifically citric acid metabolism, the regulation of proton excretion, the induction of specific transcription factors, the modulation of Al-responsive proteins, changes in citrate and nucleotide glucose transporters, and overall metal detoxification pathways in tolerant genotypes. It also considers the expression of phenolic oxidases in response to oxidative stress, their regulatory feedback on mitochondrial cytochrome proteins, and their consequences on root development. Ultimately, this review focuses on the selective metabolic pathways that facilitate Al exclusion and tolerance, emphasizing compartmentalization, antioxidative defense mechanisms, and the control of programmed cell death to manage metal toxicity.}, } @article {pmid38999592, year = {2024}, author = {Li, Q and Wang, H and Yu, J and Zhang, W and Guo, W and Liu, Y}, title = {Metabolism-Based Herbicide Resistance to Mesosulfuron-methyl and Identification of Candidate Genes in Bromus japonicus.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {13}, pages = {}, pmid = {38999592}, issn = {2223-7747}, support = {23JCQNJC00450//Tianjin Natural Science Foundation/ ; 2021CXGC010811//Key R&D Program of Shandong Province, China/ ; }, abstract = {The evolved resistance of Bromus japonicus Houtt. to ALS-inhibiting herbicides is well established. Previous studies have primarily focused on target-site resistance; however, non-target-site resistance has not been well characterized. This investigation demonstrated that ALS gene sequencing did not detect any previously known resistance mutations in a mesosulfuron-methyl-resistant (MR) population, and notably, treatment with the P450 monooxygenase (P450) inhibitor malathion markedly heightened susceptibility to mesosulfuron-methyl. Utilizing UPLC-MS/MS analysis confirmed elevated mesosulfuron-methyl metabolism in MR plants. The integration of Isoform Sequencing (Iso-Seq) and RNA Sequencing (RNA-Seq) facilitated the identification of candidate genes associated with non-target sites in a subpopulation with two generations of herbicide selection. Through qRT-PCR analysis, 21 differentially expressed genes were characterized, and among these, 10 genes (comprising three P450s, two glutathione S-transferases, one glycosyltransferase, two ATP-binding cassette transporters, one oxidase, and one hydrolase) exhibited constitutive upregulation in resistant plants. Our findings substantiated that increased herbicide metabolism is a driving force behind mesosulfuron-methyl resistance in this B. japonicus population.}, } @article {pmid38999371, year = {2024}, author = {Dell'Anna, G and Fanti, L and Fanizza, J and Barà, R and Barchi, A and Fasulo, E and Elmore, U and Rosati, R and Annese, V and Laterza, L and Fuccio, L and Azzolini, F and Danese, S and Mandarino, FV}, title = {VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.}, journal = {Journal of clinical medicine}, volume = {13}, number = {13}, pages = {}, pmid = {38999371}, issn = {2077-0383}, abstract = {Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.}, } @article {pmid38997748, year = {2024}, author = {Kato, C and Ueda, K and Morimoto, S and Takahashi, S and Nakamura, S and Ozawa, F and Ito, D and Daté, Y and Okada, K and Kobayashi, N and Nakahara, J and Okano, H}, title = {Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery.}, journal = {Inflammation and regeneration}, volume = {44}, number = {1}, pages = {32}, pmid = {38997748}, issn = {1880-9693}, support = {JP21H05278//Japan Society for the Promotion of Science/ ; JP22K15736//Japan Society for the Promotion of Science/ ; JP22K07500//Japan Society for the Promotion of Science/ ; JP20H00485//Japan Society for the Promotion of Science/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1123046//Japan Agency for Medical Research and Development/ ; JP23kk0305024//Japan Agency for Medical Research and Development/ ; JP21wm0425009//Japan Agency for Medical Research and Development/ ; JP22bm0804003//Japan Agency for Medical Research and Development/ ; JP22ek0109616//Japan Agency for Medical Research and Development/ ; JP23bm1423002//Japan Agency for Medical Research and Development/ ; }, abstract = {BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.

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

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

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

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

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

CONCLUSIONS: We provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.}, } @article {pmid38997630, year = {2024}, author = {Staderini, T and Bigi, A and Lagrève, C and Marzi, I and Bemporad, F and Chiti, F}, title = {Biophysical characterization of the phase separation of TDP-43 devoid of the C-terminal domain.}, journal = {Cellular & molecular biology letters}, volume = {29}, number = {1}, pages = {104}, pmid = {38997630}, issn = {1689-1392}, support = {AriSLA//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; project TDP-43-STRUCT//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica/ ; PRIN Project 2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; Fondi di Ateneo 2021//Università degli studi di Firenze/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *Protein Domains ; Fluorescence Recovery After Photobleaching ; Phase Separation ; }, abstract = {BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE) are associated with deposition of cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons. One complexity of this process lies in the ability of TDP-43 to form liquid-phase membraneless organelles in cells. Previous work has shown that the recombinant, purified, prion-like domain (PrLD) forms liquid droplets in vitro, but the behaviour of the complementary fragment is uncertain.

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

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

CONCLUSIONS: Similarly to PrLD, PrLD-less TDP-43 forms liquid droplets in vitro through liquid-liquid phase separation (LLPS), unlike the full-length protein that rather undergoes liquid-solid phase separation (LSPS). These results offer a rationale of the complex electrostatic forces governing phase separation of full-length TDP-43 and its fragments. On the one hand, PrLD-less TDP-43 has a low pI and oppositively charged domains, and LLPS is inhibited by salts, which attenuate inter-domain electrostatic attractions. On the other hand, PrLD is positively charged due to a high isoionic point (pI) and LLPS is therefore promoted by salts and pH increases as they both reduce electrostatic repulsions. By contrast, full-length TDP-43 undergoes LSPS most favourably at its pI, with positive and negative salt dependences at lower and higher pH, respectively, depending on whether repulsive or attractive forces dominate, respectively.}, } @article {pmid38996790, year = {2024}, author = {Alqahtani, A and Alsubai, S and Sha, M and Dutta, AK and Zhang, YD}, title = {Intellectual assessment of amyotrophic lateral sclerosis using deep resemble forward neural network.}, journal = {Neural networks : the official journal of the International Neural Network Society}, volume = {178}, number = {}, pages = {106478}, doi = {10.1016/j.neunet.2024.106478}, pmid = {38996790}, issn = {1879-2782}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications ; Humans ; *Neural Networks, Computer ; Deep Learning ; Algorithms ; Reproducibility of Results ; Machine Learning ; }, abstract = {ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disorder causing profound physical disability that severely impairs a patient's life expectancy and quality of life. It also leads to muscular atrophy and progressive weakness of muscles due to insufficient nutrition in the body. At present, there are no disease-modifying therapies to cure ALS, and there is a lack of preventive tools. The general clinical assessments are based on symptom reports, neurophysiological tests, neurological examinations, and neuroimaging. But, these techniques possess various limitations of low reliability, lack of standardized protocols, and lack of sensitivity, especially in the early stages of disease. So, effective methods are required to detect the progression of the disease and minimize the suffering of patients. Extensive studies concentrated on investigating the causes of neurological disease, which creates a barrier to precise identification and classification of genes accompanied with ALS disease. Hence, the proposed system implements a deep RSFFNNCNN (Resemble Single Feed Forward Neural Network-Convolutional Neural Network) algorithm to effectively classify the clinical associations of ALS. It involves the addition of custom weights to the kernel initializer and neutralizer 'k' parameter to each hidden layer in the network. This is done to increase the stability and learning ability of the classifier. Additionally, the comparison of the proposed approach is performed with SFNN (Single Feed NN) and ML (Machine Learning) based algorithms, namely, NB (Naïve Bayes), XGBoost (Extreme Gradient Boosting) and RF (Random Forest), to estimate the efficacy of the proposed model. The reliability of the proposed algorithm is measured by deploying performance metrics such as precision, recall, F1 score, and accuracy.}, } @article {pmid38996764, year = {2024}, author = {Montero, AS and Aliouat, I and Ribon, M and Canney, M and Goldwirt, L and Mourah, S and Berriat, F and Lobsiger, CS and Pradat, PF and Salachas, F and Bruneteau, G and Carpentier, A and Boillée, S}, title = {Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.}, journal = {EBioMedicine}, volume = {106}, number = {}, pages = {105235}, pmid = {38996764}, issn = {2352-3964}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/therapy ; Female ; *Disease Models, Animal ; Mice ; *Spinal Cord/metabolism ; *Blood-Brain Barrier/metabolism ; *Insulin-Like Growth Factor I/metabolism ; Mice, Transgenic ; Humans ; Motor Neurons/metabolism ; Ultrasonic Waves ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).

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

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

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

FUNDING: Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).}, } @article {pmid38996643, year = {2024}, author = {Sheehan, Y and Cochrane, A and Treloar, C and Grebely, J and Tedla, N and Lloyd, AR and Lafferty, L}, title = {Understanding hepatitis C virus (HCV) health literacy and educational needs among people in prison to enhance HCV care in prisons.}, journal = {The International journal on drug policy}, volume = {130}, number = {}, pages = {104516}, doi = {10.1016/j.drugpo.2024.104516}, pmid = {38996643}, issn = {1873-4758}, mesh = {Humans ; Male ; *Health Literacy ; *Hepatitis C ; *Prisoners/psychology ; Adult ; Australia ; *Prisons ; Middle Aged ; Health Knowledge, Attitudes, Practice ; Substance Abuse, Intravenous ; }, abstract = {BACKGROUND: Hepatitis C virus (HCV) is a significant concern within prison populations. Provision of HCV testing and treatment for people in prison is expanding and a key component of global elimination efforts. Despite growing service availability, several challenges remain in HCV testing and treatment engagement during incarceration. The PIVOT study demonstrated that a 'one-stop-shop' intervention (point-of-care HCV RNA testing, Fibroscan®, nurse-led clinical assessment, and fast-tracked direct-acting antiviral prescription) enhanced HCV testing and treatment at a reception prison in Australia. Utilising Squier et al's Health Literacy Skills Framework, this analysis aimed to understand HCV health literacy and educational needs among people at a reception prison in Australia.

METHODS: Semi-structured interviews were conducted with twenty-four male PIVOT study participants. Purposive sampling ensured comparable representation of those with: 1) prior HCV testing history (standard pathology / no prior testing), and 2) injecting drug use history (IDU; ever / never).

RESULTS: Varied HCV health literacy levels and educational needs were evident amongst people in prison. Whilst those with multiple incarceration episodes and IDU history (prior knowledge) appeared to have stronger HCV health literacy than those without, substantial gaps in HCV health literacy were evident. Knowledge of HCV transmission risks in prison was high, and most understood the importance of HCV testing and treatment in prison (comprehension), but ability to engage with HCV testing and treatment services, participation in safe injecting behaviours (health-related behaviours), and knowledge of re-infection and re-treatment, within the context of the prison environment, were suboptimal. There was a general desire for increased HCV education in prison.

CONCLUSION: Gaps in HCV health literacy among people in prison were evident, indicating opportunities for improvement. A targeted HCV education program for people in prison, addressing the gaps identified in this analysis, may enhance HCV testing, treatment, and prevention by fostering stronger HCV health literacy among people in prison.}, } @article {pmid38995133, year = {2024}, author = {Bacigalupo, I and Finocchietti, M and Paoletti, O and Bargagli, AM and Brunori, P and Lombardi, N and Sciancalepore, F and Agabiti, N and Kirchmayer, U}, title = {Incidence and prevalence of Amyotrophic Lateral Sclerosis in three Italian Regions: a study based on health administrative databases.}, journal = {Epidemiologia e prevenzione}, volume = {48}, number = {3}, pages = {201-209}, doi = {10.19191/EP24.3.A710.055}, pmid = {38995133}, issn = {1120-9763}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Italy/epidemiology ; Incidence ; Prevalence ; Male ; Aged ; Female ; Retrospective Studies ; Middle Aged ; Adult ; Databases, Factual ; Aged, 80 and over ; Sex Distribution ; Adolescent ; Archives ; Algorithms ; Young Adult ; Age Distribution ; }, abstract = {OBJECTIVES: to estimate Amyotrophic Lateral Sclerosis (ALS) incidence and prevalence in three Italian Regions (Lazio, Tuscany, and Umbria), using health administrative databases.

DESIGN: retrospective population-based study.

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

MAIN OUTCOMES MEASURES: prevalence and incidence rates.

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

CONCLUSIONS: ALS prevalence and incidence in three Central Italy Regions are rather similar, but slightly higher than those previously reported. This finding is plausible, given that previous results relate to at least ten years ago and evidenced increasing trends. Overall, the results of this paper encourage the use of administrative data to produce occurrence estimates, useful to both epidemiological surveillance and research and healthcare policies.}, } @article {pmid38992244, year = {2024}, author = {Hunt von Herbing, I}, title = {Energetic Costs of Stress in Developing Fishes: Quantifying Allostasis and Allostatic Load.}, journal = {Integrative and comparative biology}, volume = {64}, number = {3}, pages = {1019-1033}, doi = {10.1093/icb/icae094}, pmid = {38992244}, issn = {1557-7023}, support = {GP64231//University of North Texas/ ; }, mesh = {Animals ; *Zebrafish/physiology/growth & development ; *Allostasis/physiology ; *Energy Metabolism ; *Stress, Physiological ; Larva/growth & development/physiology ; Yolk Sac/physiology ; Hypoxia ; }, abstract = {Stress exerts negative effects on fish health through stimulation of the hypothalamic-pituitary-interrenal axis and autonomic nervous system, resulting in heightened neural and neuroendocrine responses. Energetic investment and physiological adaptation are then required to re-establish homeostatic stability or reach a new allostatic state. The cost of the energetic investment is referred to as allostatic load (AL). While determining the sources of stress and assessing their consequences have resulted in estimates of AL, most of this work has been conducted in adult mammals and humans; no ALs exist for developing fish. From a series of experiments on a model species, zebrafish (Danio rerio), whose yolk-sac larvae were exposed to two chronic stressors (high-temperature and hypoxia), ALs were quantified based on biomarkers of ontogenetic changes in growth, morphometrics, and metabolic activities. Results showed that for zebrafish yolk-sac larvae, chronic stress imposed high AL and, thus, high total allostatic energetic costs, (Rt (AL)), because of prolonged energy demand in the face of limited resources (e.g., yolk). Under severe chronic stress, energetic costs were sufficiently large that energy-limited developing fish may not be able to fully compensate, resulting in maladaptive responses from allostatic overload, leading either to death or to novel allostatic states, possibly more resilient to environmental change.}, } @article {pmid38991324, year = {2024}, author = {Reis, J and Spencer, PS}, title = {An introduction to environmental neurotoxicology: Lessons from a clinical perspective.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123108}, doi = {10.1016/j.jns.2024.123108}, pmid = {38991324}, issn = {1878-5883}, mesh = {Humans ; *Environmental Exposure/adverse effects ; *Neurotoxicity Syndromes/etiology ; Animals ; }, abstract = {In 1992, the Committee on Neurotoxicology and Models for Assessing Risk of the National Academy of Sciences in Washington DC focused with a scientific perspective on the identification of substances with neurotoxic potential, studies of exposed populations, risk assessment, and biologic markers of disease. This Committee recommended: "all physicians should be trained to take a thorough occupational-exposure history and to be aware of other possible sources of toxic exposure". Although convened after several outbreaks of neurotoxic syndromes, clinical neurological considerations were lacking. After defining keys words, namely Environment, Neurotoxicology and Neurotoxicants, we present some demonstrative cases; e.g., the Epidemic Neuropathy in Cuba, Minamata disease, ALS/PDC on Guam, and the ALS hot spot in the French Alps. Always with a clinical and practical approach, we will then review the milieux that contain and convey potential neurotoxicants, the different exposure routes and the clinical presentations. Drawing lessons from clinical cases, we offer some thoughts concerning the future of Environmental Neurotoxicology (ENT). Pointing notably to the diffuse chemical contamination of ecosystems and living beings, including Homo sapiens, we question the real impact of agents with neurotoxic potential on the human brain, considering the effects, for example, of air pollution, endocrine disruptors and nanoparticles. Concern is expressed over the lack of knowledge of the non-monotonic kinetics of many of these chemicals, the major concern being related to mixtures and low-dose exposures, as well as the delayed appearance in clinical expression of prevalent neurodegenerative diseases.}, } @article {pmid38991167, year = {2024}, author = {Cave, R}, title = {How People Living With Amyotrophic Lateral Sclerosis Use Personalized Automatic Speech Recognition Technology to Support Communication.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {11}, pages = {4186-4202}, doi = {10.1044/2024_JSLHR-24-00097}, pmid = {38991167}, issn = {1558-9102}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; *Speech Recognition Software ; Male ; Female ; *Dysarthria/etiology/psychology/rehabilitation ; Middle Aged ; Aged ; Communication ; Communication Aids for Disabled ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive, ultimately fatal disease causing progressive muscular weakness. Most people living with ALS (plwALS) experience dysarthria, eventually becoming unable to communicate using natural speech. Many wish to use speech for as long as possible. Personalized automated speech recognition (ASR) model technology, such as Google's Project Relate, is argued to better recognize speech with dysarthria, supporting maintenance of understanding through real-time captioning. The objectives of this study are how plwALS and communication partners use Relate in everyday conversation over a period of up to 12 months and how it may change with any decline in speech over time.

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

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

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

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

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

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

TRIAL REGISTRATION: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.}, } @article {pmid38990842, year = {2024}, author = {Yip, PK and Pizzasegola, C and Gladman, S and Biggio, ML and Marino, M and Jayasinghe, M and Ullah, F and Dyall, SC and Malaspina, A and Bendotti, C and Michael-Titus, A}, title = {Correction: The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0307246}, pmid = {38990842}, issn = {1932-6203}, abstract = {[This corrects the article DOI: 10.1371/journal.pone.0061626.].}, } @article {pmid38989937, year = {2025}, author = {Locatelli, M and Farina, C}, title = {Role of copper in central nervous system physiology and pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1058-1068}, pmid = {38989937}, issn = {1673-5374}, abstract = {Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.}, } @article {pmid38989900, year = {2025}, author = {Marchica, V and Biasetti, L and Barnard, J and Li, S and Nikolaou, N and Frosch, MP and Lucente, DE and Eldaief, M and King, A and Fanto, M and Troakes, C and Houart, C and Smith, BN}, title = {Annexin A11 mutations are associated with nuclear envelope dysfunction in vivo and in human tissues.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {1}, pages = {276-290}, pmid = {38989900}, issn = {1460-2156}, support = {//Motor Neurone Disease Association UK/ ; /MRF/MRF/United Kingdom ; //Van Geest Foundation/ ; //MNDA Studentship/ ; //Project Grants/ ; 855-791//Project Grant by the MNDA/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Zebrafish ; *Nuclear Envelope/metabolism/genetics ; *Mutation ; *Annexins/genetics/metabolism ; Lamin Type B/genetics/metabolism ; Frontotemporal Dementia/genetics/pathology ; Male ; Spinal Cord/metabolism/pathology ; }, abstract = {Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterized the phenotypes induced by a genetic loss-of-function and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human wild-type Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterized by Lamin B2 mislocalization. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS ± frontotemporal dementia patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.}, } @article {pmid38989463, year = {2024}, author = {Pasternack, N and Doucet-O'Hare, T and Johnson, K and , and Paulsen, O and Nath, A}, title = {Endogenous retroviruses are dysregulated in ALS.}, journal = {iScience}, volume = {27}, number = {7}, pages = {110147}, pmid = {38989463}, issn = {2589-0042}, abstract = {Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease with no cure. Human endogenous retroviruses (HERVs) have been implicated in its pathogenesis but their relevance to ALS is not fully understood. We examined bulk RNA-seq data from almost 2,000 ALS and unaffected control samples derived from the cortex and spinal cord. Using different methods of feature selection, including differential expression analysis and machine learning, we discovered that transcription of HERV-K loci 1q22 and 8p23.1 were significantly upregulated in the spinal cord of individuals with ALS. Additionally, we identified a subset of ALS patients with upregulated HERV-K expression in the cortex and spinal cord. We also found the expression of HERV-K loci 19q11 and 8p23.1 was correlated with protein coding genes previously implicated in ALS and dysregulated in ALS patients in this study. These results clarify the association of HERV-K and ALS and highlight specific genes in the pathobiology of late-stage ALS.}, } @article {pmid38988889, year = {2024}, author = {Ansari, U and Alam, M and Nadora, D and Muttalib, Z and Chen, V and Taguinod, I and FitzPatrick, M and Wen, J and Ansari, Z and Lui, F}, title = {Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review.}, journal = {AIMS neuroscience}, volume = {11}, number = {2}, pages = {166-177}, pmid = {38988889}, issn = {2373-7972}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and intricate neurodegenerative disease that impacts upper and lower motor neurons within the central nervous system, leading to their progressive destruction. Despite extensive research, the pathogenesis of this multifaceted disease remains elusive. The United States Food and Drug Administration (FDA) has granted approval for seven medications designed to address ALS and mitigate its associated symptoms. These FDA-sanctioned treatments are Qalsody, Relyvrio, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. In this review, the effects of these seven drugs on ALS based on their mechanism of action, dosing, and clinical presentations are comprehensively summarized. Each medication offers a distinct approach to manage ALS, aiming to alleviate the burdensome symptoms and slow the disease's progression, thereby improving the quality of life for individuals affected by this neurological condition. However, despite these advancements in pharmaceutical interventions, finding a definitive cure for ALS remains a significant challenge. Continuous investigation into ALS pathophysiology and therapeutic avenues remains imperative, necessitating further research collaborations and innovative approaches to unravel the complex mechanisms underlying this debilitating condition.}, } @article {pmid38988205, year = {2024}, author = {Arnaldi, P and Casarotto, E and Relucenti, M and Bellese, G and Gagliani, MC and Crippa, V and Castagnola, P and Cortese, K}, title = {A NSC-34 cell line-derived spheroid model: Potential and challenges for in vitro evaluation of neurodegeneration.}, journal = {Microscopy research and technique}, volume = {87}, number = {11}, pages = {2785-2800}, doi = {10.1002/jemt.24651}, pmid = {38988205}, issn = {1097-0029}, support = {PRIN2020PBS5MJ//Ministero dell'Università e della Ricerca/ ; PRIN2022KSJZF5//Ministero dell'Università e della Ricerca/ ; //University of Genoa/ ; 100008-2022-KC-FRA_ANATOMIA//Fondi Ricerca Ateneo/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; }, mesh = {*Spheroids, Cellular/pathology ; Animals ; Mice ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Line ; Motor Neurons/pathology ; Cell Survival ; Neurodegenerative Diseases/pathology ; Cell Culture Techniques/methods ; Spinal Cord/cytology/pathology ; Hydrogels/chemistry ; Humans ; Mitochondria/metabolism ; }, abstract = {Three-dimensional (3D) spheroid models aim to bridge the gap between traditional two-dimensional (2D) cultures and the complex in vivo tissue environment. These models, created by self-clustering cells to mimic a 3D environment with surrounding extracellular framework, provide a valuable research tool. The NSC-34 cell line, generated by fusing mouse spinal cord motor neurons and neuroblastoma cells, is essential for studying neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), where abnormal protein accumulation, such as TAR-DNA-binding protein 43 (TDP-43), occurs in affected nerve cells. However, NSC-34 behavior in a 3D context remains underexplored, and this study represents the first attempt to create a 3D model to determine its suitability for studying pathology. We generated NSC-34 spheroids using a nonadhesive hydrogel-based template and characterized them for 6 days. Light microscopy revealed that NSC-34 cells in 3D maintained high viability, a distinct round shape, and forming stable membrane connections. Scanning electron microscopy identified multiple tunnel-like structures, while ultrastructural analysis highlighted nuclear bending and mitochondria alterations. Using inducible GFP-TDP-43-expressing NSC-34 spheroids, we explored whether 3D structure affected TDP-43 expression, localization, and aggregation. Spheroids displayed nuclear GFP-TDP-43 expression, albeit at a reduced level compared with 2D cultures and generated both TDP-35 fragments and TDP-43 aggregates. This study sheds light on the distinctive behavior of NSC-34 in 3D culture, suggesting caution in the use of the 3D model for ALS or TDP-43 pathologies. Yet, it underscores the spheroids' potential for investigating fundamental cellular mechanisms, cell adaptation in a 3D context, future bioreactor applications, and drug penetration studies. RESEARCH HIGHLIGHTS: 3D spheroid generation: NSC-34 spheroids, developed using a hydrogel-based template, showed high viability and distinct shapes for 6 days. Structural features: advanced microscopy identified tunnel-like structures and nuclear and mitochondrial changes in the spheroids. Protein dynamics: the study observed how 3D structures impact TDP-43 behavior, with altered expression but similar aggregation patterns to 2D cultures. Research implications: this study reveals the unique behavior of NSC-34 in 3D culture, suggests a careful approach to use this model for ALS or TDP-43 pathologies, and highlights its potential in cellular mechanism research and drug testing applications.}, } @article {pmid38988008, year = {2025}, author = {Murakami, A and Koga, S and Fujioka, S and White, AE and Bieniek, KF and Sekiya, H and DeJesus-Hernandez, M and Finch, NA and van Blitterswijk, M and Nakamura, M and Tsuboi, Y and Murray, ME and Wszolek, ZK and Dickson, DW}, title = {Upper motor neuron-predominant motor neuron disease presenting as atypical parkinsonism: A clinicopathological study.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {1}, pages = {e13286}, pmid = {38988008}, issn = {1750-3639}, support = {P01-AG03949/GF/NIH HHS/United States ; R01-AG062348/GF/NIH HHS/United States ; 1U19AG063911/GF/NIH HHS/United States ; P30-AG062677/GF/NIH HHS/United States ; FAIN: U19AG063911/GF/NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01-NS121125/GF/NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; RF1-NS123052/GF/NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; R01 NS121125/NS/NINDS NIH HHS/United States ; U54 NS100693/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; U54-NS100693/GF/NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Motor Neuron Disease/pathology/diagnosis ; *Parkinsonian Disorders/pathology/diagnosis ; Aged, 80 and over ; Motor Neurons/pathology ; Amyotrophic Lateral Sclerosis/pathology/diagnosis ; Supranuclear Palsy, Progressive/pathology/diagnosis ; DNA-Binding Proteins/metabolism ; Corticobasal Degeneration/pathology/diagnosis ; Diagnosis, Differential ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by upper and lower motor neuron signs. There are, however, cases where upper motor neurons (UMNs) are predominantly affected, leading to clinical presentations of UMN-dominant ALS or primary lateral sclerosis. Furthermore, cases exhibiting an UMN-predominant pattern of motor neuron disease (MND) presenting with corticobasal syndrome (CBS) have been sparsely reported. This study aims to clarify the clinicopathological features of patients with UMN-predominant MND. We reviewed 24 patients with UMN-predominant MND with TDP-43 pathology in the presence or absence of frontotemporal lobar degeneration. Additionally, we reviewed the medical records of patients with pathologically-confirmed corticobasal degeneration (CBD) who received a final clinical diagnosis of CBS (n = 10) and patients with pathologically-confirmed progressive supranuclear palsy (PSP) who received a final clinical diagnosis of PSP syndrome (n = 10). Of 24 UMN-predominant MND patients, 20 had a clinical diagnosis of an atypical parkinsonian disorder, including CBS (n = 11) and PSP syndrome (n = 8). Only two patients had antemortem diagnoses of motor neuron disease. UMN-predominant MND patients with CBS less frequently exhibited apraxia than those with CBD, and they were less likely to meet clinical criteria for possible or probable CBS. Similarly, UMN-predominant MND patients with PSP syndrome less often met clinical criteria for probable PSP than PSP patients with PSP syndrome. Our findings suggest that UMN-predominant MND can mimic atypical parkinsonism, and should be considered in the differential diagnosis of CBS and PSP syndrome, in particular when criteria are not met.}, } @article {pmid38987905, year = {2024}, author = {Bergem, AK and Aamotsmo, T}, title = {Navigating parenthood in the face of amyotrophic lateral sclerosis: A qualitative exploration of partner experiences.}, journal = {Scandinavian journal of caring sciences}, volume = {38}, number = {4}, pages = {835-843}, doi = {10.1111/scs.13282}, pmid = {38987905}, issn = {1471-6712}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/psychology ; *Qualitative Research ; Adult ; Norway ; *Adaptation, Psychological ; Middle Aged ; *Parents/psychology ; Aged ; Child ; }, abstract = {INTRODUCTION: Among people diagnosed with Amyotrophic Lateral Sclerosis (ALS), there are parents with children living at home. Children in families experiencing severe illness are exposed to stress and health risks. Since 2010, healthcare personnel in Norway must assess whether patients have children under 18 years of age and make sure the children's needs for support are met. A child's ability to cope with family life affected by a serious illness depends on how the parent without the disease manages the situation. Little is known about how the partner of someone affected by ALS manages being next of kin and a parent simultaneously, and what kind of support they need.

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

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

CONCLUSIONS: Our respondents felt alone, caught between the needs of their children and partner, without necessary support from the services, and were left to handle everyday life with all new challenges on their own. Future healthcare services need to consider the challenges faced by families dealing with life-limiting illnesses. A family-focused perspective is needed, so is peer support and interventions that address both emotional and practical aspects of life with an ill partner.}, } @article {pmid38987226, year = {2024}, author = {Luo, X and Heydari, A and Renfrey, D and Gardner, Z and He, S and Tang, Y and Weiss, GA and Rogers, ML and Raston, CL}, title = {Sustainability-Driven Accelerated Shear-Mediated Immunoassay for Amyotrophic Lateral Sclerosis Detection.}, journal = {ChemSusChem}, volume = {17}, number = {21}, pages = {e202401008}, doi = {10.1002/cssc.202401008}, pmid = {38987226}, issn = {1864-564X}, support = {DP200101106//Australian Research Council/ ; IC190100034//Australian Research Council/ ; //Flinders Health Seed Foundation/ ; //Australian Nanotechnology Network/ ; //Flinders University Research Investment Fund/ ; //Australian Microscopy and Microanalysis Research Facility/ ; //Australian National Fabrication Facility (ANFF)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis ; Humans ; Immunoassay/methods ; Limit of Detection ; Biomarkers ; }, abstract = {Healthcare facilities produce millions of tons of waste annually, with a significant portion consisting of diagnostic plasticware. Here, we introduce a new detection platform that completely replaces traditional assay plates with a piece of membrane, offering a much greener and more sustainable alternative. The membrane, integrated within the portable vortex fluidic device (P-VFD), enables rapid detection of a clinically relevant protein biomarker, urinary p75[ECD]. This biomarker is utilized to evaluate the prognosis, disease severity, and progression of amyotrophic lateral sclerosis (ALS). This assay has a limit-of-detection (LOD) of 4.03 pg, which is comparable to the plate-based assay (2.24 pg) and has been optimised through a full factorial design of experiments (DOE) and response surface methodology (RSM). P-VFD has great potential in quantifying p75[ECD] in human biofluids and can significantly reduce the assay time to 5 min compared to the current plate-based p75[ECD] ELISA assay (3 days), with at least a 4.4-fold reduction in the usage of the detection antibody.}, } @article {pmid38986433, year = {2025}, author = {Rifai, OM and Waldron, FM and Sleibi, D and O'Shaughnessy, J and Leighton, DJ and Gregory, JM}, title = {Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {35}, number = {1}, pages = {e13287}, pmid = {38986433}, issn = {1750-3639}, support = {108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; 1R01NS127186/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; BB-2022-C4-L2//Target ALS/ ; }, mesh = {Humans ; *NIMA-Related Kinase 1/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Female ; Middle Aged ; Aged ; DNA-Binding Proteins/genetics/metabolism ; Mutation ; Mutation, Missense ; Adult ; }, abstract = {Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)-related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole-exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss-of-function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP-43 (pTDP-43) aggregates, in the motor cortex compared to age- and sex-matched control tissue. We show pathological, cytoplasmic TDP-43 aggregates in all three NEK1-ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1-ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1-positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co-occurring TDP-43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP-43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1-ALS.}, } @article {pmid38984697, year = {2024}, author = {Hasan, M and Alam, SM and Rahman, HZ and Khan, MAS and Huq, MR}, title = {Autonomic Dysfunction in Amyotrophic Lateral Sclerosis - A Case-Control Study.}, journal = {Acta medica academica}, volume = {53}, number = {1}, pages = {24-34}, pmid = {38984697}, issn = {1840-2879}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Case-Control Studies ; Female ; Male ; Middle Aged ; Adult ; Bangladesh/epidemiology ; *Autonomic Nervous System Diseases/physiopathology/etiology ; Galvanic Skin Response/physiology ; Autonomic Nervous System/physiopathology ; }, abstract = {INTRODUCTION: This study aimed to explore autonomic nervous system involvement in amyotrophic lateral sclerosis (ALS) patients by evaluating sympathetic skin response (SSR).

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

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

CONCLUSION: ALS is significantly associated with abnormal SSR, indicating autonomic nervous system involvement. There could also be an association between bulbar palsy and abnormal SSR among ALS patients. Further studies should be carried out to determine the association of abnormal SSR with disease severity, duration, and type.}, } @article {pmid38984619, year = {2024}, author = {Olney, N and Weiss, MD}, title = {Real world experience with sodium phenylbutyrate-taurursodiol for ALS: Lessons learned from a failed drug.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {299-301}, doi = {10.1002/mus.28203}, pmid = {38984619}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Phenylbutyrates/therapeutic use ; Male ; Female ; Middle Aged ; Treatment Failure ; Aged ; }, } @article {pmid38984582, year = {2024}, author = {Jiang, S and Nie, H and Hua, S and Xie, M and Xu, R}, title = {Preliminary Analysis of Potentially Overlapping Differentially Expressed Proteins in Both the Spinal Cord and Brain of SOD1 G93A Mice.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037293525240621120033}, pmid = {38984582}, issn = {1875-5550}, abstract = {OBJECTIVE: Proteomic elucidation is an essential step in improving our understanding of the biological properties of proteins in amyotrophic lateral sclerosis (ALS).

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

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

CONCLUSION: This study provides additional proteomic profiles of TG mice, including potential overlapping proteins in both the spinal cord and brain that participate in pathogenesis, as well as novel insights into the up- and downregulation of proteins involved in the pathogenesis of ALS.}, } @article {pmid38982381, year = {2024}, author = {Mioshi, E and Heal, S and Katangwe-Chigamba, T}, title = {'A lightbulb moment': carers' experiences of behavioural symptoms in motor neurone disease before and after MiNDToolkit.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {238}, pmid = {38982381}, issn = {1471-2377}, support = {934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; 934-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Caregivers/psychology ; Male ; *Motor Neuron Disease/psychology/therapy ; Female ; Middle Aged ; *Behavioral Symptoms/therapy/etiology ; Aged ; Adult ; Qualitative Research ; }, abstract = {BACKGROUND: To explore carers' experiences of behavioural symptoms in Motor Neurone Disease (MND), before and after using the MiNDToolkit, a novel internet-based psychoeducational intervention to support management of behavioural symptoms (BehSymp) in MND. The study also investigated carers' views and acceptability of MiNDToolkit.

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

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

CONCLUSIONS: MiNDToolkit was acceptable to carers overall. Recommended improvements should be actioned in a full-scale trial.}, } @article {pmid38981325, year = {2024}, author = {Asghar, H and Tariq, A and Rasool, G and Hayat, A}, title = {Fabrication of a salivary amylase electrochemical sensor based on surface confined MWCNTs/β-cyclodextrin/starch architect for dental caries in clinical samples.}, journal = {Bioelectrochemistry (Amsterdam, Netherlands)}, volume = {160}, number = {}, pages = {108774}, doi = {10.1016/j.bioelechem.2024.108774}, pmid = {38981325}, issn = {1878-562X}, mesh = {*beta-Cyclodextrins/chemistry ; Humans ; *Nanotubes, Carbon/chemistry ; *Biosensing Techniques/methods ; *Starch/chemistry ; *Electrochemical Techniques/methods ; *Dental Caries/diagnosis ; Saliva/chemistry ; Limit of Detection ; Salivary alpha-Amylases/analysis/metabolism ; Electrodes ; }, abstract = {Salivary α-amylase (α-ALS) has drawn attention as a possible bioindicator for dental caries. Herein, combining the synergistic properties of multi-walled carbon nanotubes (MWCNTs), β-cyclodextrin (β-CD) and starch, an electrochemical sensor is constructed employing ferrocene (FCN) as an electrochemical indicator to oversee the progression of the enzymatic catalysis of α-ALS. The method involves a two-step chemical reaction sequence on a screen-printed carbon electrode (SPCE). X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Field emission scanning electron microscope (FE-SEM), and Dynamic light scattering (DLS) were used to characterize the synthesized material, while Static water Contact angle measurements, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) were performed to monitor each step of sensor fabrication. The electrochemical sensor permitted to detect α-ALS within the linear range of 0.5-280 U mL[-1], revealing detection (LOD), and quantification (LOQ) values of 0.041 U mL[-1], and 0.159 U mL[-1], respectively. Remarkably, the sensor demonstrated exceptional specificity and selectivity, effectively discriminating against other interfering substances in saliva. Validation of the method involved analyzing α-ALS levels in artificial saliva with an accuracy range of 97 % to 103 %, as well as in real clinical saliva samples across various age groups.}, } @article {pmid38979791, year = {2024}, author = {Stabellini, N and Cullen, J and Bittencourt, MS and Moore, JX and Sutton, A and Nain, P and Hamerschlak, N and Weintraub, NL and Dent, S and Tsai, MH and Banerjee, A and Ghosh, AK and Sadler, D and Coughlin, SS and Barac, A and Shanahan, J and Montero, AJ and Guha, A}, title = {Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.}, journal = {Journal of the American Heart Association}, volume = {13}, number = {14}, pages = {e033295}, pmid = {38979791}, issn = {2047-9980}, mesh = {Humans ; Female ; *Colorectal Neoplasms/epidemiology ; *Breast Neoplasms/epidemiology ; *Lung Neoplasms/epidemiology/diagnosis ; Middle Aged ; Male ; Retrospective Studies ; Aged ; *Cardiovascular Diseases/epidemiology ; *Allostasis/physiology ; Risk Assessment ; Risk Factors ; Stress, Psychological/complications ; }, abstract = {BACKGROUND: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown.

METHODS AND RESULTS: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis.

CONCLUSIONS: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.}, } @article {pmid38979291, year = {2024}, author = {Weiss, A and Gilbert, JW and Flores, IVR and Belgrad, J and Ferguson, C and Dogan, EO and Wightman, N and Mocarski, K and Echeverria, D and Summers, A and Bramato, B and McHugh, N and Furgal, R and Yamada, N and Cooper, D and Monopoli, K and Godinho, BMDC and Hassler, MR and Yamada, K and Greer, P and Henninger, N and Brown, RH and Khvorova, A}, title = {RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979291}, issn = {2692-8205}, support = {R01 NS111990/NS/NINDS NIH HHS/United States ; S10 OD020012/OD/NIH HHS/United States ; R21 NR020231/NR/NINR NIH HHS/United States ; R21 NS131756/NS/NINDS NIH HHS/United States ; R01 NS104022/NS/NINDS NIH HHS/United States ; R35 GM131839/GM/NIGMS NIH HHS/United States ; U24 NS113844/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA[SOD1] extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.}, } @article {pmid38979278, year = {2024}, author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.25.600403}, pmid = {38979278}, issn = {2692-8205}, abstract = {Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system [1] . Human genetic studies established a causal role for protein assembly in neurodegeneration [2] . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains [1] . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B [3,4] . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.}, } @article {pmid38979270, year = {2024}, author = {Baghel, MS and Burns, GD and Tsapatsis, M and Mallika, AP and Cruz, ALF and Cao, T and Chen, XK and Rosa, I and Marx, SR and Ye, Y and Sun, S and Li, T and Wong, PC}, title = {Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979270}, issn = {2692-8205}, support = {R01 NS095969/NS/NINDS NIH HHS/United States ; R61 NS115161/NS/NINDS NIH HHS/United States ; F31 NS135935/NS/NINDS NIH HHS/United States ; R33 NS115161/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, abstract = {TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp [f/f] mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp [f/f] mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.}, } @article {pmid38979232, year = {2024}, author = {Keuss, MJ and Harley, P and Ryadnov, E and Jackson, RE and Zanovello, M and Wilkins, OG and Barattucci, S and Mehta, PR and Oliveira, MG and Parkes, JE and Sinha, A and Correa-Sánchez, AF and Oliver, PL and Fisher, EMC and Schiavo, G and Shah, M and Burrone, J and Fratta, P}, title = {Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38979232}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; }, abstract = {TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.}, } @article {pmid38979013, year = {2024}, author = {Shi, W and Ding, R and Chen, Y and Ji, F and Ji, J and Ma, W and Jin, J}, title = {The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress.}, journal = {iScience}, volume = {27}, number = {7}, pages = {110196}, pmid = {38979013}, issn = {2589-0042}, abstract = {Stress granules (SGs) are membrane-less cellular compartments which are dynamically assembled via biomolecular condensation mechanism when eukaryotic cells encounter environmental stresses. SGs are important for gene expression and cell fate regulation. Dysregulation of SG homeostasis has been linked to human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we report that the HRD1-SEL1L ubiquitin ligase complex specifically regulates the homeostasis of heat shock-induced SGs through the ubiquitin-proteasome system (UPS) and the UPS-associated ATPase p97. Mechanistically, the HRD1-SEL1L complex mediates SG homeostasis through the BiP-coupled PERK-eIF2α signaling axis of endoplasmic reticulum (ER) stress, thereby coordinating the unfolded protein response (UPR) with SG dynamics. Furthermore, we show that the distinctive branches of ER stress play differential roles in SG homeostasis. Our study indicates that the UPS and the UPR together via the HRD1-SEL1L ubiquitin ligase to maintain SG homeostasis in a stressor-dependent manner.}, } @article {pmid38978682, year = {2024}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Multimodal Speech Biomarkers for Remote Monitoring of ALS Disease Progression.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38978682}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.}, } @article {pmid38978196, year = {2024}, author = {Huang, X and Wu, J and Zhang, N and Teng, J and Yang, Q and Zhang, Y and Yin, T and Zhou, W and Fan, D and Ye, S}, title = {Smell loss is associated with cognitive impairment in amyotrophic lateral sclerosis patients.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {7}, pages = {e14851}, pmid = {38978196}, issn = {1755-5949}, support = {82001350//National Natural Science Foundation of China/ ; 2021ZD0204200//STI2030-Major Projects/ ; JCTD-2021-06//The Chinese Academy of Sciences Grants/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; DL2019002//PUTH Cohort Construction Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/epidemiology ; Male ; Female ; Middle Aged ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; *Olfaction Disorders/etiology/epidemiology ; Adult ; }, abstract = {BACKGROUND: Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients.

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

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

CONCLUSION: In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.}, } @article {pmid38978024, year = {2024}, author = {Endalamaw, A and Gilks, CF and Ambaw, F and Shiferaw, WS and Assefa, Y}, title = {Explaining inequity in knowledge, attitude, and services related to HIV/AIDS: a systematic review.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1815}, pmid = {38978024}, issn = {1471-2458}, mesh = {Humans ; *HIV Infections/psychology ; *Health Knowledge, Attitudes, Practice ; Healthcare Disparities ; }, abstract = {BACKGROUND: Equitable service provision and coverage are important responses to end the threat of the HIV/AIDS pandemic. Understanding inequity supports policies and programmes to deliver tailored interventions. There is continuous evidence generation on inequity in HIV/AIDS services. However, there was a lack of evidence on the global picture of inequity in behavioural and biomedical services related to HIV/AIDS. This systematic review assessed inequities in knowledge, attitude, HIV testing, and ART coverage across individual-level social groups and multiple (dis)advantage categories.

METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, with a PROSPERO registration number CRD42024521247. The risk of bias was assessed by using Hoy et al's and Joanna Brigg's quality appraisal checklists for cross-sectional quantitative and qualitative studies, respectively. The search date was from inception to the final database search date (May 29, 2023). The included articles were either quantitative or qualitative studies. We used mixed-methods approach to analyse the data from the review articles. Quantitative descriptive analysis was conducted to estimate frequency of articles published from different countries around the world. Qualitative content analysis of the findings from the original studies was conducted using the PROGRESS plus framework which stands for: place of residence, occupation or employment status, gender, religion, education status, socioeconomic status, and social capital.

RESULTS: Out of 6,029 articles that were accessed and screened, only 72 articles met the inclusion criteria. More articles on HIV-related equity in knowledge, attitude, testing, and ART were published in developed countries than in developing countries. Individuals from higher-income households had better knowledge about HIV/AIDS. Unfavourable attitudes towards people living with HIV and HIV/AIDS-associated stigma were common among women. HIV/AIDS service coverage (HIV testing or ART coverage) was higher among richer and urban residents. HIV/AIDS-associated stigma and lower levels of knowledge about HIV/AIDS were observed among multiple disadvantageous groups due to the intersection of two or more identities.

CONCLUSIONS: The current review revealed that there have been disparities in HIV/AIDS services between social classes. Ending service disparity towards the global threat of HIV/AIDS demands tailored interventions based on socially disadvantaged groups (e.g., poor, rural dwellers, and women) and intersectional determinants. There is a need to understand the deep-rooted causes of inequity and the challenges that an equity-oriented system faces over time. More studies on inequity are needed, including intersectional inequity, which has been rarely studied in developing countries.}, } @article {pmid38977678, year = {2024}, author = {M Amaral, D and Soares, DF and Gromicho, M and de Carvalho, M and Madeira, SC and Tomás, P and Aidos, H}, title = {Temporal stratification of amyotrophic lateral sclerosis patients using disease progression patterns.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5717}, pmid = {38977678}, issn = {2041-1723}, support = {101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; 101017598//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Humans ; *Disease Progression ; Male ; Cluster Analysis ; Female ; Middle Aged ; Aged ; }, abstract = {Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups.}, } @article {pmid38977656, year = {2024}, author = {Han, M and Raymond, J and Larson, TC and Mehta, P and Horton, DK}, title = {Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {38977656}, issn = {2196-8837}, abstract = {OBJECTIVE: To characterize the participant demographics in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database compared with the web-portal National Amyotrophic Lateral Sclerosis (ALS) Registry (the Registry).

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

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

CONCLUSION: There was a notable difference in the age distribution and minority representation of enrollees between the PRO-ACT and Registry study populations. Age distribution in the PRO-ACT database skewed to a younger and less diverse cohort. Despite the clinical heterogeneity and complex disease mechanism of ALS, identifying the underrepresented demographic niche in the PRO-ACT and Registry study populations can help improve patient participation and criteria for patient selection to enhance generalizability.}, } @article {pmid38976599, year = {2024}, author = {Xu, Z and Xu, R}, title = {Current potential diagnostic biomarkers of amyotrophic lateral sclerosis.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {917-931}, pmid = {38976599}, issn = {2191-0200}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Humans ; *Biomarkers/metabolism ; Oxidative Stress/physiology ; Proteomics/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) currently lacks the useful diagnostic biomarkers. The current diagnosis of ALS is mainly depended on the clinical manifestations, which contributes to the diagnostic delay and be difficult to make the accurate diagnosis at the early stage of ALS, and hinders the clinical early therapeutics. The more and more pathogenesis of ALS are found at the last 30 years, including excitotoxicity, the oxidative stress, the mitochondrial dysfunction, neuroinflammation, the altered energy metabolism, the RNA misprocessing and the most recent neuroimaging findings. The findings of these pathogenesis bring the new clues for searching the diagnostic biomarkers of ALS. At present, a large number of relevant studies about the diagnostic biomarkers are underway. The ALS pathogenesis related to the diagnostic biomarkers might lessen the diagnostic reliance on the clinical manifestations. Among them, the cortical altered signatures of ALS patients derived from both structural and functional magnetic resonance imaging and the emerging proteomic biomarkers of neuronal loss and glial activation in the cerebrospinal fluid as well as the potential biomarkers in blood, serum, urine, and saliva are leading a new phase of biomarkers. Here, we reviewed these current potential diagnostic biomarkers of ALS.}, } @article {pmid38975625, year = {2024}, author = {Berkman, O and Raveh, E and Harpaz, E and Kreitman, R and Ben-Ami, E and Nechushtan, E and Birman, N and Drory, VE}, title = {Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {760-766}, doi = {10.1080/21678421.2024.2376732}, pmid = {38975625}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Disease Progression ; Female ; Middle Aged ; Male ; Aged ; *Saccades/physiology ; Ocular Motility Disorders/etiology/diagnosis/physiopathology ; Biomarkers ; }, abstract = {Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs' change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, -0.41, -0.39 and -0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.}, } @article {pmid38975145, year = {2024}, author = {Zhang, J and Xie, D and Jiao, D and Zhou, S and Liu, S and Ju, Z and Hu, L and Qi, L and Yao, C and Zhao, C}, title = {From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.}, journal = {Heliyon}, volume = {10}, number = {12}, pages = {e32688}, pmid = {38975145}, issn = {2405-8440}, abstract = {The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.}, } @article {pmid38974930, year = {2024}, author = {Aziz, S and Barratt, J and Wilson-Baig, N and Lachowycz, K and Major, R and Barnard, EBG and Rees, P}, title = {A protocol for the ERICA-ARREST feasibility study of Emergency Resuscitative Endovascular Balloon occlusion of the Aorta in Out-of-Hospital Cardiac Arrest.}, journal = {Resuscitation plus}, volume = {19}, number = {}, pages = {100688}, pmid = {38974930}, issn = {2666-5204}, abstract = {BACKGROUND: Fewer than one in ten out-of-hospital cardiac arrest (OHCA) patients survive to hospital discharge in the UK. For prehospital teams to improve outcomes in patients who remain in refractory OHCA despite advanced life support (ALS); novel strategies that increase the likelihood of return of spontaneous circulation, whilst preserving cerebral circulation, should be investigated. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) has been shown to improve coronary and cerebral perfusion during cardiopulmonary resuscitation. Early, prehospital initiation of REBOA may improve outcomes in patients who do not respond to standard ALS. However, there are significant clinical, technical, and logistical challenges with rapidly delivering prehospital REBOA in OHCA; and the feasibility of delivering this intervention in the UK urban-rural setting has not been evaluated.

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

DISCUSSION: Using compressed geography, and targeted dispatch, alongside a well-established femoral arterial access programme, the ERICA-ARREST study will assess the feasibility of deploying REBOA in OHCA in a mixed UK urban and rural setting.Trial registration.ClinicalTrials.gov (NCT06071910), registration date October 10, 2023, https://classic.clinicaltrials.gov/ct2/show/NCT06071910.}, } @article {pmid38973130, year = {2024}, author = {Corcia, P and Guy, N and Pradat, PF and Soriani, MH and Verschueren, A and Couratier, P}, title = {Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2375330}, pmid = {38973130}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.}, } @article {pmid38972779, year = {2024}, author = {Pelaez, MC and Fiore, F and Larochelle, N and Dabbaghizadeh, A and Comaduran, MF and Arbour, D and Minotti, S and Marcadet, L and Semaan, M and Robitaille, R and Nalbantoglu, JN and Sephton, CF and Durham, HD}, title = {Reversal of cognitive deficits in FUS[R521G] amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {5}, pages = {e00388}, pmid = {38972779}, issn = {1878-7479}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Mice ; *Mice, Transgenic ; Heat-Shock Proteins/genetics/metabolism ; Hydroxylamines/pharmacology/therapeutic use ; Cognitive Dysfunction/drug therapy/metabolism ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism ; Humans ; Mice, Inbred C57BL ; }, abstract = {Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS[R521G] or SOD1[G93A] to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS[R521G] mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1[G93A] mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.}, } @article {pmid38972199, year = {2024}, author = {Rosén, C and Mitre, B and Nellgård, B and Axelsson, M and Constantinescu, R and Andersen, PM and Dalla, K and Blennow, K and Nilsson, G and Zetterberg, H and Rosén, H}, title = {High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.}, journal = {Journal of the neurological sciences}, volume = {463}, number = {}, pages = {123112}, doi = {10.1016/j.jns.2024.123112}, pmid = {38972199}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/blood ; *Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; Middle Aged ; Aged ; *Biomarkers/cerebrospinal fluid ; Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Disease Progression ; Adult ; Membrane Glycoproteins ; Receptors, Immunologic ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.}, } @article {pmid38971939, year = {2024}, author = {Gomez, D and Selvaraj, MG and Casas, J and Mathiyazhagan, K and Rodriguez, M and Assefa, T and Mlaki, A and Nyakunga, G and Kato, F and Mukankusi, C and Girma, E and Mosquera, G and Arredondo, V and Espitia, E}, title = {Advancing common bean (Phaseolus vulgaris L.) disease detection with YOLO driven deep learning to enhance agricultural AI.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {15596}, pmid = {38971939}, issn = {2045-2322}, mesh = {*Phaseolus/virology/microbiology ; *Deep Learning ; *Plant Diseases/virology/microbiology ; Agriculture/methods ; Plant Leaves/virology/microbiology ; Africa ; Colombia ; }, abstract = {Common beans (CB), a vital source for high protein content, plays a crucial role in ensuring both nutrition and economic stability in diverse communities, particularly in Africa and Latin America. However, CB cultivation poses a significant threat to diseases that can drastically reduce yield and quality. Detecting these diseases solely based on visual symptoms is challenging, due to the variability across different pathogens and similar symptoms caused by distinct pathogens, further complicating the detection process. Traditional methods relying solely on farmers' ability to detect diseases is inadequate, and while engaging expert pathologists and advanced laboratories is necessary, it can also be resource intensive. To address this challenge, we present a AI-driven system for rapid and cost-effective CB disease detection, leveraging state-of-the-art deep learning and object detection technologies. We utilized an extensive image dataset collected from disease hotspots in Africa and Colombia, focusing on five major diseases: Angular Leaf Spot (ALS), Common Bacterial Blight (CBB), Common Bean Mosaic Virus (CBMV), Bean Rust, and Anthracnose, covering both leaf and pod samples in real-field settings. However, pod images are only available for Angular Leaf Spot disease. The study employed data augmentation techniques and annotation at both whole and micro levels for comprehensive analysis. To train the model, we utilized three advanced YOLO architectures: YOLOv7, YOLOv8, and YOLO-NAS. Particularly for whole leaf annotations, the YOLO-NAS model achieves the highest mAP value of up to 97.9% and a recall of 98.8%, indicating superior detection accuracy. In contrast, for whole pod disease detection, YOLOv7 and YOLOv8 outperformed YOLO-NAS, with mAP values exceeding 95% and 93% recall. However, micro annotation consistently yields lower performance than whole annotation across all disease classes and plant parts, as examined by all YOLO models, highlighting an unexpected discrepancy in detection accuracy. Furthermore, we successfully deployed YOLO-NAS annotation models into an Android app, validating their effectiveness on unseen data from disease hotspots with high classification accuracy (90%). This accomplishment showcases the integration of deep learning into our production pipeline, a process known as DLOps. This innovative approach significantly reduces diagnosis time, enabling farmers to take prompt management interventions. The potential benefits extend beyond rapid diagnosis serving as an early warning system to enhance common bean productivity and quality.}, } @article {pmid38971043, year = {2024}, author = {Malmström, N and Öhlén, J and Jakobsson Larsson, B and Nilsson, S and Nygren, I and M Andersen, P and Ozanne, A}, title = {Adolescents' challenging and grief-filled transitions when living with a parent with ALS: A qualitative interpretive study.}, journal = {Social science & medicine (1982)}, volume = {354}, number = {}, pages = {117063}, doi = {10.1016/j.socscimed.2024.117063}, pmid = {38971043}, issn = {1873-5347}, mesh = {Humans ; *Qualitative Research ; *Amyotrophic Lateral Sclerosis/psychology ; Sweden ; *Grief ; Female ; Male ; Adolescent ; Adult ; Adaptation, Psychological ; Child ; Young Adult ; Parents/psychology ; Parent-Child Relations ; }, abstract = {OBJECTIVE: The study aimed to explore the meaning for adolescents of living with a parent with amyotrophic lateral sclerosis (ALS).

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

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

CONCLUSION: The unbalanced life situation may hinder the adolescents' identity formation and emancipation, which are developmentally important for managing a healthy and independent adulthood. The results emphasize the importance of early targeted support to reach this vulnerable group in order to secure their health.}, } @article {pmid38970668, year = {2024}, author = {Ludolph, AC and Dietrich, J and Dreyhaupt, J and Kassubek, J and Del Tredici, K and Rosenbohm, A}, title = {Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): a study in 910 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5357-5367}, pmid = {38970668}, issn = {1432-1459}, support = {LU 336/15-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Muscle Weakness/physiopathology/etiology/pathology ; Disease Progression ; Cohort Studies ; Adult ; Germany/epidemiology ; }, abstract = {BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally.

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

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

DISCUSSION: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.}, } @article {pmid38970158, year = {2024}, author = {Li, Z and Wen, J and Wu, W and Dai, Z and Liang, X and Zhang, N and Cheng, Q and Zhang, H}, title = {Causal relationship and shared genes between air pollutants and amyotrophic lateral sclerosis: A large-scale genetic analysis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {7}, pages = {e14812}, pmid = {38970158}, issn = {1755-5949}, support = {2023CQBSHTB3095//Chongqing Postdoctoral Research Special Funding Project/ ; CSTB2023NSCQBHX0002//Chongqing Postdoctoral Science Foundation/ ; 2023MD734131//China Postdoctoral Science Foundation/ ; 2023RC3074//Hunan Youth Science and Technology Talent Project/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Polymorphism, Single Nucleotide/genetics ; *Genome-Wide Association Study ; *Air Pollutants/adverse effects/toxicity ; *Mendelian Randomization Analysis ; Genetic Predisposition to Disease/genetics ; Particulate Matter/adverse effects ; }, abstract = {OBJECTIVE: Air pollutants have been reported to have a potential relationship with amyotrophic lateral sclerosis (ALS). The causality and underlying mechanism remained unknown despite several existing observational studies. We aimed to investigate the potential causality between air pollutants (PM2.5, NOX, and NO2) and the risk of ALS and elucidate the underlying mechanisms associated with this relationship.

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

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

CONCLUSION: Higher exposure to PM2.5 and NOX might causally increase the risk of ALS. Avoiding exposure to air pollutants and air cleaning might be necessary for ALS prevention.}, } @article {pmid38969143, year = {2024}, author = {Jha, SK and Nelson, VK and Suryadevara, PR and Panda, SP and Pullaiah, CP and Nuli, MV and Kamal, M and Imran, M and Ausali, S and Abomughaid, MM and Srivastava, R and Deka, R and Pritam, P and Gupta, N and Shyam, H and Singh, IK and Pandey, BW and Dewanjee, S and Jha, NK and Jafari, SM}, title = {Cannabidiol and neurodegeneration: From molecular mechanisms to clinical benefits.}, journal = {Ageing research reviews}, volume = {100}, number = {}, pages = {102386}, doi = {10.1016/j.arr.2024.102386}, pmid = {38969143}, issn = {1872-9649}, mesh = {Humans ; *Cannabidiol/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce psycho-motor malfunctions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of the associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol (CBD) is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. CBD has gained attention as a promising drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as the clinical applications of CBD in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.}, } @article {pmid38968328, year = {2024}, author = {Gowrishankar, S and Smith, ME and Creber, N and Muzaffar, J and Borsetto, D}, title = {Immunosuppression in stem cell clinical trials of neural and retinal cell types: A systematic review.}, journal = {PloS one}, volume = {19}, number = {7}, pages = {e0304073}, pmid = {38968328}, issn = {1932-6203}, mesh = {Humans ; *Stem Cell Transplantation/methods ; *Immunosuppression Therapy/methods ; Retina/immunology ; Immunosuppressive Agents/therapeutic use ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: Pharmacologic immunosuppression regimes are commonly employed in stem cell clinical trials to mitigate host immune rejection and promote survival and viability of transplanted cells. Immunosuppression and cell survival has been extensively studied in retinal and spinal tissues. The applicability of stem cell therapy is rapidly expanding to other sensory organs such as the ear and hearing. As regenerative therapy is directed to new areas, a greater understanding of immunosuppression strategies and their efficacy is required to facilitate translation to organ-specific biologic microenvironments.

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

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

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

DISCUSSION: A short-term course of systemic immunosuppression seemed efficacious for most included studies, with some showing grafted cells viable months to years after immunosuppression had stopped. Longer-term follow-up is required to see if this remains the case. Side effects related to immunosuppression were uncommon.}, } @article {pmid38967881, year = {2024}, author = {Rojas-López, JC and Estrada-Gualdron, PI and Ramírez-Guerrero, S and Velásquez-Cárdenas, MJ and Redondo-Escobar, J and Vargas-Arenas, S and Palacios-Sánchez, L and Palacios-Espinosa, X}, title = {Efficacy of pain management strategies in adults with Amyotrophic Lateral Sclerosis (ALS): A Systematic Review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5591-5604}, pmid = {38967881}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Pain Management/methods ; Adult ; Pain/etiology/drug therapy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness. Presence of pain in ALS patients is heterogeneously reported in studies, and mostly underrepresented in symptom scales. The aim of this study is to evaluate the efficacy of pharmacological and non-pharmacological therapeutic modalities for pain management in patients with ALS. A systematic review was conducted in four databases; PubMed, Scopus, Clinicaltrials.gov, and Cochrane-Ovid. Five randomized controlled clinical trials were included regarding pharmacological and non-pharmacological pain management interventions in adult patients with confirmed diagnosis of ALS in whom pain was objectively evaluated. Risk of bias assessment was evaluated using the RoB2.0 tool. Eligible studies were reported as a descriptive analysis. This systematic review was registered with PROSPERO ID: CRD42024495009. Five clinical trials regarding pain management strategies in ALS were eligible for analysis. Two out of five were non-pharmacological approaches whilst the remaining three provided pharmacological therapies. Of these, Mexiletine was efficient in terms of pain relief, particularly between 600 and 900 mg per day, whereas Mecasin showed no pain relief at both, high and low doses. Non-pharmacological therapies, such as exercise and osteopathic manual treatment also lacked efficacy in regard to pain management. Clinical trials focusing on pain management strategies for ALS patients are limited. Medical professionals, understandably focused on immediate life-threatening aspects, may inadvertently sideline the nuanced and intricate dimension of pain experienced by patients with ALS.}, } @article {pmid38967655, year = {2024}, author = {Müller, P and Draguhn, A and Egorov, AV}, title = {Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {476}, number = {10}, pages = {1445-1473}, pmid = {38967655}, issn = {1432-2013}, support = {HE8155/1-2//Deutsche Forschungsgemeinschaft/ ; EG134/2-1//Deutsche Forschungsgemeinschaft/ ; Treat-ION01GM1907A//Bundesministerium für Bildung und Forschung/ ; College for Clinician Scientists//Else Kröner-Fresenius-Stiftung/ ; }, mesh = {Humans ; Animals ; *Neurons/metabolism/drug effects/physiology ; Sodium Channel Blockers/pharmacology ; Sodium Channels/metabolism/drug effects ; }, abstract = {Persistent sodium current (INaP) is an important activity-dependent regulator of neuronal excitability. It is involved in a variety of physiological and pathological processes, including pacemaking, prolongation of sensory potentials, neuronal injury, chronic pain and diseases such as epilepsy and amyotrophic lateral sclerosis. Despite its importance, neither the molecular basis nor the regulation of INaP are sufficiently understood. Of particular significance is a solid knowledge and widely accepted consensus about pharmacological tools for analysing the function of INaP and for developing new therapeutic strategies. However, the literature on INaP is heterogeneous, with varying definitions and methodologies used across studies. To address these issues, we provide a systematic review of the current state of knowledge on INaP, with focus on mechanisms and effects of this current in the central nervous system. We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents.}, } @article {pmid38967638, year = {2024}, author = {Garau, J and Garofalo, M and Dragoni, F and Scarian, E and Di Gerlando, R and Diamanti, L and Zucca, S and Bordoni, M and Pansarasa, O and Gagliardi, S}, title = {RNA expression profiling in lymphoblastoid cell lines from mutated and non-mutated amyotrophic lateral sclerosis patients.}, journal = {The journal of gene medicine}, volume = {26}, number = {7}, pages = {e3711}, doi = {10.1002/jgm.3711}, pmid = {38967638}, issn = {1521-2254}, support = {//Ministero della Salute/ ; //Italian Agency for Research on ALS-ARiSLA/ ; //Italian Ministry of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Gene Expression Profiling ; *Mutation ; *Transcriptome ; Female ; Male ; Middle Aged ; C9orf72 Protein/genetics/metabolism ; Leukocytes, Mononuclear/metabolism ; Superoxide Dismutase-1/genetics ; Cell Line ; Aged ; Gene Expression Regulation ; DNA-Binding Proteins ; RNA-Binding Protein FUS ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of upper and lower motor neurons with an unknown etiology. The difficulty of recovering biological material from patients led to employ lymphoblastoid cell lines (LCLs) as a model for ALS because many pathways, typically located in neurons, are also activated in these cells.

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

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

CONCLUSIONS: We conclude that LCLs are a good model for the study of RNA deregulation in ALS.}, } @article {pmid38967302, year = {2024}, author = {Sîrbulescu, RF and Nicholson, K and Kawai, K and Hilton, OM and Sobell, D and Jin, G and Verrill, DE and Dwyer, LJ and Xiong, Y and Bachanová, P and Kim, SE and Gallup, S and Gelevski, D and Daley, H and Hernandez Rodriguez, DE and Negre, H and Sturtevant, O and Nikiforow, S and Ritz, J and Chen, YB and Reeves, PM and Sluder, AE and Berry, JD and Sadri-Vakili, G and Cudkowicz, M and Poznansky, MC}, title = {Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {13}, pages = {e23796}, doi = {10.1096/fj.202302659R}, pmid = {38967302}, issn = {1530-6860}, support = {//Ward Family Foundation/ ; //Vaccine and Immunotherapy Center Innovation Fund/ ; //Vaccine and Immunotherapy Center Education Fund/ ; //Sean M. Healey and AMG Center for ALS/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/immunology ; Animals ; Mice ; Humans ; *B-Lymphocytes/immunology ; Disease Models, Animal ; Mice, Transgenic ; Male ; Female ; Mice, Inbred C57BL ; Immunomodulation ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1[G93A] mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1[G93A] mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19[+] B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1[G93A] mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1[G93A] mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.}, } @article {pmid38967083, year = {2024}, author = {Nijs, M and Van Damme, P}, title = {The genetics of amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {560-569}, pmid = {38967083}, issn = {1473-6551}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *C9orf72 Protein/genetics ; *Genetic Predisposition to Disease/genetics ; *RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase/genetics ; Proteins/genetics ; DNA-Binding Proteins/genetics ; Genetic Testing ; }, abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS.

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

SUMMARY: Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.}, } @article {pmid38966756, year = {2024}, author = {Garg, V and Geurten, BRH}, title = {Diving deep: zebrafish models in motor neuron degeneration research.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1424025}, pmid = {38966756}, issn = {1662-4548}, abstract = {In the dynamic landscape of biomedical science, the pursuit of effective treatments for motor neuron disorders like hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) remains a key priority. Central to this endeavor is the development of robust animal models, with the zebrafish emerging as a prime candidate. Exhibiting embryonic transparency, a swift life cycle, and significant genetic and neuroanatomical congruencies with humans, zebrafish offer substantial potential for research. Despite the difference in locomotion-zebrafish undulate while humans use limbs, the zebrafish presents relevant phenotypic parallels to human motor control disorders, providing valuable insights into neurodegenerative diseases. This review explores the zebrafish's inherent traits and how they facilitate profound insights into the complex behavioral and cellular phenotypes associated with these disorders. Furthermore, we examine recent advancements in high-throughput drug screening using the zebrafish model, a promising avenue for identifying therapeutically potent compounds.}, } @article {pmid38966655, year = {2024}, author = {Saito, S and Ikeguchi, R and Kitagawa, K}, title = {Chronic cerebrospinal fluid leak can cause amyotrophic lateral sclerosis mimic.}, journal = {Journal of general and family medicine}, volume = {25}, number = {4}, pages = {237-238}, pmid = {38966655}, issn = {2189-7948}, abstract = {Chronic cerebrospinal fluid leak with spinal cord compression can mimic the symptoms of ALS, with a snake-eyes appearance on MRI.}, } @article {pmid38966427, year = {2024}, author = {Couturier, N and Hörner, SJ and Nürnberg, E and Joazeiro, C and Hafner, M and Rudolf, R}, title = {Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1429759}, pmid = {38966427}, issn = {2296-634X}, abstract = {Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca[2+] response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.}, } @article {pmid38965709, year = {2024}, author = {Arends, S and Drenthen, J and de Koning, L and van den Bergh, P and Hadden, RDM and Kuwabara, S and Reisin, RC and Shahrizaila, N and Ajroud-Driss, S and Antonini, G and Attarian, S and Balducci, C and Bertorini, T and Brannagan, TH and Cavaletti, G and Chao, CC and Chavada, G and Dillmann, KU and Dimachkie, MM and Galassi, G and Gutiérrez-Gutiérrez, G and Harbo, T and Islam, B and Islam, Z and Katzberg, H and Kusunoki, S and Manganelli, F and Miller, JAL and Pardo, J and Pereon, Y and Rajabally, YA and Sindrup, S and Stettner, M and Uncini, A and Verhamme, C and Vytopil, M and Waheed, W and Jacobs, BC and Cornblath, DR and , }, title = {Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16335}, pmid = {38965709}, issn = {1468-1331}, mesh = {Humans ; *Guillain-Barre Syndrome/diagnosis/classification/physiopathology ; *Neural Conduction/physiology ; *Electrodiagnosis/methods ; Male ; Female ; Middle Aged ; Adult ; Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Aged ; Cohort Studies ; }, abstract = {BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria.

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

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

CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.}, } @article {pmid38965379, year = {2024}, author = {Jacob, SM and Lee, S and Kim, SH and Sharkey, KA and Pfeffer, G and Nguyen, MD}, title = {Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {8}, pages = {475-494}, pmid = {38965379}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/epidemiology/metabolism ; *Sex Characteristics ; Male ; Female ; Animals ; Brain/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3-5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.}, } @article {pmid38964584, year = {2024}, author = {Peters, S and Bouma, F and Hoek, G and Janssen, N and Vermeulen, R}, title = {Air pollution exposure and mortality from neurodegenerative diseases in the Netherlands: A population-based cohort study.}, journal = {Environmental research}, volume = {259}, number = {}, pages = {119552}, doi = {10.1016/j.envres.2024.119552}, pmid = {38964584}, issn = {1096-0953}, mesh = {Humans ; Netherlands/epidemiology ; *Air Pollution/adverse effects/analysis ; Male ; *Air Pollutants/analysis/adverse effects ; *Neurodegenerative Diseases/mortality/chemically induced/epidemiology ; Middle Aged ; Female ; Cohort Studies ; *Environmental Exposure/adverse effects ; Aged ; *Particulate Matter/analysis/adverse effects ; Adult ; }, abstract = {BACKGROUND: Long-term exposure to ambient air pollution has been linked with all-cause mortality and cardiovascular and respiratory diseases. Suggestive associations between ambient air pollutants and neurodegeneration have also been reported, but due to the small effect and relatively rare outcomes evidence is yet inconclusive. Our aim was to investigate the associations between long-term air pollution exposure and mortality from neurodegenerative diseases.

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

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

CONCLUSION: Our findings, using a cohort of more than 10 million people, provide further support for associations between long-term exposure to air pollutants (PM2.5 and particularly NO2) and mortality of non-vascular dementia. No associations were found for Parkinson and MS and an inverse association was observed for Alzheimer's disease.}, } @article {pmid38963716, year = {2024}, author = {Lima, PLGSB and Couto, EM and Nóbrega, PR}, title = {Response letter to: a homozygous p.Val120Leu (c.358G > C) SOD1 mutation led to slowly progressive amyotrophic lateral sclerosis in a Brazilian family.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {803-804}, doi = {10.1080/21678421.2024.2374372}, pmid = {38963716}, issn = {2167-9223}, } @article {pmid38963497, year = {2024}, author = {Yu, G and Bai, Y and Zhang, ZY}, title = {Valosin-Containing Protein (VCP)/p97 Oligomerization.}, journal = {Sub-cellular biochemistry}, volume = {104}, number = {}, pages = {485-501}, pmid = {38963497}, issn = {0306-0225}, mesh = {*Valosin Containing Protein/metabolism/genetics/chemistry ; Humans ; Protein Multimerization ; Animals ; Mutation ; Frontotemporal Dementia/genetics/metabolism ; Adenosine Triphosphatases/metabolism/genetics/chemistry ; Osteitis Deformans/genetics/metabolism ; Cell Cycle Proteins/metabolism/genetics/chemistry ; Myositis, Inclusion Body/genetics/metabolism ; Muscular Dystrophies, Limb-Girdle ; }, abstract = {Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.}, } @article {pmid38963135, year = {2024}, author = {Turano, E and Virla, F and Scambi, I and Dabrowska, S and Bankole, O and Mariotti, R}, title = {Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally.}, journal = {European journal of histochemistry : EJH}, volume = {68}, number = {3}, pages = {}, pmid = {38963135}, issn = {2038-8306}, mesh = {Animals ; *Extracellular Vesicles/metabolism ; *Mesenchymal Stem Cells/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Adipose Tissue/metabolism ; Motor Neurons/metabolism ; Neuromuscular Junction/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving motor neuron (MN) loss in the motor cortex, brainstem and spinal cord leading to progressive paralysis and death. Due to the pathogenetic complexity, there are no effective therapies available. In this context the use of mesenchymal stem cells and their vesicular counterpart is an emerging therapeutic strategy to counteract neurodegeneration. The extracellular vesicles derived from adipose stem cells (ASC-EVs) recapitulate and ameliorate the neuroprotective effect of stem cells and, thanks to their small dimensions, makes their use suitable to develop novel therapeutic approaches for neurodegenerative diseases as ALS. Here we investigate a therapeutic regimen of ASC-EVs injection in SOD1(G93A) mice, the most widely used murine model of ALS. Repeated intranasal administrations of high doses of ASC-EVs were able to ameliorate motor performance of injected SOD1(G93A) mice at the early stage of the disease and produce a significant improvement at the end-stage in the lumbar MNs rescue. Moreover, ASC-EVs preserve the structure of neuromuscular junction without counteracting the muscle atrophy. The results indicate that the intranasal ASC-EVs administration acts in central nervous system sites rather than at peripheral level in SOD1(G93A) mice. These considerations allow us to identify future applications of ASC-EVs that involve different targets simultaneously to maximize the clinical and neuropathological outcomes in ALS in vivo models.}, } @article {pmid38963090, year = {2024}, author = {Pearson, K and Dobak, S}, title = {Current practices in the nutrition management of people with amyotrophic lateral sclerosis (ALS): a survey of U.S. ALS care teams.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {653-660}, doi = {10.1080/21678421.2024.2374382}, pmid = {38963090}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy ; Cross-Sectional Studies ; United States/epidemiology ; Male ; Patient Care Team ; Female ; Surveys and Questionnaires ; Nutrition Therapy/methods ; Nutritionists/statistics & numerical data ; }, abstract = {OBJECTIVE: To assess current practices of U.S. professionals providing outpatient ALS nutrition care.

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

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

CONCLUSIONS: Many professionals providing outpatient nutrition care to PALS possess limited experience, received insufficient training, and are not connected to other ALS dietitians. Specific nutrition care practices, including nutrient need estimation, vary widely among health professionals. Practices surrounding feeding tube discussions and refeeding syndrome may be suboptimal at many institutions. These findings highlight the need for initiatives that educate and connect practitioners providing nutrition care to PALS.}, } @article {pmid38963079, year = {2024}, author = {Naruse, H and Iseki, C and Mitsui, J and Miki, J and Nagasawa, H and Kurokawa, K and Kobayashi, R and Sato, H and Goto, J and Satake, W and Ishiura, H and Tsuji, S and Ohta, Y and Toda, T}, title = {A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {791-794}, doi = {10.1080/21678421.2024.2374374}, pmid = {38963079}, issn = {2167-9223}, mesh = {Humans ; *Protein Serine-Threonine Kinases/genetics ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Parkinsonian Disorders/genetics ; Male ; Female ; Middle Aged ; *Phenotype ; Loss of Function Mutation/genetics ; Pedigree ; Aged ; Adult ; }, abstract = {Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.}, } @article {pmid38961496, year = {2024}, author = {Linse, K and Weber, C and Reilich, P and Schöberl, F and Boentert, M and Petri, S and Rödiger, A and Posa, A and Otto, M and Wolf, J and Zeller, D and Brunkhorst, R and Koch, J and Hermann, A and Großkreutz, J and Schröter, C and Groß, M and Lingor, P and Machetanz, G and Semmler, L and Dorst, J and Lulé, D and Ludolph, A and Meyer, T and Maier, A and Metelmann, M and Regensburger, M and Winkler, J and Schrank, B and Kohl, Z and Hagenacker, T and Brakemeier, S and Weyen, U and Weiler, M and Lorenzl, S and Bublitz, S and Weydt, P and Grehl, T and Kotterba, S and Lapp, HS and Freigang, M and Vidovic, M and Aust, E and Günther, R}, title = {Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {34}, pmid = {38961496}, issn = {2524-3489}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them.

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

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

TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.}, } @article {pmid38960585, year = {2024}, author = {Dols-Icardo, O and Carbayo, Á and Jericó, I and Blasco-Martínez, O and Álvarez-Sánchez, E and López Pérez, MA and Bernal, S and Rodríguez-Santiago, B and Cusco, I and Turon-Sans, J and Cabezas-Torres, M and Caballero-Ávila, M and Vesperinas, A and Llansó, L and Pagola-Lorz, I and Torné, L and Valle-Tamayo, N and Muñoz, L and Rubio-Guerra, S and Illán-Gala, I and Cortés-Vicente, E and Gelpi, E and Rojas-García, R}, title = {Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-333834}, pmid = {38960585}, issn = {1468-330X}, abstract = {BACKGROUND AND OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing.

METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.

RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.

CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.}, } @article {pmid38960473, year = {2024}, author = {R, HC and Datta, A and S, UK and Zayed, H and D, TK and C, GPD}, title = {Decoding genetic and pathophysiological mechanisms in amyotrophic lateral sclerosis and primary lateral sclerosis: A comparative study of differentially expressed genes and implicated pathways in motor neuron disorders.}, journal = {Advances in protein chemistry and structural biology}, volume = {141}, number = {}, pages = {177-201}, doi = {10.1016/bs.apcsb.2023.12.008}, pmid = {38960473}, issn = {1876-1631}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling ; Motor Neuron Disease/genetics/metabolism ; }, abstract = {Motor Neuron Disorders (MNDs), characterized by the degradation and loss of function of motor neurons, are recognized as fatal conditions with limited treatment options and no known cure. The present study aimed to identify the pathophysiological functions and affected genes in patients with MNDs, specifically Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS). The GSE56808 dataset comprised three sample groups: six patients diagnosed with ALS (GSM1369650, GSM1369652, GSM1369654, GSM1369656, GSM1369657, GSM1369658), five patients diagnosed with PLS (GSM1369648, GSM1369649, GSM1369653, GSM1369655, GSM1369659), and six normal controls (GSM1369642, GSM1369643, GSM1369644, GSM1369645, GSM1369646, and GSM1369647). The application of computational analysis of microarray gene expression profiles enabled us to identify 346 significantly differentially expressed genes (DEGs), 169 genes for the ALS sample study, and 177 genes for the PLS sample study. Enrichment was carried out using MCODE, a Cytoscape plugin. Functional annotation of DEGs was carried out via ClueGO/CluePedia (v2.5.9) and further validated via the DAVID database. NRP2, SEMA3D, ROBO3 and, CACNB1, CACNG2 genes were identified as the gene of interest for ALS and PLS sample groups, respectively. Axonal guidance (GO:0007411) and calcium ion transmembrane transport (GO:0070588) were identified to be some of the significantly dysregulated gene ontology (GO) terms, with arrhythmogenic right ventricular cardiomyopathy (KEGG:05412) to be the top relevant KEGG pathway which is affected in MND patients. ROBO3 gene was observed to have distinctive roles in ALS and PLS-affected patients, hinting towards the differential progression of ALS from PLS. The insights derived from our comprehensive analysis accentuate the distinct variances in the underlying molecular pathogenesis of ALS and PLS. Further research should investigate the mechanistic roles of the identified DEGs and molecular pathways, leading to potential targeted therapies for ALS and PLS.}, } @article {pmid38960099, year = {2024}, author = {Bhandari, UR and Danish, SM and Ahmad, S and Ikram, M and Nadaf, A and Hasan, N and Kesharwani, P and Ahmad, FJ}, title = {New opportunities for antioxidants in amelioration of neurodegenerative diseases.}, journal = {Mechanisms of ageing and development}, volume = {221}, number = {}, pages = {111961}, doi = {10.1016/j.mad.2024.111961}, pmid = {38960099}, issn = {1872-6216}, mesh = {Humans ; *Antioxidants/pharmacology/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Oxidative Stress/drug effects ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.}, } @article {pmid38958608, year = {2024}, author = {Lang, R and Hodgson, RE and Shelkovnikova, TA}, title = {TDP-43 in nuclear condensates: where, how, and why.}, journal = {Biochemical Society transactions}, volume = {52}, number = {4}, pages = {1809-1825}, pmid = {38958608}, issn = {1470-8752}, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *Cell Nucleus/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism ; Biomolecular Condensates/metabolism ; Animals ; Neurodegenerative Diseases/metabolism ; }, abstract = {TDP-43 is an abundant and ubiquitously expressed nuclear protein that becomes dysfunctional in a spectrum of neurodegenerative diseases. TDP-43's ability to phase separate and form/enter biomolecular condensates of varying size and composition is critical for its functionality. Despite the high density of phase-separated assemblies in the nucleus and the nuclear abundance of TDP-43, our understanding of the condensate-TDP-43 relationship in this cellular compartment is only emerging. Recent studies have also suggested that misregulation of nuclear TDP-43 condensation is an early event in the neurodegenerative disease amyotrophic lateral sclerosis. This review aims to draw attention to the nuclear facet of functional and aberrant TDP-43 condensation. We will summarise the current knowledge on how TDP-43 containing nuclear condensates form and function and how their homeostasis is affected in disease.}, } @article {pmid38958573, year = {2024}, author = {Tu, S and Vucic, S and Kiernan, MC}, title = {Pathological insights derived from neuroimaging in amyotrophic lateral sclerosis: emerging clinical applications.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {577-584}, doi = {10.1097/WCO.0000000000001295}, pmid = {38958573}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Humans ; *Neuroimaging/methods ; Brain/diagnostic imaging/pathology ; }, abstract = {PURPOSE OF REVIEW: Neuroimaging has been instrumental in shaping current understanding of the pathoanatomical signature of amyotrophic lateral sclerosis (ALS) across clinically well defined patient cohorts. The potential utility of imaging as an objective disease marker, however, remains poorly defined.

RECENT FINDINGS: Increasingly advanced quantitative and computational imaging studies have highlighted emerging clinical applications for neuroimaging as a complementary clinical modality for diagnosis, monitoring, and modelling disease propagation. Multimodal neuroimaging has demonstrated novel approaches for capturing primary motor disease. Extra-motor subcortical dysfunction is increasingly recognized as key modulators of disease propagation.

SUMMARY: The neural signature of cortical and subcortical dysfunction in ALS has been well defined at the population level. Objective metrics of focal primary motor dysfunction are increasingly sensitive and translatable to the individual patient level. Integrity of extra-motor subcortical abnormalities are recognized to represent critical pathways of the ALS disease 'connectome', predicting pathological spread. Neuroimaging plays a pivotal role in capturing upper motor neuron pathology in ALS. Their potential clinical role as objective disease markers for disease classification, longitudinal monitoring, and prognosis in ALS have become increasingly well defined.}, } @article {pmid38957123, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Batouli, SAH}, title = {Quantitative susceptibility mapping in amyotrophic lateral sclerosis: automatic quantification of the magnetic susceptibility in the subcortical nuclei.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2024.2372648}, pmid = {38957123}, issn = {2167-9223}, abstract = {Objective: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs). Methods: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent t-tests, with p < 0.05 considered significant. Correlations were assessed using Pearson's correlation, with p < 0.05 considered significant. Cohen's d was reported to compare the standardized mean difference (SMD) of QSM. Results: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = -0.845), right CN (SMD = -0.851), whole CN (SMD = -1.016), and left subthalamic nucleus (STN) (SMD = -1.000). Susceptibility in the left putamen (SMD = -0.857), left thalamus (SMD = -1.081), and whole thalamus (SMD = -0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration. Conclusions: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.}, } @article {pmid38956726, year = {2024}, author = {Ye, S and Chen, L and Murphy, D and Wu, J and Zhang, H and Liu, H and Zou, B and Hou, G and Zhang, N and Yin, T and Smith, RA and Fan, D}, title = {Validation of the Center for Neurologic Study Bulbar Function Scale-Chinese version in a population with amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {246}, pmid = {38956726}, issn = {1750-1172}, support = {82001350//National Natural Science Foundation of China/ ; 81873784//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; YCXJ-JZ-2022-007//Beijing E-Town Cooperation & Development Foundation/ ; YJXJ-JZ-2021-0014//Beijing E-Town Cooperation & Development Foundation/ ; DL2019002//PUTH Cohort Construction Project/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology ; }, abstract = {OBJECTIVE: The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS.

METHODS: A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5-10 days after the first evaluation.

RESULTS: The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p < 0.001). The CNS-BFSC total score and sialorrhea and speech scores were significantly correlated with the ALSFRS-R bulbar subscore (p < 0.001). The CNS-BFSC total score and ALSFRS-R bulbar subscale score were highly predictive of a clinician diagnosis of impaired bulbar function (area under the receiver operating characteristic curve, 0.947 and 0.911, respectively; p < 0.001). A cutoff value for the CNS-BFSC total score was selected by maximizing Youden's index; this cutoff score was 33, with 86.4% sensitivity and 93.3% specificity. The CNS-BFSC total score and the sialorrhea, speech and swallowing subscores had good-retest reliability (p > 0.05). The Cronbach's α of the CNS-BFSC was 0.972.

CONCLUSION: The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.}, } @article {pmid38956470, year = {2024}, author = {Cai, H and Jiang, H and Xie, D and Lai, Z and Wu, J and Chen, M and Yang, Z and Xu, R and Zeng, S and Ma, H}, title = {Enhancing image quality in computed tomography angiography follow-ups after endovascular aneurysm repair: a comparative study of reconstruction techniques.}, journal = {BMC medical imaging}, volume = {24}, number = {1}, pages = {162}, pmid = {38956470}, issn = {1471-2342}, support = {82202217//National Natural Science Foundation of China/ ; }, mesh = {Humans ; Retrospective Studies ; Female ; *Computed Tomography Angiography/methods ; Aged ; Male ; *Endovascular Procedures/methods ; *Artifacts ; Middle Aged ; Aortic Aneurysm, Abdominal/surgery/diagnostic imaging ; Deep Learning ; Radiographic Image Interpretation, Computer-Assisted/methods ; Stents ; Endovascular Aneurysm Repair ; }, abstract = {BACKGROUND: The image quality of computed tomography angiography (CTA) images following endovascular aneurysm repair (EVAR) is not satisfactory, since artifacts resulting from metallic implants obstruct the clear depiction of stent and isolation lumens, and also adjacent soft tissues. However, current techniques to reduce these artifacts still need further advancements due to higher radiation doses, longer processing times and so on. Thus, the aim of this study is to assess the impact of utilizing Single-Energy Metal Artifact Reduction (SEMAR) alongside a novel deep learning image reconstruction technique, known as the Advanced Intelligent Clear-IQ Engine (AiCE), on image quality of CTA follow-ups conducted after EVAR.

MATERIALS: This retrospective study included 47 patients (mean age ± standard deviation: 68.6 ± 7.8 years; 37 males) who underwent CTA examinations following EVAR. Images were reconstructed using four different methods: hybrid iterative reconstruction (HIR), AiCE, the combination of HIR and SEMAR (HIR + SEMAR), and the combination of AiCE and SEMAR (AiCE + SEMAR). Two radiologists, blinded to the reconstruction techniques, independently evaluated the images. Quantitative assessments included measurements of image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), the longest length of artifacts (AL), and artifact index (AI). These parameters were subsequently compared across different reconstruction methods.

RESULTS: The subjective results indicated that AiCE + SEMAR performed the best in terms of image quality. The mean image noise intensity was significantly lower in the AiCE + SEMAR group (25.35 ± 6.51 HU) than in the HIR (47.77 ± 8.76 HU), AiCE (42.93 ± 10.61 HU), and HIR + SEMAR (30.34 ± 4.87 HU) groups (p < 0.001). Additionally, AiCE + SEMAR exhibited the highest SNRs and CNRs, as well as the lowest AIs and ALs. Importantly, endoleaks and thrombi were most clearly visualized using AiCE + SEMAR.

CONCLUSIONS: In comparison to other reconstruction methods, the combination of AiCE + SEMAR demonstrates superior image quality, thereby enhancing the detection capabilities and diagnostic confidence of potential complications such as early minor endleaks and thrombi following EVAR. This improvement in image quality could lead to more accurate diagnoses and better patient outcomes.}, } @article {pmid38956107, year = {2024}, author = {Opie-Martin, S and Iacoangeli, A and Topp, SD and Abel, O and Mayl, K and Mehta, PR and Shatunov, A and Fogh, I and Bowles, H and Limbachiya, N and Spargo, TP and Al-Khleifat, A and Williams, KL and Jockel-Balsarotti, J and Bali, T and Self, W and Henden, L and Nicholson, GA and Ticozzi, N and McKenna-Yasek, D and Tang, L and Shaw, PJ and Chio, A and Ludolph, A and Weishaupt, JH and Landers, JE and Glass, JD and Mora, JS and Robberecht, W and Damme, PV and McLaughlin, R and Hardiman, O and van den Berg, L and Veldink, JH and Corcia, P and Stevic, Z and Siddique, N and Silani, V and Blair, IP and Fan, DS and Esselin, F and de la Cruz, E and Camu, W and Basak, NA and Siddique, T and Miller, T and Brown, RH and Al-Chalabi, A and Shaw, CE}, title = {Author Correction: The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5560}, doi = {10.1038/s41467-024-49938-y}, pmid = {38956107}, issn = {2041-1723}, } @article {pmid38955238, year = {2024}, author = {Wang, M and Tang, Z}, title = {No causal relationship between serum urate and neurodegenerative diseases: A Mendelian randomization study.}, journal = {Experimental gerontology}, volume = {194}, number = {}, pages = {112503}, doi = {10.1016/j.exger.2024.112503}, pmid = {38955238}, issn = {1873-6815}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Uric Acid/blood ; *Neurodegenerative Diseases/genetics/blood ; *Amyotrophic Lateral Sclerosis/genetics/blood ; *Genome-Wide Association Study ; Parkinson Disease/genetics/blood ; Multiple Sclerosis/genetics/blood ; Alzheimer Disease/genetics/blood ; Polymorphism, Single Nucleotide ; Causality ; }, abstract = {OBJECTIVE: Observational studies have shown that increased serum urate is associated with a lower risk of neurodegenerative diseases (NDs), but the causality remains unclear. We employed a two-sample Mendelian randomization (MR) approach to assess the causal relationship between serum urate and four common subtypes of NDs, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).

METHODS: Serum urate data came from the CKDGen Consortium. GWAS data for PD, AD, ALS, and MS were obtained from four databases in the primary analysis and then acquired statistics from the FinnGen consortium for replication and meta-analysis. Inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods were applied in the MR analyses. Pleiotropic effects, heterogeneity, and leave-one-out analyses were evaluated to validate the results.

RESULTS: There was no evidence for the effect of serum urate on PD (OR: 1.00, 95 % CI: 0.90-1.11, P = 0.97), AD (OR: 1.02, 95 % CI: 1.00-1.04, P = 0.06), ALS (OR: 1.05, 95 % CI: 0.97-1.13, P = 0.22), and MS (OR: 1.01, 95 % CI: 0.89-1.14, P = 0.90) risk when combined with the FinnGen consortium, neither was any evidence of pleiotropy detected between the instrumental variables (IVs).

CONCLUSION: The MR analysis suggested that serum urate may not be causally associated with a risk of PD, AD, ALS, and MS.}, } @article {pmid38954274, year = {2024}, author = {Faltracco, V and Poletti, B and Aiello, EN and Telesca, A and Bella, ED and Bersano, E and Silani, V and Ticozzi, N and Lauria, G and Consonni, M}, title = {Emotional awareness in patients with amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {5043-5046}, pmid = {38954274}, issn = {1590-3478}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia (POR FESR 2014-2020)/ ; RRC//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; *Affective Symptoms/etiology/physiopathology ; Middle Aged ; Aged ; Emotions/physiology ; Awareness/physiology ; Neuropsychological Tests ; Cohort Studies ; }, abstract = {INTRODUCTION: It has been recently acknowledged that deficits in experiencing and processing one's own emotions, also termed alexithymia, may possibly feature the frontotemporal-spectrum disorders. This study aims to determine whether alexithymia could be included within the frontotemporal syndromes of amyotrophic lateral sclerosis (ALS).

METHODS: Alexithymic traits were estimated in a cohort of 68 non-demented ALS patients with the 20-item Toronto Alexithymia Scale (TAS-20). Patients were assessed for the identification of motor-phenotypes and frontotemporal syndromes based on current classification criteria. Spearman's coefficients explored the correlates of TAS-20 measures with motor-functional profiles, global cognitive, social-cognitive (emotion recognition and empathy) and behavioral status.

RESULTS: Abnormal TAS-20 scores were found in 13% of patients, and their distribution did not vary within motor and frontotemporal phenotypes. Significant associations were detected between TAS-20 and executive (p ≤ .011), memory (p = .006), state-anxiety (p ≤ .013) and depression measures (p ≤ .010). By contrast, TAS-20 scores were unrelated to social-cognitive performances, dysexecutive and apathetic profiles. Disease duration was the only motor-functional feature being related to the TAS-20 (p ≤ .008).

CONCLUSIONS: Alexithymia of potential clinical relevance occur in a minority of ALS patients, and its neuropsychological correlates mostly resemble those featuring the general population. Hence, it is unlikely that alexithymia is a specific feature of frontotemporal-spectrum characterizing ALS, rather it could be an expression of psychogenic factors as a reaction to the disease.}, } @article {pmid38954254, year = {2025}, author = {Wang, Y and Wang, Y and Yin, H and Xiao, Z and Ren, Z and Ma, X and Zhang, J and Fu, X and Zhang, F and Zeng, L}, title = {BI1 Activates Autophagy and Mediates TDP43 to Regulate ALS Pathogenesis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {988-1030}, pmid = {38954254}, issn = {1559-1182}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Autophagy/physiology ; Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Humans ; Mitochondria/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Apoptosis ; Mice ; Neuromuscular Junction/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease in adults. Currently, there are no known drugs or clinical approaches that have demonstrated efficacy in treating ALS. Mitochondrial function and autophagy have been identified as crucial mechanisms in the development of ALS. While Bax inhibitor 1 (BI1) has been implicated in neurodegenerative diseases, its exact mechanism remains unknown. This study investigates the therapeutic impact of BI1 overexpression on ALS both in vivo and in vitro, revealing its ability to mitigate SOD1[G93A]-induced apoptosis, nuclear damage, mitochondrial dysfunction, and axonal degeneration of motor neurons. At the same time, BI1 prolongs onset time and lifespan of ALS mice, improves motor function, and alleviates neuronal damage, muscle damage, neuromuscular junction damage among other aspects. The findings indicate that BI1 can inhibit pathological TDP43 morphology and initially stimulate autophagy through interaction with TDP43. This study establishes a solid theoretical foundation for understanding the regulation of autophagy by BI1 and TDP43 while shedding light on the pathogenesis of ALS through their interaction - offering new concepts and targets for clinical implementation and drug development.}, } @article {pmid38953009, year = {2024}, author = {Rostás, R and Fekete, I and Horváth, L and Márton, S and Fekete, K}, title = {Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis.}, journal = {Open medicine (Warsaw, Poland)}, volume = {19}, number = {1}, pages = {20240990}, pmid = {38953009}, issn = {2391-5463}, abstract = {OBJECTIVE: Our aim was to examine the significance of single-fiber electromyography (SFEMG) in patients diagnosed with amyotrophic lateral sclerosis (ALS) and determine the best correlating parameter with SFEMG parameters and clinical scales across different muscles including facial muscles.

METHODS: SFEMG examinations were conducted on the extensor digitorum (ED), frontalis, and orbicularis oculi muscles. Mean jitter, percentage of increased jitter, fiber density (FD), and impulse blocking percentage were compared to reference values and functional scales.

RESULTS: Significant differences (p < 0.001) were observed between the patients' SFEMG results and reference values in all muscles. Significant correlations were found between SFEMG parameters and clinical scales, particularly when considering both FD and jitter. A notable value of the ALS Functional Rating Scale Revised (ALSFRS-R) was detected in all muscles: 31 points in the ED muscle, 30 in the orbicularis oculi muscle, and 31 in the frontalis muscle. Below this ALSFRS-R threshold, the percentage of increased jitter was higher, while FD remained relatively low.

CONCLUSION: SFEMG examination emerges as a valuable tool for better understanding ALS and holds potential for assessing prognosis. Combined jitter and FD analysis showed the strongest correlation with clinical scales. In addition to the ED muscle, the orbicularis oculi muscle may be important in the assessment.}, } @article {pmid38951798, year = {2024}, author = {Pottinger, TD and Motelow, JE and Povysil, G and Moreno, CAM and Ren, Z and Phatnani, H and , and Aitman, TJ and Santoyo-Lopez, J and , and Mitsumoto, H and , and , and , and Goldstein, DB and Harms, MB}, title = {Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.}, journal = {BMC genomics}, volume = {25}, number = {1}, pages = {651}, pmid = {38951798}, issn = {1471-2164}, support = {P01 AG007232/AG/NIA NIH HHS/United States ; U19 AI067854/AI/NIAID NIH HHS/United States ; R01 AG037212/AG/NIA NIH HHS/United States ; UM1 AI100645/AI/NIAID NIH HHS/United States ; T32 HL144442/HL/NHLBI NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/genetics ; Ethnicity/genetics ; Genetic Predisposition to Disease ; Genetic Variation ; European People ; East Asian People ; African People ; Hispanic or Latino ; Middle Eastern People ; South Asian People ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10[-39]; OR = 4.73, p = 2 × 10[-10]; OR = 2.3, p = 7.49 × 10[-9], respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10[-7]), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10[-16]). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10[-6]).

CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.}, } @article {pmid38951432, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {Comparison of in-person vs. remote administration of cognitive screening tools for people with ALS.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {11}, pages = {5309-5317}, pmid = {38951432}, issn = {1590-3478}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; Goldstein/Oct17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Middle Aged ; Aged ; *Neuropsychological Tests ; Videoconferencing ; Cognition Disorders/diagnosis/etiology ; Cognitive Dysfunction/diagnosis/etiology ; }, abstract = {OBJECTIVE: This study investigated whether cognitive screening tools used for people with amyotrophic lateral sclerosis (pwALS) are affected by the screen being administered face-to-face or remotely online. It also investigated whether demographic variables predicted total cognitive screen scores.

METHODS: The cognitive component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASc), the cognitive component of the ALS Cognitive Behavioural Screen (ALS-CBSc), and the Mini Addenbrooke's Cognitive Examination (Mini-ACE) were administered to 41 pwALS and 41 controls face-to-face. Versions of the cognitive screens designed to be administered remotely were administered to 57 pwALS and 44 controls via videoconferencing methods. Backwards stepwise linear regressions were conducted to assess whether total scores on the ECASc, ALS-CBSc, and Mini-ACE scores were predicted by administration mode (face-to-face or remote) or demographic variables.

RESULTS: Mode of administration significantly affected scores on the ECASc and ALS-CBSc; remote administration was associated with better total scores. Administration mode did not significantly affect Mini-ACE scores. All cognitive screens were significantly affected by IQ scores; higher IQ scores predicted better screening tool scores. Only ECASc scores were significantly affected by age, with older age predicting poorer scores. Being female was associated with better Mini-ACE scores; sex did not predict ECASc and ALS-CBSc scores.

CONCLUSIONS: Our results suggest that videoconferencing versions of the ECASc and ALS-CBSc may function differently to the original, face-to-face versions. There are advantages to using remote versions of cognitive screening tools but clinicians and researchers who use them should consider that they may not yield equivalent scores.}, } @article {pmid38951089, year = {2024}, author = {Zhang, JH and Chen, ZH and Ling, L and Cheng, HM and Zhang, Y and Zhao, JR and Huang, XS}, title = {[Analysis of the characteristics of patients with amyotrophic lateral sclerosis with neuromuscular junction dysfunction prior to motor neuron degeneration].}, journal = {Zhonghua nei ke za zhi}, volume = {63}, number = {7}, pages = {660-665}, doi = {10.3760/cma.j.cn112138-20230811-00049}, pmid = {38951089}, issn = {0578-1426}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Electromyography ; *Motor Neurons/physiology ; Neuromuscular Junction/physiopathology ; Electric Stimulation ; Accessory Nerve/physiopathology ; Male ; Female ; Middle Aged ; }, abstract = {Objective: To investigate the clinical and electrophysiological characteristics of patients with amyotrophic lateral sclerosis (ALS) with positive repetitive nerve stimulation (RNS) test results on the accessory nerve and negative needle electromyography (EMG) test results on the sternocleidomastoid with the goal to enrich the knowledge of disease progression in patients with ALS. Methods: The clinical data of 612 patients diagnosed with ALS at the Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to August 2022 were collected. In total, 267 cases had undergone EMG tests on the sternocleidomastoid following a positive 3 Hz RNS test result on the accessory nerve, who were selected as the study subjects. The differences in clinical indicators were compared between RNS (+)/EMG (-) group and RNS (+)/EMG (+) group. A binomial distribution model with multiple variables was built to quantitatively analyze the major factors and their effects. Results: At the initial visit, 15.8% of patients with ALS were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid, accounting for 36.3% of RNS (+) patients. The decremental range of the 3 Hz RNS test delivered to the accessory nerve in these patients [-14% (-19%, -12%)] was lower than that in patients with RNS (+)/EMG (+) [-17% (-23%, -13%)] (P<0.05), while the ratio of upper limb onset (64.9%) and non-definite diagnosis (28.9%) were higher [54.7% and 13.5% for patients with RNS (+)/EMG (+), P<0.05]. Furthermore, the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score [40 (37, 42)], body mass index (BMI) [23.8 (22.0, 25.4) kg/m[2]] and forced vital capacity (FVC) [92.8% (76.6%, 103.8%)] were higher in patients with RNS(+)/EMG(+) (P<0.05). The multivariate model suggested that, in patients with RNS (+)/EMG (-), the ratio of upper limb onset to lower limb onset was 1.04, while that of upper limb onset to bulbar onset was 2.02, and that of lower limb onset to bulbar onset was 1.94. The ratio of non-definite ALS to definite ALS was 1.13. The ALSFRS-R score, BMI, and FVC had a protective contribution to the electrophysiological function of the motor neurons. The ratio of the effect size of the ALSFRS-R or BMI to that of FVC was 3.37 and 1.14, respectively. Conclusions: Patients with ALS that were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid had a smaller decremental range of the compound muscle action potential amplitude, and a higher proportion of upper limb onset and non-definite ALS. A higher ALSFRS-R score, BMI, and FVC have a protective effect to the electrophysiological function of motor neurons. The effect size of the ALSFRS-R score is the largest, followed by BMI and FVC.}, } @article {pmid38948094, year = {2024}, author = {Haider, KH}, title = {Priming mesenchymal stem cells to develop "super stem cells".}, journal = {World journal of stem cells}, volume = {16}, number = {6}, pages = {623-640}, pmid = {38948094}, issn = {1948-0210}, abstract = {The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.}, } @article {pmid38946834, year = {2024}, author = {Taherifard, E and Saeed, A}, title = {Predicting liver function after hemihepatectomy in patients with hepatocellular carcinoma using different modalities.}, journal = {World journal of clinical oncology}, volume = {15}, number = {6}, pages = {783-785}, pmid = {38946834}, issn = {2218-4333}, abstract = {In response to Dr. Yue et al's study on prognostic factors for post-hemihepatectomy outcomes in hepatocellular carcinoma (HCC) patients, this critical review identifies methodological limitations and proposes enhancements for future research. While the study identifies liver stiffness measure and standard residual liver volume as potential predictors, concerns regarding small sample size, reliance on biochemical markers for safety assessment, and inadequate adjustment for confounding variables are raised. Recommendations for rigorous methodology, including robust statistical analysis, consideration of confounding factors, and selection of outcome measures with clinical components, are proposed to strengthen prognostic assessments. Furthermore, validation of novel evaluation models is crucial for enhancing clinical applicability and advancing understanding of postoperative outcomes in patients with HCC undergoing hemihepatectomy.}, } @article {pmid38946579, year = {2024}, author = {Trucco, AP and Backhouse, T and Mioshi, E}, title = {Describing and assessing behavioural symptoms in amyotrophic lateral sclerosis with and without frontotemporal dementia: a scoping review.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {603-610}, pmid = {38946579}, issn = {1473-6551}, mesh = {Humans ; *Frontotemporal Dementia/psychology/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; Behavioral Symptoms/etiology/diagnosis ; }, abstract = {PURPOSE OF REVIEW: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature.

FINDINGS: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD = 4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63 months (SD = 24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives.

SUMMARY: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy.}, } @article {pmid38944367, year = {2024}, author = {Wankhede, NL and Rajendra Kopalli, S and Dhokne, MD and Badnag, DJ and Chandurkar, PA and Mangrulkar, SV and Shende, PV and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Koppula, S and Kale, MB}, title = {Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health.}, journal = {Mitochondrion}, volume = {78}, number = {}, pages = {101926}, doi = {10.1016/j.mito.2024.101926}, pmid = {38944367}, issn = {1872-8278}, mesh = {Humans ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; Animals ; }, abstract = {Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.}, } @article {pmid38943180, year = {2024}, author = {Wiesner, D and Feldengut, S and Woelfle, S and Boeckers, TM and Ludolph, AC and Roselli, F and Del Tredici, K}, title = {Neuropeptide FF (NPFF)-positive nerve cells of the human cerebral cortex and white matter in controls, selected neurodegenerative diseases, and schizophrenia.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {108}, pmid = {38943180}, issn = {2051-5960}, support = {446067541//Deutsche Forschungsgemeinschaft/ ; 443642953//Deutsche Forschungsgemeinschaft/ ; 431995586//Deutsche Forschungsgemeinschaft/ ; 251293561//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *White Matter/pathology/metabolism ; Male ; *Schizophrenia/pathology/metabolism ; Female ; *Cerebral Cortex/pathology/metabolism ; Aged ; Middle Aged ; *Neurodegenerative Diseases/pathology/metabolism ; Aged, 80 and over ; Oligopeptides ; Adult ; Neurons/pathology/metabolism ; }, abstract = {We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles.}, } @article {pmid38943019, year = {2024}, author = {He, S and He, XX and Yang, HQ and Zhang, JW and Chen, S}, title = {Two new cases with the UBQLN2 gene mutation in Han Chinese.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {5047-5051}, pmid = {38943019}, issn = {1590-3478}, mesh = {Humans ; Female ; Male ; *Autophagy-Related Proteins/genetics ; Middle Aged ; *Mutation ; Young Adult ; Amyotrophic Lateral Sclerosis/genetics ; Adaptor Proteins, Signal Transducing/genetics ; China ; Adult ; Pedigree ; East Asian People ; }, abstract = {Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. [18]F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.}, } @article {pmid38942541, year = {2024}, author = {Shukla, H and John, D and Banerjee, S and Tiwari, AK}, title = {Drug repurposing for neurodegenerative diseases.}, journal = {Progress in molecular biology and translational science}, volume = {207}, number = {}, pages = {249-319}, doi = {10.1016/bs.pmbts.2024.03.035}, pmid = {38942541}, issn = {1878-0814}, mesh = {Humans ; *Drug Repositioning ; *Neurodegenerative Diseases/drug therapy ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.}, } @article {pmid38941189, year = {2024}, author = {Huang, WP and Ellis, BCS and Hodgson, RE and Sanchez Avila, A and Kumar, V and Rayment, J and Moll, T and Shelkovnikova, TA}, title = {Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114421}, doi = {10.1016/j.celrep.2024.114421}, pmid = {38941189}, issn = {2211-1247}, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *RNA Splicing/genetics ; *Cell Nucleus/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Stress, Physiological ; Animals ; Mice ; }, abstract = {TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may have extrinsic stressors as a "second hit." TDP-43 undergoes reversible nuclear condensation in stressed cells including neurons. Here, we demonstrate that stress-inducible nuclear TDP-43 condensates are RNA-depleted, non-liquid assemblies distinct from the known nuclear bodies. Their formation requires TDP-43 oligomerization and ATP and is inhibited by RNA. Using a confocal nanoscanning assay, we find that amyotrophic lateral sclerosis (ALS)-linked mutations alter stress-induced TDP-43 condensation by changing its affinity to liquid-like ribonucleoprotein assemblies. Stress-induced nuclear condensation transiently inactivates TDP-43, leading to loss of interaction with its protein binding partners and loss of function in splicing. Splicing changes are especially prominent and persisting for STMN2 RNA, and STMN2 protein becomes rapidly depleted early during stress. Our results point to early pathological changes to TDP-43 in the nucleus and support therapeutic modulation of stress response in ALS.}, } @article {pmid38940407, year = {2024}, author = {Xu, A and Liu, T and Liu, D and Li, W and Huang, H and Wang, S and Xu, L and Liu, X and Jiang, S and Chen, Y and Sun, M and Luo, Q and Ding, T and Yao, T}, title = {Edge-Rich Pt-O-Ce Sites in CeO2 Supported Patchy Atomic-Layer Pt Enable a Non-CO Pathway for Efficient Methanol Oxidation.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {40}, pages = {e202410545}, doi = {10.1002/anie.202410545}, pmid = {38940407}, issn = {1521-3773}, support = {12025505//the National Natural Science Foundation of China/ ; 22179125//the National Natural Science Foundation of China/ ; 12205304//the National Natural Science Foundation of China/ ; KY9990000214//USTC research startup funds/ ; 2021YFA1600800//the National Key R&D Program of China/ ; XDB0450200//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; GXXT-2020-053//the University of China Innovation Program of Anhui Province/ ; 2022458//the Youth Innovation Promotion Association CAS/ ; 2021TQ0319//the Fellowship of China Postdoctoral Science Foundation/ ; BX20240350//the Fellowship of China Postdoctoral Science Foundation/ ; WK2060000038//the Fundamental Research Funds for the Central Universities/ ; WK2310000113//the Fundamental Research Funds for the Central Universities/ ; }, abstract = {Rational design of efficient methanol oxidation reaction (MOR) catalyst that undergo non-CO pathway is essential to resolve the long-standing poisoning issue. However, it remains a huge challenge due to the rather difficulty in maximizing the non-CO pathway by the selective coupling between the key *CHO and *OH intermediates. Here, we report a high-performance electrocatalyst of patchy atomic-layer Pt epitaxial growth on CeO2 nanocube (Pt ALs/CeO2) with maximum electronic metal-support interaction for enhancing the coupling selectively. The small-size monolayer material achieves an optimal geometrical distance between edge Pt-O-Ce sites and *OH absorbed on CeO2, which well restrains the dehydrogenation of *CHO, resulting in the non-CO pathway. Meanwhile, the *CHO/*CO intermediate generated at inner Pt-O-Ce sites can migrate to edge, inducing the subsequent coupling reaction, thus avoiding poisoning while promoting reaction efficiency. Consequently, Pt ALs/CeO2 exhibits exceptionally catalytic stability with negligible degradation even under 1000 s pure CO poisoning operation and high mass activity (14.87 A/mgPt), enabling it one of the best-performing alkali-stable MOR catalysts.}, } @article {pmid38939990, year = {2024}, author = {Song, XY and Fan, CX and Rahman, AU and Choudhary, MI and Wang, XP}, title = {Neuro-regeneration or Repair: Cell Therapy of Neurological Disorders as A Way Forward.}, journal = {Current neuropharmacology}, volume = {22}, number = {14}, pages = {2272-2283}, pmid = {38939990}, issn = {1875-6190}, mesh = {Humans ; *Nervous System Diseases/therapy ; Animals ; *Cell- and Tissue-Based Therapy/methods ; Nerve Regeneration/physiology ; Stem Cell Transplantation/methods ; }, abstract = {The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the leading cause of medical burden globally. Most neurological disorders cannot be cured, and primary treatments focus on managing their symptoms and slowing down their progression. Cell therapy for neurological disorders offers several therapeutic potentials and provides hope for many patients. Here we provide a general overview of cell therapy in neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), stroke and traumatic brain injury (TBI), involving many forms of stem cells, including embryonic stem cells and induced pluripotent stem cells. We also address the current concerns and perspectives for the future. Most studies for cell therapy in neurological diseases are in the pre-clinical stage, and there is still a great need for further research to translate neural replacement and regenerative therapies into clinical settings.}, } @article {pmid38939546, year = {2024}, author = {Kararia, N and Kararia, V and Sharma, D and Gupta, S and Chaturvedi, S and Chaturvedi, Y}, title = {Comparative evaluation of the accuracy of two electronic apex locators in detecting simulated incomplete vertical root fractures: An in vitro stereomicroscopic study.}, journal = {Journal of conservative dentistry and endodontics}, volume = {27}, number = {5}, pages = {540-544}, pmid = {38939546}, issn = {2950-4708}, abstract = {AIM: The aim of this study was to compare the accuracy of two different electronic apex locators (EALs) in detecting simulated incomplete vertical root fractures (VRFs).

MATERIALS AND METHODS: Thirty freshly extracted single-rooted teeth were randomly divided into three groups of 10 teeth each labeled as Groups A, B, and C. Incomplete VRFs were simulated in the coronal, middle, and apical one-third of the roots for Groups A, B, and C, respectively. The teeth were embedded in alginate mold and fracture location was determined with Root ZX and Propex EALs for each sample and each group. To calculate the actual length (AL), each sample was sectioned at the upper level of the vertical fracture, and the length was measured by setting the stopper of the #10 K file under a stereomicroscope at ×30 magnification. The electronic lengths and ALs were compared using computer software, and the results were analyzed using SPSS 28.0 at a 95% confidence level.

RESULTS: No significant differences were seen in the accuracy of the two EALs when compared with ALs. Root ZX showed significantly longer measurements than ALs in groups B and C.

CONCLUSION: The tested EALs showed low accuracy (20%) in detecting simulated incomplete VRFs with a tendency for longer measurements compared to ALs.}, } @article {pmid38937912, year = {2024}, author = {Verde, F and Licaj, S and Soranna, D and Ticozzi, N and Silani, V and Zambon, A}, title = {Cerebrospinal fluid and blood neurofilament light chain levels in amyotrophic lateral sclerosis and frontotemporal degeneration: A meta-analysis.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16371}, pmid = {38937912}, issn = {1468-1331}, support = {//Ministero della Salute/ ; //BIBLIOSAN/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; *Frontotemporal Lobar Degeneration/blood/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid/blood ; Frontotemporal Dementia/cerebrospinal fluid/blood ; }, abstract = {BACKGROUND AND PURPOSE: Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta-analysis of NFL in ALS and FTD was performed.

METHODS: Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated.

RESULTS: In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences.

DISCUSSION: Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias.}, } @article {pmid38936435, year = {2024}, author = {Tondo, G and Mazzini, L and Caminiti, SP and Gallo, C and Matheoud, R and Comi, C and Sacchetti, GM and Perani, D and De Marchi, F}, title = {Coupling motor evoked potentials and brain [[18]F]FDG-PET in Amyotrophic Lateral Sclerosis: preliminary findings on disease severity.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106579}, doi = {10.1016/j.nbd.2024.106579}, pmid = {38936435}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism/physiopathology ; Male ; Female ; Middle Aged ; *Fluorodeoxyglucose F18 ; *Positron-Emission Tomography/methods ; *Transcranial Magnetic Stimulation/methods ; Aged ; Retrospective Studies ; *Brain/diagnostic imaging/metabolism/physiopathology ; *Evoked Potentials, Motor/physiology ; Adult ; Severity of Illness Index ; }, abstract = {BACKGROUND: The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation.

OBJECTIVE: To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [[18]F]FDG-PET measures of neural dysfunction.

METHODS: We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [[18]F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [[18]F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC).

RESULTS: Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [[18]F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC.

CONCLUSION: This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.}, } @article {pmid38935506, year = {2024}, author = {Halim, DO and Krishnan, G and Hass, EP and Lee, S and Verma, M and Almeida, S and Gu, Y and Kwon, DY and Fazzio, TG and Gao, FB}, title = {The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.}, journal = {Cell reports}, volume = {43}, number = {7}, pages = {114375}, pmid = {38935506}, issn = {2211-1247}, support = {RF1 NS101986/NS/NINDS NIH HHS/United States ; R21 NS119952/NS/NINDS NIH HHS/United States ; R01 HD104971/HD/NICHD NIH HHS/United States ; R37 NS057553/NS/NINDS NIH HHS/United States ; R21 NS112766/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA Repeat Expansion/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded G4C2 repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded G4C2 repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of G4C2 repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.}, } @article {pmid38934637, year = {2024}, author = {Tankus, A and Stern, E and Klein, G and Kaptzon, N and Nash, L and Marziano, T and Shamia, O and Gurevitch, G and Bergman, L and Goldstein, L and Fahoum, F and Strauss, I}, title = {A Speech Neuroprosthesis in the Frontal Lobe and Hippocampus: Decoding High-Frequency Activity into Phonemes.}, journal = {Neurosurgery}, volume = {}, number = {}, pages = {}, doi = {10.1227/neu.0000000000003068}, pmid = {38934637}, issn = {1524-4040}, support = {17630//Ministry of Science and Technology, Israel/ ; }, abstract = {BACKGROUND AND OBJECTIVES: Loss of speech due to injury or disease is devastating. Here, we report a novel speech neuroprosthesis that artificially articulates building blocks of speech based on high-frequency activity in brain areas never harnessed for a neuroprosthesis before: anterior cingulate and orbitofrontal cortices, and hippocampus.

METHODS: A 37-year-old male neurosurgical epilepsy patient with intact speech, implanted with depth electrodes for clinical reasons only, silently controlled the neuroprosthesis almost immediately and in a natural way to voluntarily produce 2 vowel sounds.

RESULTS: During the first set of trials, the participant made the neuroprosthesis produce the different vowel sounds artificially with 85% accuracy. In the following trials, performance improved consistently, which may be attributed to neuroplasticity. We show that a neuroprosthesis trained on overt speech data may be controlled silently.

CONCLUSION: This may open the way for a novel strategy of neuroprosthesis implantation at earlier disease stages (eg, amyotrophic lateral sclerosis), while speech is intact, for improved training that still allows silent control at later stages. The results demonstrate clinical feasibility of direct decoding of high-frequency activity that includes spiking activity in the aforementioned areas for silent production of phonemes that may serve as a part of a neuroprosthesis for replacing lost speech control pathways.}, } @article {pmid38934512, year = {2024}, author = {Zhang, J and Cao, W and Xie, J and Pang, C and Gao, L and Zhu, L and Li, Y and Yu, H and Du, L and Fan, D and Deng, B}, title = {Metabolic Syndrome and Risk of Amyotrophic Lateral Sclerosis: Insights from a Large-Scale Prospective Study.}, journal = {Annals of neurology}, volume = {96}, number = {4}, pages = {788-801}, doi = {10.1002/ana.27019}, pmid = {38934512}, issn = {1531-8249}, support = {12101460//National Natural Science Foundation of China/ ; 81901273//National Natural Science Foundation of China/ ; LQ21H090018//Natural Science Foundation of Zhejiang Province/ ; LQ22A010005//Natural Science Foundation of Zhejiang Province/ ; LQ22H020003//Natural Science Foundation of Zhejiang Province/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; KY2024-R054//Ethical Decision Committee of the Research Administration at First Affiliated Hospital of Wenzhou Medical University/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Male ; Female ; *Metabolic Syndrome/epidemiology ; Middle Aged ; Prospective Studies ; Aged ; Risk Factors ; Adult ; United Kingdom/epidemiology ; Body Mass Index ; Hypertension/epidemiology/complications ; }, abstract = {OBJECTIVE: Although metabolic abnormalities are implicated in the etiology of neurodegenerative diseases, their role in the development of amyotrophic lateral sclerosis (ALS) remains a subject of controversy. We aimed to identify the association between metabolic syndrome (MetS) and the risk of ALS.

METHODS: This study included 395,987 participants from the UK Biobank to investigate the relationship between MetS and ALS. Cox regression model was used to estimate hazard ratios (HR). Stratified analyses were performed based on gender, body mass index (BMI), smoking status, and education level. Mediation analysis was conducted to explore potential mechanisms.

RESULTS: In this study, a total of 539 cases of ALS were recorded after a median follow-up of 13.7 years. Patients with MetS (defined harmonized) had a higher risk of developing ALS after adjusting for confounding factors (HR: 1.50, 95% CI: 1.19-1.89). Specifically, hypertension and high triglycerides were linked to a higher risk of ALS (HR: 1.53, 95% CI: 1.19-1.95; HR: 1.31, 95% CI: 1.06-1.61, respectively). Moreover, the quantity of metabolic abnormalities showed significant results. Stratified analysis revealed that these associations are particularly significant in individuals with a BMI <25. These findings remained stable after sensitivity analysis. Notably, mediation analysis identified potential metabolites and metabolomic mediators, including alkaline phosphatase, cystatin C, γ-glutamyl transferase, saturated fatty acids to total fatty acids percentage, and omega-6 fatty acids to omega-3 fatty acids ratio.

INTERPRETATION: MetS exhibits a robust association with an increased susceptibility to ALS, particularly in individuals with a lower BMI. Furthermore, metabolites and metabolomics, as potential mediators, provide invaluable insights into the intricate biological mechanisms. ANN NEUROL 2024;96:788-801.}, } @article {pmid38934400, year = {2025}, author = {Chen, Y and Wei, Y and Liu, J and Zhu, T and Zhou, C and Zhang, D}, title = {Spatial transcriptomics combined with single-nucleus RNA sequencing reveals glial cell heterogeneity in the human spinal cord.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3302-3316}, doi = {10.4103/NRR.NRR-D-23-01876}, pmid = {38934400}, issn = {1673-5374}, abstract = {JOURNAL/nrgr/04.03/01300535-202511000-00032/figure1/v/2024-12-20T164640Z/r/image-tiff Glial cells play crucial roles in regulating physiological and pathological functions, including sensation, the response to infection and acute injury, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system, and satellite glial cells and Schwann cells in the peripheral nervous system. Despite the greater understanding of glial cell types and functional heterogeneity achieved through single-cell and single-nucleus RNA sequencing in animal models, few studies have investigated the transcriptomic profiles of glial cells in the human spinal cord. Here, we used high-throughput single-nucleus RNA sequencing and spatial transcriptomics to map the cellular and molecular heterogeneity of astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these findings with those from mice. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were each divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into five, four, and five distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cell types between humans and mice. Additionally, we detected sex differences in gene expression in human spinal cord glial cells. Specifically, in all astrocyte subtypes, the levels of NEAT1 and CHI3L1 were higher in males than in females, whereas the levels of CST3 were lower in males than in females. In all microglial subtypes, all differentially expressed genes were located on the sex chromosomes. In addition to sex-specific gene differences, the levels of MT-ND4 , MT2A , MT-ATP6 , MT-CO3 , MT-ND2 , MT-ND3 , and MT-CO2 in all spinal cord oligodendrocyte subtypes were higher in females than in males. Collectively, the present dataset extensively characterizes glial cell heterogeneity and offers a valuable resource for exploring the cellular basis of spinal cord-related illnesses, including chronic pain, amyotrophic lateral sclerosis, and multiple sclerosis.}, } @article {pmid38934222, year = {2024}, author = {Kim, A and Lee, DY and Sung, JJ}, title = {Cdk5 inhibition in the SOD1[G93A] transgenic mouse model of amyotrophic lateral sclerosis suppresses neurodegeneration and extends survival.}, journal = {Journal of neurochemistry}, volume = {168}, number = {9}, pages = {2908-2925}, doi = {10.1111/jnc.16160}, pmid = {38934222}, issn = {1471-4159}, support = {2018R1A5A2025964//National Research Foundation of Korea/ ; 2019M3C7A1031867//National Research Foundation of Korea/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Cells, Cultured ; *Cyclin-Dependent Kinase 5/metabolism/genetics/antagonists & inhibitors ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons/pathology/metabolism ; Nerve Degeneration/pathology/genetics/metabolism ; Superoxide Dismutase ; *Superoxide Dismutase-1/genetics ; tau Proteins/metabolism/genetics ; }, abstract = {Deregulated cyclin-dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous postmortem studies had revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS); hence, we investigated the effects of Cdk5 inhibition on ALS model mice and neurons in this study. For the in vitro study, motor neuron cell lines with wild-type superoxide dismutase 1 (SOD1) or SOD1[G93A] and primary neuronal cultures from SOD1[G93A] transgenic (TG) mice or non-TG mice were compared for the expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth by applying Cdk5-small interfering RNA or Cdk5-short hairpin RNA (shRNA). For the in vivo study, SOD1[G93A] mice and non-TG mice were intrathecally injected with adeno-associated virus 9 (AAV9)-scramble (SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Weight and motor function were measured three times per week from 60 days of age, longevity was evaluated, and the tissues were collected from 90-day-old or 120-day-old mice. Neurons with SOD1[G93A] showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, and enhanced neuroinflammation and apoptosis, all of which were reversed by Cdk5 inhibition. Weights did not show significant differences among non-TG and SOD1[G93A] mice with or without Cdk5 silencing. SOD1[G93A] mice treated with AAV9-Cdk5-shRNA showed significantly delayed disease onset, delayed rotarod failure, and prolonged survival compared with those treated with AAV9-SCR-shRNA. The brain and spinal cord of SOD1[G93A] mice intrathecally injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis, and an increased number of motor neurons compared to those of SOD1[G93A] mice injected with AAV9-SCR-shRNA. Cdk5 inhibition could be an important mechanism in the development of a new therapeutic strategy for ALS.}, } @article {pmid38932502, year = {2024}, author = {Stegmann, G and Krantsevich, C and Liss, J and Charles, S and Bartlett, M and Shefner, J and Rutkove, S and Kawabata, K and Talkar, T and Berisha, V}, title = {Automated speech analytics in ALS: higher sensitivity of digital articulatory precision over the ALSFRS-R.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {767-775}, pmid = {38932502}, issn = {2167-9223}, support = {R01 DC006859/DC/NIDCD NIH HHS/United States ; R43 DC017625/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Speech Disorders/etiology/diagnosis/physiopathology ; Speech/physiology ; Adult ; Speech Production Measurement/methods ; Algorithms ; Severity of Illness Index ; Disease Progression ; }, abstract = {Objective: Although studies have shown that digital measures of speech detected ALS speech impairment and correlated with the ALSFRS-R speech item, no study has yet compared their performance in detecting speech changes. In this study, we compared the performances of the ALSFRS-R speech item and an algorithmic speech measure in detecting clinically important changes in speech. Importantly, the study was part of a FDA submission which received the breakthrough device designation for monitoring ALS; we provide this paper as a roadmap for validating other speech measures for monitoring disease progression. Methods: We obtained ALSFRS-R speech subscores and speech samples from participants with ALS. We computed the minimum detectable change (MDC) of both measures; using clinician-reported listener effort and a perceptual ratings of severity, we calculated the minimal clinically important difference (MCID) of each measure with respect to both sets of clinical ratings. Results: For articulatory precision, the MDC (.85) was lower than both MCID measures (2.74 and 2.28), and for the ALSFRS-R speech item, MDC (.86) was greater than both MCID measures (.82 and .72), indicating that while the articulatory precision measure detected minimal clinically important differences in speech, the ALSFRS-R speech item did not. Conclusion: The results demonstrate that the digital measure of articulatory precision effectively detects clinically important differences in speech ratings, outperforming the ALSFRS-R speech item. Taken together, the results herein suggest that this speech outcome is a clinically meaningful measure of speech change.}, } @article {pmid38932488, year = {2024}, author = {Spencer, D and Polke, J and Campbell, J and Houlden, H and Radunovic, A}, title = {'Outcomes of genetic testing in the London MND Center: the importance of achieving timely results and correlations to family history'.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {737-742}, doi = {10.1080/21678421.2024.2370808}, pmid = {38932488}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Genetic Testing/methods ; London/epidemiology ; Middle Aged ; Aged ; Adult ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Mutation/genetics ; Aged, 80 and over ; Genetic Predisposition to Disease/genetics ; Medical History Taking/methods ; }, abstract = {Background: Despite recognition of the importance of genetic factors in the pathogenesis of MND and the increasing availability of genetic testing, testing practice remains highly variable. With the arrival of gene-targeted therapies there is a growing need to promptly identify actionable genetic results and patient death before receipt of results raises ethical dilemmas and limits access to novel therapies. Objective: To identify pathogenic mutations within a London tertiary MND center and their correlation with family history. To record waiting times for genetic results and deaths prior to receipt of results. Methods: In this series of 100 cases, genetic testing was offered to all patients with an MND diagnosis from the tertiary clinic. Data on demographics, disease progression and a detailed family history were taken. Time to receipt of genetic results and patient deaths prior to this were recorded. Results: Of the 97 patients who accepted testing a genetic cause was identified in 10%, including seven C9orf72 and two positive SOD1 cases. Only three patients with positive genetic findings had a family history of MND, although alternative neurological diagnoses and symptoms in the family were frequently reported. 14% of patients who underwent testing were deceased by the time results were received, including one actionable SOD1 case. Conclusions: Genetic testing should be made available to all patients who receive an MND diagnosis as family history alone is inadequate to identify potential familial cases. Time to receipt of results remains a significant issue due to the limited life expectancy following diagnosis.}, } @article {pmid38929462, year = {2024}, author = {De Marchi, I and Buffone, F and Mauro, A and Bruini, I and Vismara, L}, title = {Manual Therapy of Dysphagia in a Patient with Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {6}, pages = {}, pmid = {38929462}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; Male ; *Deglutition Disorders/etiology/therapy ; Middle Aged ; Manipulation, Osteopathic/methods ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable rare neurodegenerative condition, with 45% of cases showing the symptom of dysphagia; its clinical signs are atrophy, weakness, and fasciculations of the facial muscles, tongue, and pharynx. Furthermore, dysphagia is the main cause of aspiration pneumonia. The traditional treatment for dysphagia varies based on the patient's difficulty of swallowing. The initial phase consists of dietary consistency adjustments, progressing to alternatives like nasogastric tubes or percutaneous endoscopic gastrostomy (PEG) in advanced stages. Osteopathic manipulative treatment (OMT) is a complementary 'hands-on' approach that has already shown positive results as an add-on therapy in various health conditions. This study is a case report of a man diagnosed with ALS with initial dysphagia, managed with a protocol that extraordinarily included OMT. The patient showed somatic dysfunctions in the mediastinal region, upper cervical region, and occipital area which are all anatomically related to the nervous system, especially the glossopharyngeal reflex. At the end of the rehabilitation protocol, there was a reduction in the swallowing problems measured with Strand Scale and swallowing tests, and the patient reported an improved psycho-physical well-being assessed with the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40). Instead, the neurological function measured with ALSFRS-S remained stable. Although the nature of this study design prevents any causal assumption, the positive results should lead to future randomized controlled trials to assess the effectiveness of OMT as an adjunctive therapeutic proposal to improve the health of ALS patients.}, } @article {pmid38929429, year = {2024}, author = {Hillaert, A and Sanmiguel Serpa, LC and Xu, Y and Hesta, M and Bogaert, S and Vanderperren, K and Pullens, P}, title = {Optimization of Fair Arterial Spin Labeling Magnetic Resonance Imaging (ASL-MRI) for Renal Perfusion Quantification in Dogs: Pilot Study.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {12}, pages = {}, pmid = {38929429}, issn = {2076-2615}, support = {01D27919//Special Research Fund of Ghent University, Belgium/ ; }, abstract = {Arterial spin labeling (ASL) MRI allows non-invasive quantification of renal blood flow (RBF) and shows great potential for renal assessment. To our knowledge, renal ASL-MRI has not previously been performed in dogs. The aim of this pilot study was to determine parameters essential for ALS-MRI-based quantification of RBF in dogs: T1, blood (longitudinal relaxation time), λ (blood tissue partition coefficient) and TI (inversion time). A Beagle was scanned at 3T with a multi-TI ASL sequence, with TIs ranging from 250 to 2500 ms, to determine the optimal TI value. The T1 of blood for dogs was determined by scanning a blood sample with a 2D IR TSE sequence. The water content of the dog's kidney was determined by analyzing kidney samples from four dogs with a moisture analyzer and was subsequently used to calculate λ. The optimal TI and the measured values for T1,blood, and λ were 2000 ms, 1463 ms and 0.91 mL/g, respectively. These optimized parameters for dogs resulted in lower RBF values than those obtained from inline generated RBF maps. In conclusion, this study determined preliminary parameters essential for ALS-MRI-based RBF quantification in dogs. Further research is needed to confirm these values, but it may help guide future research.}, } @article {pmid38928874, year = {2024}, author = {Szulc, A and Wiśniewska, K and Żabińska, M and Gaffke, L and Szota, M and Olendzka, Z and Węgrzyn, G and Pierzynowska, K}, title = {Effectiveness of Flavonoid-Rich Diet in Alleviating Symptoms of Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {12}, pages = {}, pmid = {38928874}, issn = {2304-8158}, support = {533-0C20-GS0D-24//University of Gdansk/ ; }, abstract = {Over the past decades, there has been a significant increase in the burden of neurological diseases, including neurodegenerative disorders, on a global scale. This is linked to a widespread demographic trend in which developed societies are aging, leading to an increased proportion of elderly individuals and, concurrently, an increase in the number of those afflicted, posing one of the main public health challenges for the coming decades. The complex pathomechanisms of neurodegenerative diseases and resulting varied symptoms, which differ depending on the disease, environment, and lifestyle of the patients, make searching for therapies for this group of disorders a formidable challenge. Currently, most neurodegenerative diseases are considered incurable. An important aspect in the fight against and prevention of neurodegenerative diseases may be broadly understood lifestyle choices, and more specifically, what we will focus on in this review, a diet. One proposal that may help in the fight against the spread of neurodegenerative diseases is a diet rich in flavonoids. Flavonoids are compounds widely found in products considered healthy, such as fruits, vegetables, and herbs. Many studies indicated not only the neuroprotective effects of these compounds but also their ability to reverse changes occurring during the progression of diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Here, we present the main groups of flavonoids, discussing their characteristics and mechanisms of action. The most widely described mechanisms point to neuroprotective functions due to strong antioxidant and anti-inflammatory effects, accompanied with their ability to penetrate the blood-brain barrier, as well as the ability to inhibit the formation of protein aggregates. The latter feature, together with promoting removal of the aggregates is especially important in neurodegenerative diseases. We discuss a therapeutic potential of selected flavonoids in the fight against neurodegenerative diseases, based on in vitro studies, and their impact when included in the diet of animals (laboratory research) and humans (population studies). Thus, this review summarizes flavonoids' actions and impacts on neurodegenerative diseases. Therapeutic use of these compounds in the future is potentially possible but depends on overcoming key challenges such as low bioavailability, determining the therapeutic dose, and defining what a flavonoid-rich diet is and determining its potential negative effects. This review also suggests further research directions to address these challenges.}, } @article {pmid38928564, year = {2024}, author = {Lin, CY and Vanoverbeke, V and Trent, D and Willey, K and Lee, YS}, title = {The Spatiotemporal Expression of SOCS3 in the Brainstem and Spinal Cord of Amyotrophic Lateral Sclerosis Mice.}, journal = {Brain sciences}, volume = {14}, number = {6}, pages = {}, pmid = {38928564}, issn = {2076-3425}, support = {2022-040//Cleveland Clinic Technology Development Investment Project and Ohio Third Frontier Technology Validation and Start-up Fund/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons from the brain and spinal cord. The excessive neuroinflammation is thought to be a common determinant of ALS. Suppressor of cytokine signaling-3 (SOCS3) is pathologically upregulated after injury/diseases to negatively regulate a broad range of cytokines/chemokines that mediate inflammation; however, the role that SOCS3 plays in ALS pathogenesis has not been explored. Here, we found that SOCS3 protein levels were significantly increased in the brainstem of the superoxide dismutase 1 (SOD1)-G93A ALS mice, which is negatively related to a progressive decline in motor function from the pre-symptomatic to the early symptomatic stage. Moreover, SOCS3 levels in both cervical and lumbar spinal cords of ALS mice were also significantly upregulated at the pre-symptomatic stage and became exacerbated at the early symptomatic stage. Concomitantly, astrocytes and microglia/macrophages were progressively increased and reactivated over time. In contrast, neurons were simultaneously lost in the brainstem and spinal cord examined over the course of disease progression. Collectively, SOCS3 was first found to be upregulated during ALS progression to directly relate to both increased astrogliosis and increased neuronal loss, indicating that SOCS3 could be explored to be as a potential therapeutic target of ALS.}, } @article {pmid38928553, year = {2024}, author = {Di Martino, P and Marcozzi, V and Bibbò, S and Ghinassi, B and Di Baldassarre, A and Gaggi, G and Di Credico, A}, title = {Unraveling the Epigenetic Landscape: Insights into Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.}, journal = {Brain sciences}, volume = {14}, number = {6}, pages = {}, pmid = {38928553}, issn = {2076-3425}, support = {MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, Developmental Neurotoxi-city of Endocrine Disruptors from Plastic Pollutants.//NextGenerationEU "MUR-Fondo Promozione e Sviluppo-DM 737/2021, DEFENDANTs, De-velopmental Neurotoxicity of Endocrine Disruptors from Plastic Pollutants./ ; }, abstract = {Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are examples of neurodegenerative movement disorders (NMDs), which are defined by a gradual loss of motor function that is frequently accompanied by cognitive decline. Although genetic abnormalities have long been acknowledged as significant factors, new research indicates that epigenetic alterations are crucial for the initiation and development of disease. This review delves into the complex interactions that exist between the pathophysiology of NMDs and epigenetic mechanisms such DNA methylation, histone modifications, and non-coding RNAs. Here, we examine how these epigenetic changes could affect protein aggregation, neuroinflammation, and gene expression patterns, thereby influencing the viability and functionality of neurons. Through the clarification of the epigenetic terrain underpinning neurodegenerative movement disorders, this review seeks to enhance comprehension of the underlying mechanisms of the illness and augment the creation of innovative therapeutic strategies.}, } @article {pmid38927681, year = {2024}, author = {Adler, GL and Le, K and Fu, Y and Kim, WS}, title = {Human Endogenous Retroviruses in Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927681}, issn = {2073-4425}, mesh = {Humans ; *Endogenous Retroviruses/genetics/pathogenicity ; *Neurodegenerative Diseases/virology/genetics ; Amyotrophic Lateral Sclerosis/virology/genetics ; Animals ; }, abstract = {Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by the fact that they comprise approximately 8% of the human genome. HERVs have been implicated in the pathogenesis of neurodegenerative diseases, a group of CNS diseases characterized by a progressive loss of structure and function of neurons, resulting in cell death and multiple physiological dysfunctions. Much evidence indicates that HERVs are initiators or drivers of neurodegenerative processes in multiple sclerosis and amyotrophic lateral sclerosis, and clinical trials have been designed to target HERVs. In recent years, the role of HERVs has been explored in other major neurodegenerative diseases, including frontotemporal dementia, Alzheimer's disease and Parkinson's disease, with some interesting discoveries. This review summarizes and evaluates the past and current research on HERVs in neurodegenerative diseases. It discusses the potential role of HERVs in disease manifestation and neurodegeneration. It critically reviews antiretroviral strategies used in the therapeutic intervention of neurodegenerative diseases.}, } @article {pmid38927674, year = {2024}, author = {Gotte, G}, title = {Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS).}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927674}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Ribonuclease, Pancreatic/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; Animals ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS.}, } @article {pmid38927671, year = {2024}, author = {Carata, E and Muci, M and Mariano, S and Di Giulio, S and Nigro, A and Romano, A and Panzarini, E}, title = {Extracellular Vesicles from NSC-34 MN-like Cells Transfected with Mutant SOD1 Modulate Inflammatory Status of Raw 264.7 Macrophages.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927671}, issn = {2073-4425}, mesh = {Animals ; *Extracellular Vesicles/metabolism/genetics ; Mice ; RAW 264.7 Cells ; *Superoxide Dismutase-1/genetics/metabolism ; *Macrophages/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Motor Neurons/metabolism ; Inflammation/genetics/metabolism/pathology ; Mutation ; Transfection ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting the brain and spinal cord. Non-neuronal cells, including macrophages, may contribute to the disruption of motor neurons (MNs), neuromuscular junction dismantling and clinical signs of ALS. Understanding the modality and the effect of MNs-macrophage communication is pivotal. Here, we focus on extracellular vesicle (EVS)-mediated communication and, in particular, we analyze the response of macrophages. NSC-34 cells transfected with mutant SOD1 (G93A, A4V, G85R, G37R) and differentiated towards MN-like cells, and Raw 264.7 macrophages are the cellular models of the study. mSOD1 NSC-34 cells release a high number of vesicles, both large-lEVs (300 nm diameter) and small-sEVs (90 nm diameter), containing inflammation-modulating molecules, and are efficiently taken up by macrophages. RT-PCR analysis of inflammation mediators demonstrated that the conditioned medium of mSOD1 NSC-34 cells polarizes Raw 264.7 macrophages towards both pro-inflammatory and anti-inflammatory phenotypes. sEVs act on macrophages in a time-dependent manner: an anti-inflammatory response mediated by TGFβ firstly starts (12 h); successively, the response shifts towards a pro-inflammation IL-1β-mediated (48 h). The response of macrophages is strictly dependent on the SOD1 mutation type. The results suggest that EVs impact physiological and behavioral macrophage processes and are of potential relevance to MN degeneration.}, } @article {pmid38927616, year = {2024}, author = {Wang, H and Guan, L and Ma, X and Wang, Y and Wang, J and Zhang, P and Deng, M}, title = {Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis.}, journal = {Genes}, volume = {15}, number = {6}, pages = {}, pmid = {38927616}, issn = {2073-4425}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; China ; East Asian People/genetics ; *Kinesins/genetics ; Mutation ; *Mutation, Missense ; Pedigree ; Phenotype ; *Whole Genome Sequencing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.}, } @article {pmid38927501, year = {2024}, author = {Parvanovova, P and Evinova, A and Grofik, M and Hnilicova, P and Tatarkova, Z and Turcanova-Koprusakova, M}, title = {Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry.}, journal = {Biomedicines}, volume = {12}, number = {6}, pages = {}, pmid = {38927501}, issn = {2227-9059}, abstract = {Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology of the disease, since the mitochondria are involved in many processes in the cell; however, the exact mechanism of involvement is still unclear. We used peripheral blood mononuclear cells isolated from whole fresh blood from patients with amyotrophic lateral sclerosis for measurement and matched an age- and sex-matched set of healthy subjects. The group of patients consisted of patients examined and diagnosed at the neurological clinic of the University Hospital Martin. The set of controls consisted of healthy individuals who were actively searched, and controls were selected on the basis of age and sex. The group consisted of 26 patients with sporadic forms of ALS (13 women, 13 men), diagnosed based on the definitive criteria of El Escorial. The average age of patients was 54 years, and the average age of healthy controls was 56 years. We used a high-resolution O2K respirometry method, Oxygraph-2k, to measure mitochondrial respiration. Basal respiration was lower in patients by 29.48%, pyruvate-stimulated respiration (respiratory chain complex I) was lower by 29.26%, and maximal respiratory capacity was lower by 28.15%. The decrease in succinate-stimulated respiration (respiratory chain complex II) was 26.91%. Our data confirm changes in mitochondrial respiration in ALS patients, manifested by the reduced function of complex I and complex II of the respiratory chain. These defects are severe enough to confirm this disease's hypothesized mitochondrial damage. Therefore, research interest in the future should be directed towards a deeper understanding of the involvement of mitochondria and respiratory complexes in the pathophysiology of the disease. This understanding could develop new biomarkers in diagnostics and subsequent therapeutic interventions.}, } @article {pmid38927130, year = {2024}, author = {Vilardo, B and De Marchi, F and Raineri, D and Manfredi, M and De Giorgis, V and Bebeti, A and Scotti, L and Kustrimovic, N and Cappellano, G and Mazzini, L and Chiocchetti, A}, title = {Shotgun Proteomics Links Proteoglycan-4[+] Extracellular Vesicles to Cognitive Protection in Amyotrophic Lateral Sclerosis.}, journal = {Biomolecules}, volume = {14}, number = {6}, pages = {}, pmid = {38927130}, issn = {2218-273X}, support = {953121//European Union's Horizon 2020 Research and Innovation Program/ ; FOHN//Ministero dell'Istruzione e del Merito/ ; AGING//Ministero dell'Istruzione e del Merito/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; Male ; Middle Aged ; Female ; *Biomarkers/blood/metabolism ; Aged ; Proteoglycans/metabolism ; Cognition ; Case-Control Studies ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder lacking reliable biomarkers for early diagnosis and disease progression monitoring. This study aimed to identify the novel biomarkers in plasmatic extracellular vesicles (EVs) isolated from ALS patients and healthy controls (HCs). A total of 61 ALS patients and 30 age-matched HCs were enrolled in the study and the protein content of circulating EVs was analyzed by shotgun proteomics. The study was divided into a discovery phase (involving 12 ALS and 12 HC patients) and a validation one (involving 49 ALS and 20 HC patients). In the discovery phase, more than 300 proteins were identified, with 32 proteins showing differential regulation in ALS patients compared to HCs. In the validation phase, over 400 proteins were identified, with 20 demonstrating differential regulation in ALS patients compared to HCs. Notably, seven proteins were found to be common to both phases, all of which were significantly upregulated in EVs from ALS patients. Most of them have previously been linked to ALS since they have been detected in the serum or cerebrospinal fluid of ALS patients. Among them, proteoglycan (PRG)-4, also known as lubricin, was of particular interest since it was significantly increased in ALS patients with normal cognitive and motor functions. This study highlights the significance of EVs as a promising avenue for biomarker discovery in ALS. Moreover, it sheds light on the unexpected role of PRG-4 in relation to cognitive status in ALS patients.}, } @article {pmid38926444, year = {2024}, author = {Bhuyan, P and Chatterjee, K}, title = {Estimating prevalence of post-war health disorders using multiple systems data.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {14763}, pmid = {38926444}, issn = {2045-2322}, support = {Category-I Research Project Grant (No. 3878/RP: PSEISMC-RDA HIVS)//Indian Institute of Management Calcutta/ ; Core Research Grant (No. CRG/2019/003204)//Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India/ ; }, mesh = {Humans ; Prevalence ; *Amyotrophic Lateral Sclerosis/epidemiology ; Veterans/statistics & numerical data ; Algorithms ; Monte Carlo Method ; Gulf War ; }, abstract = {Effective surveillance on the long-term public health impact due to war and terrorist attacks remains limited. Such health issues are commonly under-reported, specifically for a large group of individuals. For this purpose, efficient estimation of the size or undercount of the population under the risk of physical and mental health hazards is of utmost necessity. A novel trivariate Bernoulli model is developed allowing heterogeneity among the individuals and dependence between the sources of information, and an estimation methodology using a Monte Carlo-based EM algorithm is proposed. Simulation results show the superiority of the performance of the proposed method over existing competitors and robustness under model mis-specifications. The method is applied to analyse two real case studies on monitoring amyotrophic lateral sclerosis (ALS) cases for the Gulf War veterans and the 9/11 terrorist attack survivors at the World Trade Center, USA. The average annual cumulative incidence rate for ALS disease increases by 33 % and 16 % for deployed and no-deployed military personnel, respectively, after adjusting the undercount. The number of individuals exposed to the risk of physical and mental health effects due to WTC terrorist attacks increased by 42 % . These results provide interesting insights that can assist in effective decision-making and policy formulation for monitoring the health status of post-war survivors.}, } @article {pmid38925911, year = {2024}, author = {De La Cruz, E and Esselin, F and Polge, A and Mouzat, K and Guissart, C}, title = {Most SOD1 mutations are pathogenic, and their identification can lead to early access to treatment.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {12}, pages = {1219-1220}, doi = {10.1136/jnnp-2024-333939}, pmid = {38925911}, issn = {1468-330X}, } @article {pmid38925110, year = {2024}, author = {Wyse-Sookoo, K and Luo, S and Candrea, D and Schippers, A and Tippett, DC and Wester, B and Fifer, M and Vansteensel, MJ and Ramsey, NF and Crone, NE}, title = {Stability of ECoG high gamma signals during speech and implications for a speech BCI system in an individual with ALS: a year-long longitudinal study.}, journal = {Journal of neural engineering}, volume = {21}, number = {4}, pages = {}, pmid = {38925110}, issn = {1741-2552}, support = {T32 EB003383/EB/NIBIB NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Brain-Computer Interfaces ; Longitudinal Studies ; *Electrocorticography/methods ; *Speech/physiology ; Male ; Gamma Rhythm/physiology ; Middle Aged ; Female ; Electrodes, Implanted ; }, abstract = {Objective.Speech brain-computer interfaces (BCIs) have the potential to augment communication in individuals with impaired speech due to muscle weakness, for example in amyotrophic lateral sclerosis (ALS) and other neurological disorders. However, to achieve long-term, reliable use of a speech BCI, it is essential for speech-related neural signal changes to be stable over long periods of time. Here we study, for the first time, the stability of speech-related electrocorticographic (ECoG) signals recorded from a chronically implanted ECoG BCI over a 12 month period.Approach.ECoG signals were recorded by an ECoG array implanted over the ventral sensorimotor cortex in a clinical trial participant with ALS. Because ECoG-based speech decoding has most often relied on broadband high gamma (HG) signal changes relative to baseline (non-speech) conditions, we studied longitudinal changes of HG band power at baseline and during speech, and we compared these with residual high frequency noise levels at baseline. Stability was further assessed by longitudinal measurements of signal-to-noise ratio, activation ratio, and peak speech-related HG response magnitude (HG response peaks). Lastly, we analyzed the stability of the event-related HG power changes (HG responses) for individual syllables at each electrode.Main Results.We found that speech-related ECoG signal responses were stable over a range of syllables activating different articulators for the first year after implantation.Significance.Together, our results indicate that ECoG can be a stable recording modality for long-term speech BCI systems for those living with severe paralysis.Clinical Trial Information.ClinicalTrials.gov, registration number NCT03567213.}, } @article {pmid38924779, year = {2024}, author = {Bratches, RWR and Cohen, J and Carpenter-Song, E and Mistler, L and Barr, PJ}, title = {The Feasibility and Acceptability of Sharing Video Recordings of Amyotrophic Lateral Sclerosis Clinical Encounters With Patients and Their Caregivers: Pilot Randomized Clinical Trial.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e57519}, pmid = {38924779}, issn = {2561-326X}, abstract = {BACKGROUND: Multidisciplinary clinics (MDCs) provide benefits to patients with amyotrophic lateral sclerosis (ALS) and their caregivers, but MDC visits are information-heavy and can last 4 hours, with patients and caregivers meeting with multiple specialists within each MDC visit. There are questions about the effectiveness of current methods of sharing information from MDCs with patients. Video recordings are a promising new method of sharing information that may allow patients and caregivers to revisit the MDC and remind them of clinical recommendations and conversations.

OBJECTIVE: The objective of this trial is to determine the feasibility and acceptability of sharing information through video recordings of ALS MDC visits with patients and caregivers.

METHODS: This study was a randomized, controlled pilot trial with 3 months of follow-up from April 2021 to March 2022 in a rural multidisciplinary neurology clinic. We recruited patients with ALS, their caregivers, and their clinicians. Patients and their caregivers were randomized to either receive their normal after-visit summary (treatment as usual) or to receive their normal after-visit summary and a video recording of their MDC visit (video). Each specialist visit had its own recording and was accessible by patients and caregivers using a secure web-based platform called HealthPAL over a 3-month follow-up period. Primary study outcomes were feasibility and acceptability of the video intervention measured by recruitment rate (target: 70%), percentage of participants watching videos (target: 75%), and the Feasibility of Intervention Measure and Acceptability of Intervention Measure (targets: 3/5). We hypothesized that video recording would be feasible and acceptable to patients and their caregivers.

RESULTS: Of the 30 patients approached, 24 were recruited, while all caregivers (n=21) and clinicians (n=34) approached were recruited. A total of 144 specialist visits were recorded, approximately 12 specialist visits at a median of one MDC visit per patient. Of the recorded patients, 75% (9/12) viewed videos. High median intervention feasibility (4, SD 0.99) and acceptability (4, SD 1.22) of intervention measures were reported by patients and caregivers in the intervention arm. High median intervention feasibility (5, SD 0.21) and acceptability (4.88, SD 0.4) were reported by clinicians. Of the 24 patients, 50% (n=12) did not complete a 3-month follow-up, primarily due to death (n=10).

CONCLUSIONS: Video recording is highly feasible and acceptable for patients, caregivers, and clinicians at a rural ALS clinic. Our level of attrition is a useful benchmark for future studies in MDC populations. Despite high rates of patient death, 1-week assessments highlight the value of recordings for both patients and caregivers.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04719403; https://clinicaltrials.gov/study/NCT04719403.}, } @article {pmid38924719, year = {2024}, author = {Shaw, PJ and Cooper-Knock, J}, title = {Physical Activity as a Risk Factor for Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209689}, doi = {10.1212/WNL.0000000000209689}, pmid = {38924719}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Risk Factors ; *Exercise ; }, } @article {pmid38924713, year = {2024}, author = {Vaage, AM and Meyer, HE and Landgraff, IK and Myrstad, M and Holmøy, T and Nakken, O}, title = {Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209575}, doi = {10.1212/WNL.0000000000209575}, pmid = {38924713}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology ; Male ; Female ; Adult ; Middle Aged ; Prospective Studies ; Norway/epidemiology ; *Physical Fitness/physiology ; Risk Factors ; Heart Rate/physiology ; Exercise/physiology ; Cohort Studies ; Proportional Hazards Models ; Motor Activity/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Observational studies have demonstrated an increased amyotrophic lateral sclerosis (ALS) risk among professional athletes in various sports. For moderately increased levels of physical activity and fitness, the results are diverging. Through a cohort study, we aimed to assess the relationship between indicators of physical activity and fitness (self-reported physical activity and resting heart rate) and long-term ALS risk.

METHODS: From a large Norwegian cardiovascular health survey (1985-1999), we collected information on self-reported physical activity in leisure time, resting heart rate, and other cardiovascular risk factors. Patients with ALS were identified through health registries covering the whole population. We fitted Cox proportional hazard models to assess the risk of ALS according to levels of self-reported physical activity in 3 categories (1: sedentary; 2: minimum 4 hours per week of walking or cycling; 3: minimum 4 hours per week of recreational sports or hard training), and resting heart rate modeled both on the continuous scale and as quartiles of distribution.

RESULTS: Out of 373,696 study participants (mean 40.9 [SD 1.1] years at inclusion), 504 (41.2% women) developed ALS during a mean follow-up time of 27.2 (SD 5.0) years. Compared with participants with the lowest level of physical activity, the hazard ratio was 0.71 (95% CI 0.53-0.95) for those with the highest level. There were no clear associations between resting heart rate and ALS in the total sample. In men, the hazard ratio of ALS was 0.71 (95% CI 0.53-0.95) for those reporting moderate levels of physical activity and 0.59 (95% CI 0.42-0.84) for those reporting high levels, compared with those reporting low levels. Men with resting heart rate in the lowest quartile had 32% reduced risk of ALS (hazard ratio 0.68, 95% CI 0.49-0.94) compared with those in the second highest quartile. In women, no association was detected between neither self-reported levels of physical activity nor resting heart rate and ALS risk.

DISCUSSION: Indicators of high levels of physical activity and fitness are associated with a reduced risk of ALS more than 30 years later in men, but not in women.}, } @article {pmid38924633, year = {2024}, author = {Wolf, J and Buckley, GJ and Rozanski, EA and Fletcher, DJ and Boller, M and Burkitt-Creedon, JM and Weigand, KA and Crews, M and Fausak, ED and , }, title = {2024 RECOVER Guidelines: Advanced Life Support. Evidence and knowledge gap analysis with treatment recommendations for small animal CPR.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {44-75}, doi = {10.1111/vec.13389}, pmid = {38924633}, issn = {1476-4431}, support = {//Zoetis Animal Health/ ; //Boehringer Ingelheim Animal Health/ ; }, mesh = {Animals ; Dogs ; Cats ; *Dog Diseases/therapy/drug therapy ; Cardiopulmonary Resuscitation/veterinary/standards ; Cat Diseases/therapy/drug therapy ; Veterinary Medicine/standards ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: To systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps.

DESIGN: Standardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4 weeks prior to finalization.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: Seventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats.

CONCLUSIONS: These updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.}, } @article {pmid38924627, year = {2024}, author = {Burkitt-Creedon, JM and Boller, M and Fletcher, DJ and Brainard, BM and Buckley, GJ and Epstein, SE and Fausak, ED and Hopper, K and Lane, SL and Rozanski, EA and Wolf, J}, title = {2024 RECOVER Guidelines: Updated treatment recommendations for CPR in dogs and cats.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {34 Suppl 1}, number = {}, pages = {104-123}, doi = {10.1111/vec.13391}, pmid = {38924627}, issn = {1476-4431}, support = {//Boehringer Ingelheim Animal Health/ ; //Zoetis Animal Health/ ; }, mesh = {Dogs ; Animals ; Cats ; *Cardiopulmonary Resuscitation/veterinary/standards/methods ; *Cat Diseases/therapy ; Dog Diseases/therapy ; Heart Arrest/veterinary/therapy ; }, abstract = {OBJECTIVE: After the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring.

DESIGN: These RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4 weeks.

SETTING: Transdisciplinary, international collaboration in university, specialty, and emergency practice.

RESULTS: A total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided.

CONCLUSIONS: While the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10 years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.}, } @article {pmid38924530, year = {2024}, author = {Deutsch, AJ and Elbasiouny, SM}, title = {Dysregulation of persistent inward and outward currents in spinal motoneurons of symptomatic SOD1-G93A mice.}, journal = {The Journal of physiology}, volume = {602}, number = {15}, pages = {3715-3736}, pmid = {38924530}, issn = {1469-7793}, support = {NS131816-S2/NS/NINDS NIH HHS/United States ; R01 NS131816/NS/NINDS NIH HHS/United States ; AG067758/AG/NIA NIH HHS/United States ; NS091836/NS/NINDS NIH HHS/United States ; R01 NS091836/NS/NINDS NIH HHS/United States ; NS131816/NS/NINDS NIH HHS/United States ; R01 AG067758/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics/pathology ; Mice ; *Mice, Transgenic ; Spinal Cord/physiology ; Superoxide Dismutase-1/genetics ; Male ; Female ; Mice, Inbred C57BL ; Action Potentials ; }, abstract = {Persistent inward currents (PICs) and persistent outward currents (POCs) regulate the excitability and firing behaviours of spinal motoneurons (MNs). Given their potential role in MN excitability dysfunction in amyotrophic lateral sclerosis (ALS), PICs have been previously studied in superoxide dismutase 1 (SOD1)-G93A mice (the standard animal model of ALS); however, conflicting results have been reported on how the net PIC changes during disease progression. Also, individual PICs and POCs have never been examined before in symptomatic ALS. To fill this gap, we measured the net and individual PIC and POC components of wild-type (WT) and SOD MNs in current clamp and voltage clamp during disease progression (assessed by neuroscores). We show that SOD MNs of symptomatic mice experience a much larger net PIC, relative to WT cells from age-matched littermates. Specifically, the Na[+] and Ca[2+] PICs are larger, whereas the lasting SK-mediated (SKL) POC is smaller than WT (Na[+] PIC is the largest and SKL POC is the smallest components in SOD MNs). We also show that PIC dysregulation is present at symptom onset, is sustained throughout advanced disease stages and is proportional to SOD MN cell size (largest dysregulation is in the largest SOD cells, the most vulnerable in ALS). Additionally, we show that studying disease progression using neuroscores is more accurate than using SOD mouse age, which could lead to misleading statistics and age-based trends. Collectively, this study contributes novel PIC and POC data, reveals ionic mechanisms contributing to the vulnerability differential among MN types/sizes, and provides insights on the roles PIC and POC mechanisms play in MN excitability dysfunction in ALS. KEY POINTS: Individual persistent inward currents (PICs) and persistent outward currents (POCs) have never been examined before in spinal motoneurons (MNs) of symptomatic amyotrophic lateral sclerosis (ALS) mice. Thus, we contribute novel PIC and POC data to the ALS literature. Male SOD MNs of symptomatic mice have elevated net PIC, with larger Na[+] and Ca[2+] PICs but reduced SKL POC vs. wild-type littermates. Na[+] PIC is the largest and SKL POC is the smallest current in SOD cells. The PIC/POC dysregulation is present at symptom onset. PIC dysregulation is sustained throughout advanced disease, and is proportional to SOD MN size (largest dysregulation is in the largest cells, the most vulnerable in ALS). Thus, we reveal ionic mechanisms contributing to the vulnerability differential among MN types/sizes in ALS. Studying disease progression using SOD mice neuroscores is more accurate than using age, which could distort the statistical differences between SOD and WT PIC/POC data and the trends during disease progression.}, } @article {pmid38924023, year = {2024}, author = {Spoden, C and Wenzel, O and Erdmann, A and Neitzke, G and Hirschberg, I}, title = {Coping and end-of-life decision-making in ALS: A qualitative interview study.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0306102}, pmid = {38924023}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; *Decision Making ; *Terminal Care/psychology ; Aged ; *Qualitative Research ; Adult ; Germany ; Interviews as Topic ; }, abstract = {How do people with amyotrophic lateral sclerosis (PALS) deal with their diagnosis and engage in end-of-life decision-making? What informational or supportive needs do they have for counselling about life-sustaining treatment and end-of-life care? Which correlating conditions and influences relate to these needs and how do they connect to the wish to die or wish to live? We conducted a qualitative interview study with 13 people with ALS in Germany from March 2019 to April 2021. Data collection and analysis followed a grounded theory-based approach and revealed close relationships between coping, informational needs and the preparedness for decision-making. We identified the coping strategies 'avoid thinking about end-of-life' and its counterpart, 'planning ahead to be well-prepared,' and differentiated the latter into the patterns 'withdrawing from life and taking precautions against life-prolongation' and 'searching for a new meaning in life and preparing for life-sustaining treatment'. The approaches are based on individual perceptions, attitudes and motives and can be positively/negatively reinforced by healthcare professionals (HCP), family and other interpersonal networks, but also by disease progression and in reaction to health care services. Type and degree of needs concerning information and counselling differed according to coping strategies. These strategies may vary over time, resulting in different support needs. Our findings signify that deep insight is needed into PALS' coping processes to understand their decision-making about life-sustaining treatment. Healthcare professionals should be sensitive to illness experiences beyond medical aspects and foster coping as a biographical process to better support people with ALS.}, } @article {pmid38923692, year = {2024}, author = {Snyder, A and Ryan, VH and Hawrot, J and Lawton, S and Ramos, DM and Qi, YA and Johnson, KR and Reed, X and Johnson, NL and Kollasch, AW and Duffy, MF and VandeVrede, L and Cochran, JN and Miller, BL and Toro, C and Bielekova, B and Marks, DS and Yokoyama, JS and Kwan, JY and Cookson, MR and Ward, ME}, title = {An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20}, number = {8}, pages = {5220-5235}, pmid = {38923692}, issn = {1552-5279}, support = {K01AG049152//NIH National Institute on Aging/ ; K01 AG049152/AG/NIA NIH HHS/United States ; U54NS123985//NIH National Institute of Neurological Disorders and Stroke/ ; ZIAAG000534/AG/NIA NIH HHS/United States ; FI2 GM142475/GM/NIGMS NIH HHS/United States ; //Chan-Zuckerberg Initiative's Neurodegeneration Challenge Network/ ; P30AG062422//NIH National Institute on Aging/ ; ZIA AG000539/ImNIH/Intramural NIH HHS/United States ; 1ZIAAG000539-01//NIH National Institute on Aging/ ; R00 AG068271/AG/NIA NIH HHS/United States ; //Global Brain Health Institute/ ; //NIH Undiagnosed Diseases Program, Undiagnosed Diseases Network/ ; P50 AG023501/AG/NIA NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; R01 AG062588/AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; R00AG068271//NIH National Institute on Aging/ ; P01AG019724//NIH National Institute on Aging/ ; 75N95022C00031/DA/NIDA NIH HHS/United States ; U54 NS123985/NS/NINDS NIH HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; R01AG057234//NIH National Institute on Aging/ ; FI2GM142475//NIH National Institute of General Medical Sciences/ ; P30 AG062422/AG/NIA NIH HHS/United States ; K23AG073514//NIH National Institute on Aging/ ; P01 AG019724/AG/NIA NIH HHS/United States ; 2016-A-005-SUP//Larry L. Hillblom Foundation/ ; //NIH Office of Intramural Training and Education/ ; R01 AG057234/AG/NIA NIH HHS/United States ; //Rainwater Charitable Foundation/ ; //Bluefield Project to Cure Frontotemporal Dementia/ ; //French Foundation/ ; U19AG079774//NIH National Institute on Aging/ ; P50AG023501//NIH National Institute on Aging/ ; ZIA AG000534/ImNIH/Intramural NIH HHS/United States ; //Intramural Research Programs of the National Institute of Neurological Disorders and Stroke/ ; P01AG1972403//NIH National Institute on Aging/ ; //HudsonAlpha Foundation Memory and Mobility Fund/ ; R01AG062588//NIH National Institute on Aging/ ; K23 AG073514/AG/NIA NIH HHS/United States ; //Mary Oakley Foundation/ ; }, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism ; *Annexins/genetics ; Male ; Mutation/genetics ; Female ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Neurons/metabolism/pathology ; Frontotemporal Dementia/genetics/pathology ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.

METHODS: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.

RESULTS: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.

DISCUSSION: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.

HIGHLIGHTS: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.}, } @article {pmid38923364, year = {2024}, author = {Yang, XD and Gong, B and Chen, W and Chen, JJ and Qian, C and Lu, R and Min, Y and Jiang, T and Li, L and Yu, HQ}, title = {In Situ Quantitative Monitoring of Adsorption from Aqueous Phase by UV-vis Spectroscopy: Implication for Understanding of Heterogeneous Processes.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {11}, number = {32}, pages = {e2402732}, pmid = {38923364}, issn = {2198-3844}, support = {//Program for Changjiang Scholars and Innovative Research Team in University/ ; 51821006//National Natural Science Foundation of China/ ; 52027815//National Natural Science Foundation of China/ ; 52192684//National Natural Science Foundation of China/ ; 22276217//National Natural Science Foundation of China/ ; }, abstract = {The development of in situ techniques to quantitatively characterize the heterogeneous reactions is essential for understanding physicochemical processes in aqueous phase. In this work, a new approach coupling in situ UV-vis spectroscopy with a two-step algorithm strategy is developed to quantitatively monitor heterogeneous reactions in a compact closed-loop incorporation. The algorithm involves the inverse adding-doubling method for light scattering correction and the multivariate curve resolution-alternating least squares (MCR-ALS) method for spectral deconvolution. Innovatively, theoretical spectral simulations are employed to connect MCR-ALS solutions with chemical molecular structural evolution without prior information for reference spectra. As a model case study, the aqueous adsorption kinetics of bisphenol A onto polyamide microparticles are successfully quantified in a one-step UV-vis spectroscopic measurement. The practical applicability of this approach is confirmed by rapidly screening a superior adsorbent from commercial materials for antibiotic wastewater adsorption treatment. The demonstrated capabilities are expected to extend beyond monitoring adsorption systems to other heterogeneous reactions, significantly advancing UV-vis spectroscopic techniques toward practical integration into automated experimental platforms for probing aqueous chemical processes and beyond.}, } @article {pmid38923228, year = {2024}, author = {Koch, T and Fabian, R and Weinhold, L and Koch, FW and Barakat, S and Castro-Gomez, S and Grehl, T and Bernsen, S and Weydt, P}, title = {Cardiac troponin T as a serum biomarker of respiratory impairment in amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {8}, pages = {2063-2072}, pmid = {38923228}, issn = {2328-9503}, support = {//Boris Canessa Foundation/ ; 21060//Alzheimer Forschung Initiative e.V/ ; 2021-1A-12//Hertie Network of Excellence in Clinical Neuroscience/ ; //BONFOR-Forschungskommission der Medizinischen Fakultät Bonn/ ; //Neuro-aCSis Bonn Neuroscience Clinician Scientist Program/ ; EXC2151-390873048//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/physiopathology ; *Troponin T/blood ; Male ; Middle Aged ; Female ; *Biomarkers/blood ; Aged ; Retrospective Studies ; Vital Capacity/physiology ; Respiratory Insufficiency/blood/etiology ; Adult ; Neurofilament Proteins/blood ; }, abstract = {OBJECTIVE: Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis.

METHODS: In this retrospective observation, we analyzed two independent hospital-based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (nd = 298; nv = 49), serum neurofilament light chain (nd = 117; nv = 17), and respiratory tests (nd = 93; nv = 49).

RESULTS: Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = -0.45, p = 0.001) and slow vital capacity % (r = -0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62-0.84) and <50% (AUC 0.80, 95% CI 0.68-0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61-0.83) and <50% (AUC 0.79, 95% CI 0.67-0.91).

INTERPRETATION: Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function.}, } @article {pmid38922880, year = {2025}, author = {Goldschmidt-Clermont, PJ and Khan, A and Jimsheleishvili, G and Graham, P and Brooks, A and Silvera, R and Goldschmidt, AJP and Pearse, DD and Dietrich, WD and Levi, AD and Guest, JD}, title = {Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.}, journal = {Neural regeneration research}, volume = {20}, number = {4}, pages = {1207-1216}, pmid = {38922880}, issn = {1673-5374}, abstract = {Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.}, } @article {pmid38921286, year = {2024}, author = {Katz, L and Gur, A}, title = {Psychosocial Intervention for Family Caregivers of ALS Patients: A Systematic Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38921286}, issn = {2227-9032}, abstract = {PROPOSAL: This systematic review aims to comprehensively examine all existing knowledge on psychosocial interventions for family caregivers for ALS patients. Also, the study will present the gaps in knowledge, recommendations for future research, and guidelines for psychosocial interventions that are focused and adapted to the needs of family caregivers of ALS patients.

MATERIALS AND METHODS: The systematic review was conducted according to the PRISMA guidelines and identified studies on psychosocial intervention for family caregivers of ALS patients, using five electronic databases: PsychNET, PubMed, EBSCO, PRIMO, and PROQUEST. Seven articles met the criteria and were included in the review. A thematic analysis was conducted to extract major themes.

RESULTS: Three major themes emerged from the data: (1) Personal benefits; (2) Interpersonal benefits; and (3) Charting challenges and pathways to improve psychosocial interventions.

CONCLUSIONS: Based on the findings, practical guidelines were formulated that focus on the group's composition, the facilitator's role, the contents, the relationships within the group, and the opportunities and limitations of online interventions.}, } @article {pmid38921029, year = {2024}, author = {Carata, E and Muci, M and Di Giulio, S and Di Giulio, T and Mariano, S and Panzarini, E}, title = {The Neuromuscular Disorder Mediated by Extracellular Vesicles in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5999-6017}, pmid = {38921029}, issn = {1467-3045}, abstract = {Amyotrophic lateral sclerosis (ALS) represents a neurodegenerative disorder characterized by the progressive loss of both upper and lower motor neurons, resulting in muscular atrophy and eventual paralysis. While much research has concentrated on investigating the impact of major mutations associated with ALS on motor neurons and central nervous system (CNS) cells, recent studies have unveiled that ALS pathogenesis extends beyond CNS imbalances, encompassing dysregulation in other tissues such as skeletal muscle. Evidence from animal models and patients supports this broader perspective. Skeletal muscle, once considered solely as an effector organ, is now recognized as possessing significant secretory activity capable of influencing motor neuron survival. However, the precise cellular and molecular mechanisms underlying the detrimental effects observed in muscle and its associated structures in ALS remain poorly understood. Additionally, emerging data suggest that extracellular vesicles (EVs) may play a role in the establishment and function of the neuromuscular junction (NMJ) under both physiological and pathological conditions and in wasting and regeneration of skeletal muscles, particularly in neurodegenerative diseases like ALS. This review aims to explore the key findings about skeletal muscle involvement in ALS, shedding light on the potential underlying mechanisms and contributions of EVs and their possible application for the design of biosensors.}, } @article {pmid38920997, year = {2024}, author = {Nowak, I and Paździor, M and Sarna, R and Madej, M}, title = {Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases.}, journal = {Current issues in molecular biology}, volume = {46}, number = {6}, pages = {5436-5453}, pmid = {38920997}, issn = {1467-3045}, abstract = {Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.}, } @article {pmid38920691, year = {2024}, author = {Ilieva, MS}, title = {Non-Coding RNAs in Neurological and Neuropsychiatric Disorders: Unraveling the Hidden Players in Disease Pathogenesis.}, journal = {Cells}, volume = {13}, number = {12}, pages = {}, pmid = {38920691}, issn = {2073-4409}, mesh = {Humans ; *RNA, Untranslated/genetics/metabolism ; *Nervous System Diseases/genetics/metabolism ; *Mental Disorders/genetics/metabolism ; RNA, Circular/genetics/metabolism ; Animals ; RNA, Long Noncoding/genetics/metabolism ; Gene Expression Regulation ; MicroRNAs/genetics/metabolism ; }, abstract = {Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms underlying their pathogenesis. In recent years, the focus has shifted toward the intricate world of non-coding RNAs (ncRNAs), a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. This review explores the emerging significance of ncRNAs in the context of neurological and neuropsychiatric disorders, shedding light on their diverse functions and regulatory mechanisms. The dysregulation of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has been implicated in the pathophysiology of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and mood disorders. This review delves into the specific roles these ncRNAs play in modulating key cellular processes, including synaptic plasticity, neuroinflammation, and apoptosis, providing a nuanced understanding of their impact on disease progression. Furthermore, it discusses the potential diagnostic and therapeutic implications of targeting ncRNAs in neurological and neuropsychiatric disorders. The identification of specific ncRNA signatures holds promise for the development of novel biomarkers for early disease detection, while the manipulation of ncRNA expression offers innovative therapeutic avenues. Challenges and future directions in the field are also considered, highlighting the need for continued research to unravel the complexities of ncRNA-mediated regulatory networks in the context of neurological and neuropsychiatric disorders. This review aims to provide a comprehensive overview of the current state of knowledge and stimulate further exploration into the fascinating realm of ncRNAs in the brain's intricate landscape.}, } @article {pmid38920626, year = {2024}, author = {Cihankaya, H and Bader, V and Winklhofer, KF and Vorgerd, M and Matschke, J and Stahlke, S and Theiss, C and Matschke, V}, title = {Elevated NLRP3 Inflammasome Activation Is Associated with Motor Neuron Degeneration in ALS.}, journal = {Cells}, volume = {13}, number = {12}, pages = {}, pmid = {38920626}, issn = {2073-4409}, support = {91753179//German Academic Exchange Service/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Motor Neurons/metabolism/pathology ; *Inflammasomes/metabolism ; Mice ; *MicroRNAs/metabolism/genetics ; Spinal Cord/pathology/metabolism ; Disease Models, Animal ; Nerve Degeneration/pathology/metabolism ; Microglia/metabolism/pathology ; Mice, Inbred C57BL ; Caspase 1/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the central nervous system. Recent research has increasingly linked the activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome to ALS pathogenesis. NLRP3 activation triggers Caspase 1 (CASP 1) auto-activation, leading to the cleavage of Gasdermin D (GSDMD) and pore formation on the cellular membrane. This process facilitates cytokine secretion and ultimately results in pyroptotic cell death, highlighting the complex interplay of inflammation and neurodegeneration in ALS. This study aimed to characterize the NLRP3 inflammasome components and their colocalization with cellular markers using the wobbler mouse as an ALS animal model. Firstly, we checked the levels of miR-223-3p because of its association with NLRP3 inflammasome activity. The wobbler mice showed an increased expression of miR-223-3p in the ventral horn, spinal cord, and cerebellum tissues. Next, increased levels of NLRP3, pro-CASP 1, cleaved CASP 1 (c-CASP 1), full-length GSDMD, and cleaved GDSMD revealed NLRP3 inflammasome activation in wobbler spinal cords, but not in the cerebellum. Furthermore, we investigated the colocalization of the aforementioned proteins with neurons, microglia, and astrocyte markers in the spinal cord tissue. Evidently, the wobbler mice displayed microgliosis, astrogliosis, and motor neuron degeneration in this tissue. Additionally, we showed the upregulation of protein levels and the colocalization of NLRP3, c-CASP1, and GSDMD in neurons, as well as in microglia and astrocytes. Overall, this study demonstrated the involvement of NLRP3 inflammasome activation and pyroptotic cell death in the spinal cord tissue of wobbler mice, which could further exacerbate the motor neuron degeneration and neuroinflammation in this ALS mouse model.}, } @article {pmid38918634, year = {2024}, author = {Zhang, N and Westerhaus, A and Wilson, M and Wang, E and Goff, L and Sockanathan, S}, title = {Physiological regulation of neuronal Wnt activity is essential for TDP-43 localization and function.}, journal = {The EMBO journal}, volume = {43}, number = {16}, pages = {3388-3413}, pmid = {38918634}, issn = {1460-2075}, support = {T32GM007445//HHS | National Institutes of Health (NIH)/ ; T32 GM007445/GM/NIGMS NIH HHS/United States ; F31AG072745//HHS | National Institutes of Health (NIH)/ ; R01 AG068043/AG/NIA NIH HHS/United States ; 5RO1AG068043//HHS | National Institutes of Health (NIH)/ ; F31 AG072745/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Wnt Signaling Pathway ; *Neurons/metabolism ; Mice ; *Phosphoric Diester Hydrolases/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Active Transport, Cell Nucleus ; Cell Nucleus/metabolism ; }, abstract = {Nuclear exclusion of the RNA- and DNA-binding protein TDP-43 can induce neurodegeneration in different diseases. Diverse processes have been implicated to influence TDP-43 mislocalization, including disrupted nucleocytoplasmic transport (NCT); however, the physiological pathways that normally ensure TDP-43 nuclear localization are unclear. The six-transmembrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) cleaves the glycosylphosphatidylinositol (GPI) anchor that tethers some proteins to the membrane. Here we show that GDE2 maintains TDP-43 nuclear localization by regulating the dynamics of canonical Wnt signaling. Ablation of GDE2 causes aberrantly sustained Wnt activation in adult neurons, which is sufficient to cause NCT deficits, nuclear pore abnormalities, and TDP-43 nuclear exclusion. Disruption of GDE2 coincides with TDP-43 abnormalities in postmortem tissue from patients with amyotrophic lateral sclerosis (ALS). Further, GDE2 deficits are evident in human neural cell models of ALS, which display erroneous Wnt activation that, when inhibited, increases mRNA levels of genes regulated by TDP-43. Our study identifies GDE2 as a critical physiological regulator of Wnt signaling in adult neurons and highlights Wnt pathway activation as an unappreciated mechanism contributing to nucleocytoplasmic transport and TDP-43 abnormalities in disease.}, } @article {pmid38918466, year = {2024}, author = {Bahram Sangani, N and Koetsier, J and Mélius, J and Kutmon, M and Ehrhart, F and Evelo, CT and Curfs, LMG and Reutelingsperger, CP and Eijssen, LMT}, title = {A novel insight into neurological disorders through HDAC6 protein-protein interactions.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {14666}, pmid = {38918466}, issn = {2045-2322}, mesh = {*Histone Deacetylase 6/metabolism/genetics ; Humans ; *Protein Interaction Maps ; Nervous System Diseases/metabolism/genetics ; Alzheimer Disease/metabolism/genetics ; Phosphorylation ; Acetylation ; Parkinson Disease/metabolism/genetics/pathology ; }, abstract = {Due to its involvement in physiological and pathological processes, histone deacetylase 6 (HDAC6) is considered a promising pharmaceutical target for several neurological manifestations. However, the exact regulatory role of HDAC6 in the central nervous system (CNS) is still not fully understood. Hence, using a semi-automated literature screening technique, we systematically collected HDAC6-protein interactions that are experimentally validated and reported in the CNS. The resulting HDAC6 network encompassed 115 HDAC6-protein interactions divided over five subnetworks: (de)acetylation, phosphorylation, protein complexes, regulatory, and aggresome-autophagy subnetworks. In addition, 132 indirect interactions identified through HDAC6 inhibition were collected and categorized. Finally, to display the application of our HDAC6 network, we mapped transcriptomics data of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis on the network and highlighted that in the case of Alzheimer's disease, alterations predominantly affect the HDAC6 phosphorylation subnetwork, whereas differential expression within the deacetylation subnetwork is observed across all three neurological disorders. In conclusion, the HDAC6 network created in the present study is a novel and valuable resource for the understanding of the HDAC6 regulatory mechanisms, thereby providing a framework for the integration and interpretation of omics data from neurological disorders and pharmacodynamic assessments.}, } @article {pmid38918327, year = {2024}, author = {Sharma, V and Sharma, P and Singh, TG}, title = {Mechanistic insights on TLR-4 mediated inflammatory pathway in neurodegenerative diseases.}, journal = {Pharmacological reports : PR}, volume = {76}, number = {4}, pages = {679-692}, pmid = {38918327}, issn = {2299-5684}, mesh = {Humans ; *Toll-Like Receptor 4/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; *Signal Transduction ; NF-kappa B/metabolism ; Inflammation/metabolism/drug therapy ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant issue in healthcare, needing a thorough knowledge of their complex molecular mechanisms. A diverse set of cell signaling mediators and their interactions play critical roles in neuroinflammation. The release of pro-inflammatory mediators in response to neural dysfunction is detrimental to normal cell survival. Moreover, the important role of nuclear factor-κB (NF-κB) in the central nervous system through Toll-like receptor (TLR) activation has been well established. Therefore, through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (TLR-4/NF-κB inhibitors) and neurodegeneration encompassing Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and stroke. Insights garnered from this exploration underscore the potential of TLR-4 as a therapeutic target. Through the revelation of these insights, our aim is to establish a foundation for the development of enhanced and focused therapeutic approaches in the continuous endeavor to combat neurodegeneration. This review thus serves as a roadmap, guiding future research endeavors toward innovative strategies for combatting the complex interplay between TLR-4 signaling and NDDs.}, } @article {pmid38917863, year = {2024}, author = {Chou, CZ and Everett, EA and McFarlin, J and Ramanathan, U}, title = {End-of-Life and Hospice Care in Neurologic Diseases.}, journal = {Seminars in neurology}, volume = {44}, number = {5}, pages = {523-533}, doi = {10.1055/s-0044-1787809}, pmid = {38917863}, issn = {1098-9021}, mesh = {Humans ; *Nervous System Diseases/therapy ; *Hospice Care ; *Terminal Care/methods ; Advance Care Planning ; }, abstract = {The care of a patient with neurologic disease at end-of-life requires expertise in addressing advance care planning, hospice, symptom management, and caregiver support. Neurologists caring for patients with advanced neurologic disease often identify changes in disease trajectory, functional status, or goals of care that prompt discussions of advance care planning and hospice. Patients nearing end-of-life may develop symptoms such as dyspnea, secretions, delirium, pain, and seizures. Neurologists may be the primary clinicians managing these symptoms, particularly in the hospitalized patient, though they may also lend their expertise to non-neurologists about expected disease trajectories and symptoms in advanced neurologic disease. This article aims to help neurologists guide patients and caregivers through the end-of-life process by focusing on general knowledge that can be applied across diseases as well as specific considerations in severe stroke and traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, and dementia.}, } @article {pmid38917432, year = {2024}, author = {Atkinson, RAK and Collins, JM and Sreedharan, J and King, AE and Fernandez-Martos, CM}, title = {Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {11}, pages = {907-916}, pmid = {38917432}, issn = {1554-6578}, support = {//"la Caixa" Banking Foundation/ ; PR-HR18-000341b//Fundación Luzón/ ; //Victorian Brain Bank/ ; //The Florey, The Alfred, Victorian Institute of Forensic Medicine/ ; //Coroners Court of Victoria/ ; //Fundación Luzón/ ; //The Alfred, Victorian Institute of Forensic Medicine/ ; //Parkinson's Victoria/ ; //FightMND/ ; //Yulgilbar Foundation/ ; //Ian and Maria Cootes/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Male ; Female ; Aged ; *Frontotemporal Dementia/metabolism/pathology/genetics ; Middle Aged ; *Neuropeptide Y/metabolism ; Receptors, Leptin/metabolism/genetics ; Receptor, Insulin/metabolism ; Aged, 80 and over ; Spinal Cord/metabolism/pathology ; RNA, Messenger/metabolism ; Motor Cortex/metabolism/pathology ; Antigens, CD ; }, abstract = {Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.}, } @article {pmid38917317, year = {2024}, author = {LaBarbera, VA and Gill, E and Hill, NS and Sachs, G}, title = {The Louise Wilcox ALS Clinic at Rhode Island Hospital: 25th Anniversary (1999-2024).}, journal = {Rhode Island medical journal (2013)}, volume = {107}, number = {7}, pages = {51-53}, pmid = {38917317}, issn = {2327-2228}, mesh = {Rhode Island ; Humans ; *Amyotrophic Lateral Sclerosis/history ; Anniversaries and Special Events ; }, } @article {pmid38916909, year = {2024}, author = {Honda, H and Sadashima, S and Yoshimura, M and Sakurada, N and Koyama, S and Yagita, K and Hamasaki, H and Noguchi, H and Arahata, H and Sasagasako, N}, title = {Altered expression of human myxovirus resistance protein A in amyotrophic lateral sclerosis.}, journal = {Journal of neuropathology and experimental neurology}, volume = {83}, number = {9}, pages = {745-751}, doi = {10.1093/jnen/nlae052}, pmid = {38916909}, issn = {1554-6578}, mesh = {Humans ; *Myxovirus Resistance Proteins/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Female ; Male ; Middle Aged ; Aged ; *Spinal Cord/metabolism/pathology ; Adult ; Aged, 80 and over ; Anterior Horn Cells/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. The etiology of sporadic ALS (sALS) has not yet been clarified. An increasing body of evidence suggests the involvement of viral infections and interferons (IFNs). Human myxovirus resistance protein A (MxA) is an IFN-induced dynamin-like GTPase that acts as a potent antiviral factor. This study examined MxA expression in ALS patient spinal cords using immunohistochemistry. Thirty-two cases of sALS (pathologically proven ALS-TDP), 10 non-ALS, other neurological disease control cases were examined. In most ALS cases, MxA cytoplasmic condensates were observed in the remaining spinal anterior horn neurons. The ALS group had a significantly higher rate of MxA-highly expressing neurons than the non-ALS group. Colocalization of MxA cytoplasmic condensate and transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusions was rarely observed. Because MxA has antiviral activity induced by IFNs, our results suggest that IFNs are involved in the pathogenesis of ALS in spinal cord anterior horn neurons. Our study also suggests that monitoring viral infections and IFN activation in patients with ALS may be critically important.}, } @article {pmid38916676, year = {2024}, author = {Schaub, A and Erdmann, H and Scholz, V and Timmer, M and Cordts, I and Günther, R and Reilich, P and Abicht, A and Schöberl, F}, title = {Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {9}, pages = {5804-5812}, pmid = {38916676}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/genetics ; *Phenotype ; *Replication Protein C/genetics ; Male ; Female ; Cohort Studies ; Germany ; *DNA Repeat Expansion ; Middle Aged ; Aged ; Adult ; }, abstract = {Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif 'ACAAG'.}, } @article {pmid38915796, year = {2024}, author = {Thonhoff, JR and Beers, DR and Zhao, W and Faridar, A and Thome, A and Wen, S and Zhang, A and Wang, J and Appel, SH}, title = {A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1415106}, pmid = {38915796}, issn = {1664-2295}, abstract = {OBJECTIVE: To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS.

METHODS: In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 10[6] IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally.

RESULTS: CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants.

CONCLUSION: The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT06307301.}, } @article {pmid38915767, year = {2024}, author = {Ambrosini, A and Dalla Bella, E and Ravasi, M and Melazzini, M and Lauria, G}, title = {New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1407912}, pmid = {38915767}, issn = {2296-858X}, abstract = {Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind.}, } @article {pmid38915526, year = {2024}, author = {Mackness, BC and Morgan, BR and Deveau, LM and Kathuria, SV and Zitzewitz, JA and Massi, F}, title = {A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.12.598648}, pmid = {38915526}, issn = {2692-8205}, abstract = {Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.}, } @article {pmid38914810, year = {2024}, author = {Manchia, M and Paribello, P and Pinna, M and Steardo, L and Carpiniello, B and Pinna, F and Pisanu, C and Squassina, A and Hajek, T}, title = {Lithium and its effects: does dose matter?.}, journal = {International journal of bipolar disorders}, volume = {12}, number = {1}, pages = {23}, pmid = {38914810}, issn = {2194-7511}, abstract = {BACKGROUND: Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium's clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations.

CONTENT: This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors' preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections.

CONCLUSIONS: Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium's ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.}, } @article {pmid38914784, year = {2024}, author = {Sang, A and Zhuo, S and Bochanis, A and Manautou, JE and Bahal, R and Zhong, XB and Rasmussen, TP}, title = {Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.}, journal = {BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy}, volume = {38}, number = {4}, pages = {511-526}, pmid = {38914784}, issn = {1179-190X}, support = {R01 HL147028/HL/NHLBI NIH HHS/United States ; R35 GM140862/GM/NIGMS NIH HHS/United States ; R35GM140862/GM/NIGMS NIH HHS/United States ; R01HL147028/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/pharmacology ; United States ; *United States Food and Drug Administration ; *Drug Approval ; RNA, Messenger/genetics/metabolism ; Animals ; RNA Splicing/drug effects ; }, abstract = {Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].}, } @article {pmid38914219, year = {2024}, author = {Asahina, R and Takahashi, M and Takano, H and Yao, R and Abe, M and Goshima, Y and Ohshima, T}, title = {The role of CRMP4 in LPS-induced neuroinflammation.}, journal = {Brain research}, volume = {1841}, number = {}, pages = {149094}, doi = {10.1016/j.brainres.2024.149094}, pmid = {38914219}, issn = {1872-6240}, mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Microglia/metabolism/drug effects ; *Mice, Knockout ; *Nerve Tissue Proteins/metabolism/genetics ; Mice ; *Neuroinflammatory Diseases/metabolism/chemically induced ; Inflammation/metabolism/chemically induced ; Interleukin-10/metabolism ; Substantia Nigra/metabolism/drug effects ; Mice, Inbred C57BL ; Corpus Striatum/metabolism/drug effects ; Male ; Microfilament Proteins/metabolism ; Arginase/metabolism ; }, abstract = {Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4[-/-] mice compared to Crmp4[+/+]mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4[-/-] mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.}, } @article {pmid38914173, year = {2024}, author = {Tortarolo, M and Re Cecconi, AD and Camporeale, L and Margotta, C and Nardo, G and Pasetto, L and Bonetto, V and Galbiati, M and Crippa, V and Poletti, A and Piccirillo, R and Bendotti, C}, title = {Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.}, journal = {Neurobiology of disease}, volume = {199}, number = {}, pages = {106576}, doi = {10.1016/j.nbd.2024.106576}, pmid = {38914173}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; *Sunitinib/pharmacology ; *Muscle, Skeletal/drug effects/metabolism/pathology ; *STAT3 Transcription Factor/metabolism/antagonists & inhibitors ; *Mice, Transgenic ; *Indoles/pharmacology ; Mice ; *Disease Models, Animal ; *Spinal Cord/metabolism/drug effects/pathology ; *Mice, Inbred C57BL ; *Pyrroles/pharmacology ; Superoxide Dismutase/metabolism/genetics ; Muscular Atrophy/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Disease Progression ; }, abstract = {Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.}, } @article {pmid38913386, year = {2024}, author = {Shamaskin-Garroway, AM and Shamaskin, J}, title = {Slowing Down-A Family's Experience With ALS.}, journal = {JAMA neurology}, volume = {81}, number = {9}, pages = {907-908}, doi = {10.1001/jamaneurol.2024.1922}, pmid = {38913386}, issn = {2168-6157}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Family/psychology ; Male ; Female ; Middle Aged ; }, } @article {pmid38911266, year = {2024}, author = {Huang, X and Lee, S and Chen, K and Kawaguchi, R and Wiskow, O and Ghosh, S and Frost, D and Perrault, L and Pandey, R and Klim, JR and Boivin, B and Hermawan, C and Livak, KJ and Geschwind, DH and Wainger, BJ and Eggan, KC and Bean, BP and Woolf, CJ}, title = {Downregulation of the silent potassium channel Kv8.1 increases motor neuron vulnerability in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae202}, pmid = {38911266}, issn = {2632-1297}, abstract = {While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1 gene, is a 'silent' ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in amyotrophic lateral sclerosis patient-derived motor neurons carrying a superoxide dismutase 1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1-deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected and distinct roles of Kv8.1 and Kv2.2 in amyotrophic lateral sclerosis-related neurodegeneration.}, } @article {pmid38909659, year = {2024}, author = {Issa, NT and Bunick, CG}, title = {In response to Reynolds et al's "guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e113-e114}, doi = {10.1016/j.jaad.2024.05.091}, pmid = {38909659}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/therapy/diagnosis/drug therapy ; *Practice Guidelines as Topic ; }, } @article {pmid38909349, year = {2024}, author = {Ketabforoush, A and Faghihi, F and Azedi, F and Ariaei, A and Habibi, MA and Khalili, M and Ashtiani, BH and Joghataei, MT and Arnold, WD}, title = {Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Clinical drug investigation}, volume = {44}, number = {7}, pages = {495-512}, pmid = {38909349}, issn = {1179-1918}, mesh = {Humans ; *Taurochenodeoxycholic Acid/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *Phenylbutyrates/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.}, } @article {pmid38909342, year = {2024}, author = {Réginault, T and Wibart, P and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Factors associated with survival after early at-home NIV initiation in ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5590-5597}, pmid = {38909342}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality/physiopathology ; Male ; Female ; *Noninvasive Ventilation ; Middle Aged ; Retrospective Studies ; Aged ; Respiratory Insufficiency/therapy/mortality/etiology ; Home Care Services ; }, abstract = {BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial.

OBJECTIVE: To identify factors at 1 month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1 month after early at-home NIV initiation on patient survival.

METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2 years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis.

RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for > 5 h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio = 0.4; 95% confidence interval: 0.27-0.9].

CONCLUSION: The use of NIV for > 5 h/day during the early NIV initiation period was associated with increased survival.}, } @article {pmid38909069, year = {2024}, author = {Ngo, TD and Kieu, HD and Nguyen, MH and Nguyen, TH and Can, VM and Nguyen, BH and Le, TH}, title = {An EEG & eye-tracking dataset of ALS patients & healthy people during eye-tracking-based spelling system usage.}, journal = {Scientific data}, volume = {11}, number = {1}, pages = {664}, pmid = {38909069}, issn = {2052-4463}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Brain-Computer Interfaces ; *Electroencephalography ; *Eye-Tracking Technology ; }, abstract = {This research presents a dataset consisting of electroencephalogram and eye tracking recordings obtained from six patients with amyotrophic lateral sclerosis (ALS) in a locked-in state and one hundred seventy healthy individuals. The ALS patients exhibited varying degrees of disease progression, ranging from partial mobility and weakened speech to complete paralysis and loss of speech. Despite these physical impairments, the ALS patients retained good eye function, which allowed them to use a virtual keyboard for communication. Data from ALS patients was recorded multiple times at their homes, while data from healthy individuals was recorded once in a laboratory setting. For each data recording, the experimental design involved nine recording sessions per participant, each corresponding to a common human action or demand. This dataset can serve as a valuable benchmark for several applications, such as improving spelling systems with brain-computer interfaces, investigating motor imagination, exploring motor cortex function, monitoring motor impairment progress in patients undergoing rehabilitation, and studying the effects of ALS on cognitive and motor processes.}, } @article {pmid38908354, year = {2024}, author = {Kim, K and Choi, D and Shim, H and Lee, CA}, title = {Effects of gamification in advanced life support training for clinical nurses: A cluster randomized controlled trial.}, journal = {Nurse education today}, volume = {140}, number = {}, pages = {106263}, doi = {10.1016/j.nedt.2024.106263}, pmid = {38908354}, issn = {1532-2793}, mesh = {Humans ; Female ; Adult ; Male ; *COVID-19/nursing ; Cardiopulmonary Resuscitation/education ; Clinical Competence/standards ; Advanced Cardiac Life Support/education ; Games, Experimental ; }, abstract = {BACKGROUND: Cardiopulmonary resuscitation training is a mandatory competency, especially for healthcare professionals. However, the spread of COVID-19 caused a sharp decline in the number of participants on advanced life support training, thereby accelerating the diversification of educational methods. Gamification is an increasingly popular method of diversifying instruction, but its effectiveness remains controversial.

AIM: To evaluate the effectiveness of gamification learning in advanced life support training.

DESIGN: A cluster randomized controlled trial.

SETTING: A single advanced life support training center.

PARTICIPANTS: Clinical nurses who are currently practicing in a hospital.

METHODS: A part of the existing advanced life support course was gamified using Kahoot! platform. Conventional learning and gamified learning were each conducted 11 times, and the level of knowledge after training was assessed. The assessment questions were categorized into advanced life support algorithms, teamwork, and cardiac arrest rhythms.

RESULTS: A total of 267 were enrolled in the study, and 148 and 139 learners were assigned to CL and GL, respectively. There was no difference in post-training knowledge related to teamwork, and cardiac arrest rhythms between the conventional learning and gamified learning groups, but knowledge related to the advanced life support algorithm was low in the gamified learning group.

CONCLUSIONS: Even if the learners are the same, advanced life support gamification training can lead to negative outcomes depending on the simplicity or goal of the training content. To improve the effectiveness of the training, various methods of gamification training should be applied depending on the goal and content of the training.}, } @article {pmid38908196, year = {2024}, author = {Donders, Z and Skorupska, IJ and Willems, E and Mussen, F and Broeckhoven, JV and Carlier, A and Schepers, M and Vanmierlo, T}, title = {Beyond PDE4 inhibition: A comprehensive review on downstream cAMP signaling in the central nervous system.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {177}, number = {}, pages = {117009}, doi = {10.1016/j.biopha.2024.117009}, pmid = {38908196}, issn = {1950-6007}, mesh = {Humans ; *Cyclic AMP/metabolism ; *Phosphodiesterase 4 Inhibitors/pharmacology ; Animals ; *Central Nervous System/drug effects/metabolism ; *Signal Transduction/drug effects ; *Central Nervous System Diseases/drug therapy/metabolism/enzymology ; *Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; }, abstract = {Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.}, } @article {pmid38908137, year = {2024}, author = {Cain, CN and Synovec, RE}, title = {Enhancing gas chromatography-mass spectrometry resolution and pure analyte discovery using intra-chromatogram elution profile matching.}, journal = {Talanta}, volume = {278}, number = {}, pages = {126453}, doi = {10.1016/j.talanta.2024.126453}, pmid = {38908137}, issn = {1873-3573}, abstract = {Chemometric decomposition methods like multivariate curve resolution-alternating least squares (MCR-ALS) are often employed in gas chromatography-mass spectrometry (GC-MS) to improve analyte identification and quantitation. However, these methods can perform poorly for analytes with a low chromatographic resolution (Rs) and a high degree of spectral contamination from noise and background interferences. Thus, we propose a novel computational algorithm, termed mzCompare, to improve analyte identification and quantitation when coupled to MCR-ALS. The mzCompare method utilizes an underlying requirement that the retention time and peak shape between mass channels (m/z) of the same analyte should be similar. By discovering the selective m/z for a given analyte in a chromatogram, a pure elution profile can be generated and used as an equality constraint in MCR-ALS. The performance of the mzCompare methodology is demonstrated with both experimental and simulated chromatograms. Experimentally, unresolved analytes with a Rs as low as 0.05 could be confidently identified with mzCompare assisted MCR-ALS. Furthermore, application of the mzCompare algorithm to a complex aerospace fuel resulted in the discovery of 335 analytes, a 44 % increase compared to conventional peak detection methods. GC-MS simulations of target-interferent analyte pairs demonstrated that the performance of MCR-ALS deteriorated below a Rs of ∼0.25. However, mzCompare assisted MCR-ALS showed excellent identification and acceptable quantitative accuracy at a Rs of ∼0.02. These results show that the mzCompare algorithm can help analysts overcome modeling ambiguities resulting from the chemometric multiplex disadvantage.}, } @article {pmid38907861, year = {2024}, author = {Yang, T and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Li, C and Shang, H}, title = {Clinical and genetic characteristics of ALS patients with variants in genes regulating DNA methylation.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5556-5566}, pmid = {38907861}, issn = {1432-1459}, support = {82371430//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; YCXJ-JZ-2022-007//Beijing E-town Coorperation & Development Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Methylation ; Female ; Male ; Middle Aged ; Aged ; China ; Genetic Predisposition to Disease/genetics ; DNA-Binding Proteins/genetics ; Cohort Studies ; Adult ; Dioxygenases ; Genetic Variation ; }, abstract = {BACKGROUND: Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS.

METHODS: Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival.

RESULTS: A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039).

CONCLUSIONS: This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.}, } @article {pmid38907103, year = {2024}, author = {Limone, F and Mordes, DA and Couto, A and Joseph, BJ and Mitchell, JM and Therrien, M and Ghosh, SD and Meyer, D and Zhang, Y and Goldman, M and Bortolin, L and Cobos, I and Stevens, B and McCarroll, SA and Kadiu, I and Burberry, A and Pietiläinen, O and Eggan, K}, title = {Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS.}, journal = {Nature aging}, volume = {4}, number = {7}, pages = {984-997}, pmid = {38907103}, issn = {2662-8465}, support = {K08 NS104270/NS/NINDS NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Neurons/metabolism/pathology ; Risk Factors ; Microglia/metabolism/pathology ; Cell Nucleus/metabolism/genetics ; Oligodendroglia/metabolism/pathology ; Male ; Single-Cell Analysis ; Sequence Analysis, RNA ; Female ; Middle Aged ; Nerve Degeneration/genetics/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1[+] ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.}, } @article {pmid38906677, year = {2024}, author = {Au, WH and Miller-Fleming, L and Sanchez-Martinez, A and Lee, JA and Twyning, MJ and Prag, HA and Raik, L and Allen, SP and Shaw, PJ and Ferraiuolo, L and Mortiboys, H and Whitworth, AJ}, title = {Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.}, journal = {Life science alliance}, volume = {7}, number = {9}, pages = {}, pmid = {38906677}, issn = {2575-1077}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Oxidative Stress ; *NF-E2-Related Factor 2/metabolism/genetics ; *C9orf72 Protein/genetics/metabolism ; *Mitochondria/metabolism ; Animals ; *Disease Models, Animal ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Humans ; *Signal Transduction ; *Frontotemporal Dementia/genetics/metabolism ; *Phenotype ; Drosophila Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mitophagy/genetics ; Dimethyl Fumarate/pharmacology ; Male ; }, abstract = {Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.}, } @article {pmid38906263, year = {2024}, author = {Veenstra, J and Ozog, D}, title = {Response to Barbieri, "Response to Veenstra et al's 'benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk'".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e111-e112}, doi = {10.1016/j.jaad.2024.06.036}, pmid = {38906263}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/drug therapy ; *Leukemia, Myeloid, Acute/drug therapy/chemically induced ; *Benzoyl Peroxide/therapeutic use/adverse effects ; Dermatologic Agents/adverse effects/therapeutic use ; }, } @article {pmid38906259, year = {2024}, author = {Barbieri, JS}, title = {Response to Veenstra et al's "Benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e109-e110}, doi = {10.1016/j.jaad.2024.05.090}, pmid = {38906259}, issn = {1097-6787}, mesh = {Humans ; *Acne Vulgaris/drug therapy ; *Leukemia, Myeloid, Acute/drug therapy/chemically induced ; *Benzoyl Peroxide/therapeutic use/adverse effects ; Dermatologic Agents/adverse effects/therapeutic use ; }, } @article {pmid38905535, year = {2024}, author = {}, title = {Addendum: Relyvrio withdrawn.}, journal = {The Medical letter on drugs and therapeutics}, volume = {66}, number = {1704}, pages = {96}, doi = {10.58347/tml.2024.1704e}, pmid = {38905535}, issn = {1523-2859}, mesh = {Humans ; Phenylbutyrates ; }, } @article {pmid38905382, year = {2024}, author = {Jing, Z and Qi, X and Teng, J}, title = {Dietary factors and risk for amyotrophic lateral sclerosis: A two sample mendelian randomization study.}, journal = {Medicine}, volume = {103}, number = {25}, pages = {e38473}, pmid = {38905382}, issn = {1536-5964}, mesh = {*Mendelian Randomization Analysis/methods ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/etiology ; Humans ; *Diet ; Risk Factors ; Fruit ; Genome-Wide Association Study ; Vegetables ; Coffee/adverse effects ; Meat/adverse effects ; }, abstract = {Correlations between dietary factors and amyotrophic lateral sclerosis (ALS) have been found in previous observational studies. However, no further studies have used Mendelian randomization to further explore the causal relationship between dietary factors and ALS. Clarifying these relationships is a crucial part of developing nutritional recommendations for ALS prevention. The exposure and outcome datasets employed in this study were extracted from the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/). The exposure datasets involved in our Mendelian analyses consisted of meat intake (processed meat intake, poultry intake, beef intake, pork intake, non-oily fish intake, and oily fish intake), staple foods intake (bread intake and cereal intake), vegetable intake (cooked vegetable intake, salad/raw vegetable intake), fruit intake (fresh fruit intake and dried fruit intake), and beverage intake (coffee intake and tea intake). The weighted median, MR-Egger, Inverse Variance Weighted, Simple mode and Weighted mode methods were all utilized. And we applied Inverse Variance Weighted method as the main judgement criterion for Mendelian randomization analysis. Heterogeneity and pleiotropy analyses were conducted to confirm the validity of the outcomes. Genetically predicted that oily fish intake (OR: 0.7648; 95% CI: 0.5905-0.9904; P = .0420), coffee intake (OR: 0.7385; 95% CI: 0.5660-0.9637; P = .0256), and fresh fruit intake (OR: 0.6165; 95% CI: 0.4007-0.9487; P = .0278) were causally associated with a decreased risk of ALS. Negative results (P > .05) were received for all other dietary factors. This study found that oily fish intake, coffee intake and fresh fruit intake reduced the risk of developing ALS. Additionally, other factors were not associated with ALS.}, } @article {pmid38905379, year = {2024}, author = {Park, BK and Oh, SI and Kang, M and Seok, HY and Park, JM and Kim, S and Kim, HI and Kim, JA and Park, JS}, title = {Reliability and Validity of the Korean version of the Center for Neurologic Study Bulbar Function Scale (K-CNS-BFS): An observational study.}, journal = {Medicine}, volume = {103}, number = {25}, pages = {e38216}, pmid = {38905379}, issn = {1536-5964}, mesh = {Humans ; Male ; Female ; Republic of Korea ; Middle Aged ; Reproducibility of Results ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; Aged ; *Severity of Illness Index ; Adult ; }, abstract = {Bulbar dysfunction in amyotrophic lateral sclerosis (ALS) significantly affects daily life, leading to weight loss and reduced survival. Methods for evaluating bulbar dysfunction, including videofluoroscopic swallowing studies and the bulbar component of the ALS Functional Rating Scale-Revised (ALSFRS-R), have been employed; however, Korean-specific tools are lacking. The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) comprehensively evaluates bulbar symptoms. This study aimed to develop and validate the Korean version of the CNS-BFS (K-CNS-BFS) to assess bulbar dysfunction in Korean patients with ALS. Twenty-seven patients with ALS were recruited from a tertiary hospital in South Korea based on revised El Escorial criteria. Demographic, clinical, and measurement data were collected. The K-CNS-BFS was evaluated for reliability and validity. Reliability assessment revealed strong internal consistency (Cronbach alpha) for the K-CNS-BFS subscales and total score. Test-retest reliability showed significant correlation. Content validity index was excellent, and convergent validity demonstrated significant correlations between the K-CNS-BFS and relevant measures. Discriminant validity was observed between the K-CNS-BFS and motor/respiratory subscores of the ALSFRS-R. Construct validity demonstrated significant correlations between the K-CNS-BFS subscales and total score. This is the first study to investigate the reliability and validity of the Korean version of the CNS-BFS, which showed consistent and reliable scores that correlated with tests for bulbar or general dysfunction. The K-CNS-BFS effectively measured bulbar dysfunction similar to the original CNS-BFS. The K-CNS-BFS is a reliable and valid tool for assessing bulbar dysfunction in patients with ALS in South Korea.}, } @article {pmid38904901, year = {2024}, author = {Aiello, EN and Torre, S and Solca, F and Curti, B and De Luca, G and Gendarini, C and Cocuzza, A and Colombo, E and Maranzano, A and Verde, F and Morelli, C and Messina, S and Doretti, A and Silani, V and Ticozzi, N and Poletti, B}, title = {Ecological validity of performance-based cognitive screeners in amyotrophic lateral sclerosis: preliminary evidence.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {11}, pages = {5319-5325}, pmid = {38904901}, issn = {1590-3478}, support = {Ministero della Salute//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Middle Aged ; *Caregivers/psychology ; Aged ; *Neuropsychological Tests/standards ; Reproducibility of Results ; Cognition Disorders/diagnosis/etiology ; Adult ; }, abstract = {BACKGROUND: This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the veridicality, of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioral Screen (ALS-CBS™), by relating their scores to caregiver-report ratings of cognitive changes.

METHODS: N = 147 patient-caregiver dyads were recruited. Patients were administered the ECAS and ALS-CBS™, whilst caregiver the Caregiver Behavioral Questionnaire (CBQ) and Beaumont Behavioural Inventory (BBI). An Ecological Cognitive Functioning Index (ECFI) was derived from those items of the CBQ and BBI that tap on executive and language changes. Ecological validity was assessed via both correlational and predictive analyses net of caregiver-rated behavioural changes (as assessed by the ECAS-Carer Interview).

RESULTS: The ECFI was associated with the total scores on both the ECAS (p = .014) and ALS-CBS™ (p = .017). When looking at ECAS and ALS-CBS™ subscales, those assessing verbal fluency were selectively associated with the ECFI. The ECFI was higher in patients performing defectively on the ECAS (p = .004) and on the ALS-CBS™ (p = .027).

DISCUSSION: This study suggests that both the ECAS and the ALS-CBS™ represent a valid estimate of non-demented ALS patients' cognitive status in the real world, also highlighting the clinical relevance of cognitive changes reported by caregivers.}, } @article {pmid38904729, year = {2024}, author = {Portes E Silva, KR and Nogueira, EM and Jesus Mendes, AL and Pena, ALB and Simões E Silva, AC}, title = {The potential role of renin angiotensin system in acute leukemia: a narrative review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {775}, pmid = {38904729}, issn = {1573-4978}, support = {304496/2023-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Renin-Angiotensin System/physiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; *Angiotensin II/metabolism ; Leukemia, Myeloid, Acute/metabolism/pathology ; Signal Transduction ; Angiotensin I/metabolism ; Neovascularization, Pathologic/metabolism ; Animals ; Peptide Fragments/metabolism ; }, abstract = {Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.}, } @article {pmid38903602, year = {2024}, author = {Al-Kuraishy, HM and Jabir, MS and Sulaiman, GM and Mohammed, HA and Al-Gareeb, AI and Albuhadily, AK and Jawad, SF and Swelum, AA and Abomughaid, MM}, title = {The role of statins in amyotrophic lateral sclerosis: protective or not?.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422912}, pmid = {38903602}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.}, } @article {pmid38903475, year = {2024}, author = {Dash, D and Teplansky, K and Ferrari, P and Babajani-Feremi, A and Calley, CS and Heitzman, D and Austin, SG and Wang, J}, title = {Automatic detection of ALS from single-trial MEG signals during speech tasks: a pilot study.}, journal = {Frontiers in psychology}, volume = {15}, number = {}, pages = {1114811}, pmid = {38903475}, issn = {1664-1078}, abstract = {Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (∼ 98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from single-trial neural signals.}, } @article {pmid38903116, year = {2024}, author = {Matera, AG and Steiner, RE and Mills, CA and Herring, LE and Garcia, EL}, title = {Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38903116}, issn = {2692-8205}, support = {P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM136435/GM/NIGMS NIH HHS/United States ; }, abstract = {Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.}, } @article {pmid38902980, year = {2024}, author = {Dratch, L and Kinnamon, DD and Harrington, EA and Goldman, J and Fong, JC and Jones, T and Uhlmann, WR and Roggenbuck, J}, title = {Response to "assessment of risk of ALS conferred by the GGGGCC hexanucleotide expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion".}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {797-799}, doi = {10.1080/21678421.2024.2362854}, pmid = {38902980}, issn = {2167-9223}, } @article {pmid38902734, year = {2024}, author = {Hu, Y and Hruscha, A and Pan, C and Schifferer, M and Schmidt, MK and Nuscher, B and Giera, M and Kostidis, S and Burhan, Ö and van Bebber, F and Edbauer, D and Arzberger, T and Haass, C and Schmid, B}, title = {Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {50}, pmid = {38902734}, issn = {1750-1326}, mesh = {Animals ; *Zebrafish ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Zebrafish Proteins/metabolism/genetics ; Animals, Genetically Modified ; Neuromuscular Junction/metabolism/pathology ; }, abstract = {BACKGROUND: The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing.

METHODS: CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis.

RESULTS: CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish's embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction.

CONCLUSIONS: The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression.}, } @article {pmid38902629, year = {2024}, author = {Takemoto, Y and Ito, D and Komori, S and Kishimoto, Y and Yamada, S and Hashizume, A and Katsuno, M and Nakatochi, M}, title = {Comparing preprocessing strategies for 3D-Gene microarray data of extracellular vesicle-derived miRNAs.}, journal = {BMC bioinformatics}, volume = {25}, number = {1}, pages = {221}, pmid = {38902629}, issn = {1471-2105}, support = {JP21wm0425013//Japan Agency for Medical Research and Development/ ; 23H00420//Japan Society for the Promotion of Science/ ; 16H06277//Japan Society for the Promotion of Science/ ; }, mesh = {*Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/genetics/metabolism ; Humans ; *Oligonucleotide Array Sequence Analysis/methods ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Gene Expression Profiling/methods ; }, abstract = {BACKGROUND: Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray's 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology.

RESULTS: Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement.

CONCLUSIONS: This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.}, } @article {pmid38902525, year = {2024}, author = {Kitamura, A and Fujimoto, A and Kawashima, R and Lyu, Y and Sasaki, K and Hamada, Y and Moriya, K and Kurata, A and Takahashi, K and Brielmann, R and Bott, LC and Morimoto, RI and Kinjo, M}, title = {Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {743}, pmid = {38902525}, issn = {2399-3642}, support = {JP22gm6410028//Japan Agency for Medical Research and Development (AMED)/ ; JP22ym0126814//Japan Agency for Medical Research and Development (AMED)/ ; 24H02286//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H04826//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 16KK0156//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 18K06201//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22H02578//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 22K19886//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JPMJSP2119//MEXT | Japan Science and Technology Agency (JST)/ ; JPMJFS2101//MEXT | Japan Science and Technology Agency (JST)/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry/genetics ; Humans ; Animals ; Protein Multimerization ; Caenorhabditis elegans/metabolism/genetics ; Intrinsically Disordered Proteins/chemistry/metabolism/genetics ; }, abstract = {Carboxy terminal fragments (CTFs) of TDP-43 contain an intrinsically disordered region (IDR) and form cytoplasmic condensates containing amyloid fibrils. Such condensates are toxic and associated with pathogenicity in amyotrophic lateral sclerosis. However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive. Here, we show that truncated RNA/DNA-recognition motif (RRM) at the N-terminus of TDP-43 CTFs leads to the structural transition of the IDR, whereas the IDR itself of TDP-43 CTFs is difficult to assemble even if they are proximate intermolecularly. Hetero-oligomers of TDP-43 CTFs that have recruited other proteins are more toxic than homo-oligomers, implicating loss-of-function of the endogenous proteins by such oligomers is associated with cytotoxicity. Furthermore, such toxicity of TDP-43 CTFs was cell-nonautonomously affected in the nematodes. Therefore, misfolding and oligomeric characteristics of the truncated RRM at the N-terminus of TDP-43 CTFs define their condensation properties and toxicity.}, } @article {pmid38901111, year = {2024}, author = {Pavey, NA and Menon, P and Peterchev, AV and Kiernan, MC and Vucic, S}, title = {Abnormalities of cortical stimulation strength-duration time constant in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {164}, number = {}, pages = {161-167}, pmid = {38901111}, issn = {1872-8952}, support = {R01 MH128422/MH/NIMH NIH HHS/United States ; R01 NS117405/NS/NINDS NIH HHS/United States ; RF1 MH124943/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; *Transcranial Magnetic Stimulation/methods ; Middle Aged ; *Motor Cortex/physiopathology ; Aged ; *Evoked Potentials, Motor/physiology ; Adult ; Motor Neurons/physiology ; }, abstract = {OBJECTIVES: Strength-duration time constant (SDTC) may now be determined for cortical motor neurones, with activity mediated by transient Na[+] conductances. The present study determined whether cortical SDTC is abnormal and linked to the pathogenesis of amyotrophic lateral sclerosis.

METHODS: Cortical SDTC and rheobase were estimated from 17 ALS patients using a controllable pulse parameter transcranial magnetic stimulation (cTMS) device. Resting motor thresholds (RMTs) were determined at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M-ratio of 0.1, using a figure-of-eight coil applied to the primary motor cortex.

RESULTS: SDTC was significantly reduced in ALS patients (150.58 ± 9.98 µs; controls 205.94 ± 13.7 µs, P < 0.01). The reduced SDTC correlated with a rate of disease progression (Rho = -0.440, P < 0.05), ALS functional rating score (ALSFRS-R) score (Rho = 0.446, P < 0.05), and disease duration (R = 0.428, P < 0.05). The degree of change in SDTC was greater in patients with cognitive abnormalities as manifested by an abnormal total Edinburgh Cognitive ALS Screen score (140.5 ± 28.7 µs, P < 0.001) and ALS-specific subscore (141.7 ± 33.2 µs, P = 0.003).

CONCLUSIONS: Cortical SDTC reduction was associated with a more aggressive ALS phenotype, or with more prominent cognitive impairment.

SIGNIFICANCE: An increase in transient Na[+] conductances may account for the reduction in SDTC, linked to the pathogenesis of ALS.}, } @article {pmid38900989, year = {2024}, author = {Tahedl, M and Tan, EL and Kleinerova, J and Delaney, S and Hengeveld, JC and Doherty, MA and Mclaughlin, RL and Pradat, PF and Raoul, C and Ango, F and Hardiman, O and Chang, KM and Lope, J and Bede, P}, title = {Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209623}, doi = {10.1212/WNL.0000000000209623}, pmid = {38900989}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology/physiopathology ; Male ; Female ; Middle Aged ; *Cerebellum/diagnostic imaging/pathology ; Aged ; *C9orf72 Protein/genetics ; Prospective Studies ; Ataxin-2/genetics ; Magnetic Resonance Imaging ; Disease Progression ; Cerebral Cortex/diagnostic imaging/pathology/physiopathology ; Adult ; Longitudinal Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS.

METHODS: A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures.

RESULTS: A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 ("ATXN2"). Flocculonodular lobule (padj = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura (padj = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients (padj = 0.003, t(249) = 3.04 and padj = 0.05, t(249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline (padj = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline (padj = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection (padj = 0.025, t(199) = -2.26), and progressive flocculonodular lobule degeneration (padj = 0.017, t(249) = -2.24). C9POS patients showed progressive ventral dentate atrophy (padj = 0.007, t(249) = -2.75). The CSTs (padj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers (padj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection (padj = 0.001, t(190) = 6.93).

DISCUSSION: ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.}, } @article {pmid38900757, year = {2024}, author = {Serian, A and Finsel, J and Ludolph, AC and Uttner, I and Lulé, D}, title = {Screening instruments of cognition: The relation of the mini-mental state examination to the Edinburgh cognitive and behavioural ALS screen in amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304593}, pmid = {38900757}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology/complications/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Mental Status and Dementia Tests ; Cognition/physiology ; Cognitive Dysfunction/diagnosis/epidemiology ; Neuropsychological Tests ; Cognition Disorders/diagnosis ; }, abstract = {OBJECTIVE: The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is an established cognitive screening instrument for patients with amyotrophic lateral sclerosis (ALS). Different from tools like the Mini-Mental State Examination (MMSE), it is adjusted for motor impairment, yet, the latter remains one of the most widely used screening instruments, also in ALS studies. Thus, it is of utmost importance to relate outcome scores of both instruments to allow for comparison in ALS patients. This study reports on the performance of ALS patients in both tests with regard to incidence and degree of cognitive impairment, and the correspondence of both, ECAS and MMSE scores.

METHODS: We examined N = 84 ALS patients with the German versions of the ECAS and the MMSE. Performance in both tests regarding incidence and degree of cognitive impairment, and correspondence of frequency of cognitive impairment according to both tests was examined. The relationship between ECAS and MMSE scores was modelled with a non-linear regression model.

RESULTS: All ALS patients were able to complete the ECAS, 89.3% (N = 75) were capable to complete the MMSE. Prevalence of cognitive impairment was in both tests 22.7%, however agreement was only 52.9%. Despite, regression analyses yielded a strong positive relationship (adjusted R2 = .68) between the ECAS total score and the MMSE total score. Both tests were able to identify all patients with dementia.

CONCLUSION: These results suggest that the MMSE is not ideal for cognitive screening in early-stage ALS patients. However, a rough translation of MMSE scores in ECAS scores is possible to estimate the cognitive performance level of patients, with the ECAS being more discriminative in the lower range of cognitive dysfunction (ECAS score: 80-136), for which the MMSE does not define cognitive impairment (corresponding MMSE score: 27-30).}, } @article {pmid38900570, year = {2024}, author = {Privado, J and Sanchis Sanchis, E and Sancho-Cantus, D and Cubero-Plazas, L and Navarro-Illana, E and de la Rubia Ortí, JE}, title = {Prediction of caregiver psychological distress in amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {Rehabilitation psychology}, volume = {69}, number = {4}, pages = {364-374}, doi = {10.1037/rep0000554}, pmid = {38900570}, issn = {1939-1544}, support = {//Catholic University of Valencia San Vicente Mártir/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; *Caregivers/psychology ; Female ; Cross-Sectional Studies ; Middle Aged ; *Psychological Distress ; Aged ; Adult ; Stress, Psychological/psychology/complications ; }, abstract = {PURPOSE/OBJECTIVE: To propose a predictive model for caregivers' psychological distress (including anxiety, depression, and cognitive overload) based on different data gathered from amyotrophic lateral sclerosis (ALS) patients (cognitive level, psychological distress, type of ALS, and sex).

RESEARCH METHOD/DESIGN: A cross-sectional study with a sample of 51 ALS patients and their respective main carers. Various instruments were used such as the Beck Anxiety Inventory, ALS Depression Inventory-12, and the Edinburgh Cognitive and Behavioral ALS Screen, Zarit Burden Interview, Self-Rating Depression Scale, and Self-Rating Anxiety Scale for caregivers.

RESULTS: ALS type, sex, and cognition were predictive variables for caregiver distress, with the main explanatory variable being the distress of the patients themselves. Spinal ALS led to higher psychological distress in caregivers (β = .38), as did male patients with ALS and preserved cognition.

CONCLUSIONS/IMPLICATIONS: The proposed confirmatory model demonstrates that patients' psychological distress is the best predictor of psychological distress in their caregivers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, } @article {pmid38898687, year = {2024}, author = {Lee, B and Lee, SM and Song, JW and Choi, JW}, title = {Gut Microbiota Metabolite Messengers in Brain Function and Pathology at a View of Cell Type-Based Receptor and Enzyme Reaction.}, journal = {Biomolecules & therapeutics}, volume = {32}, number = {4}, pages = {403-423}, pmid = {38898687}, issn = {1976-9148}, abstract = {The human gastrointestinal (GI) tract houses a diverse microbial community, known as the gut microbiome comprising bacteria, viruses, fungi, and protozoa. The gut microbiome plays a crucial role in maintaining the body's equilibrium and has recently been discovered to influence the functioning of the central nervous system (CNS). The communication between the nervous system and the GI tract occurs through a two-way network called the gut-brain axis. The nervous system and the GI tract can modulate each other through activated neuronal cells, the immune system, and metabolites produced by the gut microbiome. Extensive research both in preclinical and clinical realms, has highlighted the complex relationship between the gut and diseases associated with the CNS, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review aims to delineate receptor and target enzymes linked with gut microbiota metabolites and explore their specific roles within the brain, particularly their impact on CNS-related diseases.}, } @article {pmid38898538, year = {2024}, author = {Bravo-Miana, RDC and Arizaga-Echebarria, JK and Otaegui, D}, title = {Central nervous system-derived extracellular vesicles: the next generation of neural circulating biomarkers?.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {32}, pmid = {38898538}, issn = {2047-9158}, support = {PI20/1253//Instituto de Salud Carlos III/ ; KK-2021/00009//Departamento de Desarrollo Económico, Sostenibilidad y Medio Ambiente/ ; ECTRIMS Postdoctoral Research Fellowship 2023//European Committee for Treatment and Research in Multiple Sclerosis/ ; Predoctoral fellowship//Basque Government/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/blood ; *Central Nervous System/metabolism ; *Neurodegenerative Diseases/blood/diagnosis/metabolism ; Animals ; }, abstract = {The central nervous system (CNS) is integrated by glial and neuronal cells, and both release extracellular vesicles (EVs) that participate in CNS homeostasis. EVs could be one of the best candidates to operate as nanosized biological platforms for analysing multidimensional bioactive cargos, which are protected during systemic circulation of EVs. Having a window into the molecular level processes that are happening in the CNS could open a new avenue in CNS research. This raises a particular point of interest: can CNS-derived EVs in blood serve as circulating biomarkers that reflect the pathological status of neurological diseases? L1 cell adhesion molecule (L1CAM) is a widely reported biomarker to identify CNS-derived EVs in peripheral blood. However, it has been demonstrated that L1CAM is also expressed outside the CNS. Given that principal data related to neurodegenerative diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease were obtained using L1CAM-positive EVs, efforts to overcome present challenges related to its specificity are required. In this sense, other surface biomarkers for CNS-derived EVs, such as glutamate aspartate transporter (GLAST) and myelin oligodendrocyte glycoprotein (MOG), among others, have started to be used. Establishing a panel of EV biomarkers to analyse CNS-derived EVs in blood could increase the specificity and sensitivity necessary for these types of studies. This review covers the main evidence related to CNS-derived EVs in cerebrospinal fluid and blood samples of patients with neurological diseases, focusing on the reported biomarkers and the technical possibilities for their isolation. EVs are emerging as a mirror of brain physiopathology, reflecting both localized and systemic changes. Therefore, when the technical hindrances for EV research and clinical applications are overcome, novel disease-specific panels of EV biomarkers would be discovered to facilitate transformation from traditional medicine to personalized medicine.}, } @article {pmid38898231, year = {2024}, author = {Gao, J and Gunasekar, S and Xia, ZJ and Shalin, K and Jiang, C and Chen, H and Lee, D and Lee, S and Pisal, ND and Luo, JN and Griciuc, A and Karp, JM and Tanzi, R and Joshi, N}, title = {Gene therapy for CNS disorders: modalities, delivery and translational challenges.}, journal = {Nature reviews. Neuroscience}, volume = {25}, number = {8}, pages = {553-572}, pmid = {38898231}, issn = {1471-0048}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Central Nervous System Diseases/therapy/genetics ; Animals ; Translational Research, Biomedical/methods ; Gene Transfer Techniques/trends ; }, abstract = {Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.}, } @article {pmid38898006, year = {2024}, author = {Nógrádi, B and Nógrádi-Halmi, D and Erdélyi-Furka, B and Kádár, Z and Csont, T and Gáspár, R}, title = {Mechanism of motoneuronal and pyramidal cell death in amyotrophic lateral sclerosis and its potential therapeutic modulation.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {291}, pmid = {38898006}, issn = {2058-7716}, support = {BO/00574/22//Magyar Tudományos Akadémia (Hungarian Academy of Sciences)/ ; ÚNKP-23-5 -SZTE-711//Emberi Eroforrások Minisztériuma (Ministry of Human Capacities)/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder clinically characterized by muscle atrophy and progressive paralysis. Loss of motoneurons and pyramidal cells is thought to be the center piece of the complex and multifaceted ALS pathology, however, the exact mechanisms laying behind motoneuronal cell death in the spinal cord and motor cortex are still unknown. It was originally proposed that apoptosis plays a fundamental role in motoneuronal demise, nonetheless, later it became clear that other forms of regulated cell death, including necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, may also contribute to motoneuron loss. Over the past years, multiple studies aimed to improve our understanding of the contributory role of these mechanisms as well as to offer novel targets for potential therapeutic interventions. The pharmacological inhibition of the ferroptotic pathway and the modulation of the autophagic machinery seem to have particularly promising effects, reducing motoneuron loss and slowing disease progression in transgenic models of ALS. Nevertheless, the potential beneficial effects of necroptosis-targeting interventions were mostly disproven in the latest studies. In this review we aim to summarize the current view on regulated cell death mechanisms that lead to motoneuronal and pyramidal cell degeneration in ALS and showcase their applicability as future drug targets.}, } @article {pmid38897956, year = {2024}, author = {Takahashi, R and Furuta, M and Nagashima, K and Ikeda, Y}, title = {Concurrent Amyotrophic Lateral Sclerosis and Huntington's Disease: A Case Report.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {}, number = {}, pages = {}, doi = {10.2169/internalmedicine.3232-23}, pmid = {38897956}, issn = {1349-7235}, abstract = {Huntington's disease (HD) is a dominantly inherited neurological disorder characterized by chorea, psychiatric symptoms, and cognitive decline but typically lacks muscular atrophy and weakness. We herein report a case of genetically confirmed HD showing progressive systemic weakness with findings of upper and lower motor neuron involvement due to amyotrophic lateral sclerosis (ALS). The current patient and the previously reported cases with complications of HD and ALS indicate that cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene might have a pathogenic role in causing the two neurological disorders.}, } @article {pmid38896345, year = {2024}, author = {Robinson, JL and Suh, E and Xu, Y and Hurtig, HI and Elman, L and McMillan, CT and Irwin, DJ and Porta, S and Van Deerlin, VM and Lee, EB}, title = {Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {104}, pmid = {38896345}, issn = {1432-0533}, support = {RF1 AG065341/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P01AG066597/AG/NIA NIH HHS/United States ; U19AG062418/AG/NIA NIH HHS/United States ; R01 AG075276/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; RF1AG065341/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Aged ; *Annexins/genetics/metabolism ; Female ; Male ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Middle Aged ; Aged, 80 and over ; TDP-43 Proteinopathies/pathology/genetics ; Neurodegenerative Diseases/pathology/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/pathology/metabolism ; Brain/pathology/metabolism ; Protein Aggregation, Pathological/pathology/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.}, } @article {pmid38896262, year = {2024}, author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Clinical and genetic characteristics of 1672 cases of amyotrophic lateral sclerosis in China: a single-center retrospective study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5541-5548}, pmid = {38896262}, issn = {1432-1459}, support = {XDB39040100//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; 2022-PUMCH-B-017//High-level Hospital Construction Project of Guangdong Provincial People's Hospital/ ; 2022YFC2703904//Key Technologies Research and Development Program/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 81971293//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Middle Aged ; Female ; Adult ; Aged ; Young Adult ; Adolescent ; Aged, 80 and over ; China/epidemiology ; Retrospective Studies ; *C9orf72 Protein/genetics ; Age of Onset ; Mutation ; Phenotype ; Exome Sequencing ; Genotype ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis.

METHODS: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed.

RESULTS: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset.

CONCLUSION: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment.}, } @article {pmid38896163, year = {2024}, author = {Woodworth, DC and Nguyen, KM and Sordo, L and Scambray, KA and Head, E and Kawas, CH and Corrada, MM and Nelson, PT and Sajjadi, SA}, title = {Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer's Coordinating Center database.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {103}, pmid = {38896163}, issn = {1432-0533}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; T32AG073088/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; T32 AG073088/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; R01 AG062706/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01AG062706/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Aged ; Male ; *Alzheimer Disease/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *TDP-43 Proteinopathies/pathology ; Aged, 80 and over ; Databases, Factual ; Frontotemporal Lobar Degeneration/pathology/metabolism ; Brain/pathology/metabolism ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Hippocampus/pathology/metabolism ; Middle Aged ; }, abstract = {TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.}, } @article {pmid38895672, year = {2024}, author = {Deng, J and Sun, WT and Gong, K and Wang, LP and Li, FZ}, title = {Internal limiting membrane peeling combined with silicone oil or air tamponade for highly myopic foveoschisis.}, journal = {International journal of ophthalmology}, volume = {17}, number = {6}, pages = {1079-1085}, pmid = {38895672}, issn = {2222-3959}, abstract = {AIM: To compare the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) and silicone oil or sterile air tamponade for the treatment of myopic foveoschisis (MF) in highly myopic eyes.

METHODS: This retrospective study included 48 myopic eyes of 40 patients with MF and axial lengths (ALs) ranging from 26-32 mm treated between January 2020 and January 2022. All patients were underwent PPV combined with ILM peeling followed by sterile air or silicone oil tamponade and followed up at least 12mo. Based on the features on spectral-domain optical coherence tomography (SD-OCT), the eyes were divided into the MF-only group (Group A, n=15 eyes), MF with central foveal detachment group (Group B, n=20 eyes), and MF with lamellar macular hole group (Group C, n=13 eyes). According to AL, eyes were further divided into three groups: Group D (26.01-28.00 mm, n=12 eyes), Group E (28.01-30.00 mm, n=26 eyes), and Group F (30.01-32.00 mm, n=10 eyes). The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and complications were recorded.

RESULTS: The patients included 16 males and 24 females with the mean age of 56±9.82y. The BCVA and CFT improved in all groups after surgery (P<0.01), while there was no significant difference of the CFT in Group A, B, and C postoperatively (P>0.05). The intergroup differences of BCVA and CFT postoperatively were statistically significant in Group D, E, and F. Twenty eyes were injected with sterile air, and 28 eyes were injected with silicone oil for tamponade based on the AL. However, there was no statistically significant difference among Groups D, E, and F in terms of the results of sterile air or silicone oil tamponade. The mean recovery time was 5.9mo for MF patients subjected to silicone oil tamponade and 7.7mo for patients subjected to sterile air tamponade, and the difference was not statistically significant.

CONCLUSION: PPV and ILM peeling combined with silicone oil or sterile air tamponade can achieve good results for MF in highly myopic eyes with ALs≤32 mm.}, } @article {pmid38895610, year = {2024}, author = {Kaundun, SS and Martin-Sanz, A and Rodríguez, M and Serbanoiu, T and Moreno, J and Mcindoe, E and le Goupil, G}, title = {First case of evolved herbicide resistance in the holoparasite sunflower broomrape, Orobanche cumana Wallr.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1420009}, pmid = {38895610}, issn = {1664-462X}, abstract = {The development and commercialisation of sunflower varieties tolerant to acetolactate synthase (ALS)-inhibiting herbicides some 20 years ago provided farmers with an alternative method for the cost-effective control of Orobanche cumana. In 2020, however, two independent sunflower broomrape populations from Drama (GR-DRA) and Orestiada (GR-ORE), Greece, were reported to be heavily infested with O. cumana after application of the ALS-inhibiting herbicide imazamox. Here we have investigated the race of GR-DRA and GR-ORE and determined the basis of resistance to imazamox in the two Greek O. cumana samples. Using a set of five diagnostic sunflower varieties characterised by different resistant genes with respect to O. cumana infestation, we have clearly established that the GR-ORE and GR-DRA populations belong to the invasive broomrape races G and G+, respectively. Live underground tubercles and emerged shoots were identified at the recommended field rate of imazamox for GR-DRA and GR-ORE but not for two other standard sensitive populations in a whole plant dose response test using two different herbicide-tolerant sunflower hybrids as hosts. Sequencing of the ALS gene identified an alanine 205 to aspartate mutation in all GR-ORE samples. Most GR-DRA tubercles were characterised by a second serine 653 to asparagine ALS mutation whilst a few GR-DRA individuals contained the A205D mutation. Mutations at ALS codons 205 and 653 are known to impact on the binding and efficacy of imazamox and other imidazolinone herbicides. The knowledge generated here will be important for tracking and managing broomrape resistance to ALS-inhibiting herbicides in sunflower growing regions.}, } @article {pmid38895485, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.06.597745}, pmid = {38895485}, issn = {2692-8205}, abstract = {UNLABELLED: Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

AUTHOR SUMMARY: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.}, } @article {pmid38895380, year = {2024}, author = {König, LE and Rodriguez, S and Hug, C and Daneshvari, S and Chung, A and Bradshaw, GA and Sahin, A and Zhou, G and Eisert, RJ and Piccioni, F and Das, S and Kalocsay, M and Sokolov, A and Sorger, P and Root, DE and Albers, MW}, title = {TYK2 as a novel therapeutic target in Alzheimer's Disease with TDP-43 inclusions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38895380}, issn = {2692-8205}, support = {R01 AG058063/AG/NIA NIH HHS/United States ; U54 CA225088/CA/NCI NIH HHS/United States ; }, abstract = {Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)[1,2] and amyotrophic lateral sclerosis (ALS)[3], raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS[4]. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death[4]. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.}, } @article {pmid38895337, year = {2024}, author = {Vazquez-Sanchez, S and Tilkin, B and Gasset-Rosa, F and Zhang, S and Piol, D and McAlonis-Downes, M and Artates, J and Govea-Perez, N and Verresen, Y and Guo, L and Cleveland, DW and Shorter, J and Da Cruz, S}, title = {Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.03.593639}, pmid = {38895337}, issn = {2692-8205}, abstract = {RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic FTLD. Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.}, } @article {pmid38895204, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 [S59L].}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.04.597429}, pmid = {38895204}, issn = {2692-8205}, abstract = {Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10(CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H [S81L] , and human cell models expressing CHCHD10 [S59L] , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 [S59L] . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 [S59L] -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 [S59L] -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 [S59L] -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H [S81L] . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 [S59L] . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 [S59L] -induced ALS-FTD and possibly other related diseases.}, } @article {pmid38894936, year = {2024}, author = {Brown, SP}, title = {Diagnosis of Cervical Spinal Cord Multiple Sclerosis by a Chiropractic Physician: A Case Report.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e62618}, pmid = {38894936}, issn = {2168-8184}, abstract = {We present a case report of diagnosis of cervical spine multiple sclerosis by a chiropractic physician. This unique case contributes an account of a challenging differential diagnosis to the literature. A 30-year-old male presented with a three-year history of diffuse left upper extremity motor strength deficits and paresthesia (numbness and tingling). The patient had seen multiple physicians for these symptoms with no diagnosis of multiple sclerosis and no advanced imaging. The differential diagnosis included lower cervical spine nerve root compression or neurological disorders such as amyotrophic lateral sclerosis, cerebral lesion, motor neuropathy, multiple sclerosis, or spinal cord lesion. MRI of the cervical spine with and without IV contrast revealed evidence of spinal cord multiple sclerosis. The patient was referred to a neurologist where the diagnosis of multiple sclerosis was confirmed. A 10-year follow-up showed the patient was controlling his condition with medications and had no disability. This case underscores the importance for physicians to consider neurological conditions and advanced imaging in the presence of diffuse motor strength deficits and paresthesia in the absence of injury, pain, or any other symptoms.}, } @article {pmid38894913, year = {2024}, author = {Sabnis, RW and Sabnis, AR}, title = {Novel Compounds as S1P5 Modulators for Treating Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {15}, number = {6}, pages = {750-751}, pmid = {38894913}, issn = {1948-5875}, abstract = {Provided herein are novel compounds as S1P5 modulators, pharmaceutical compositions, use of such compounds in treating neurodegenerative diseases, particularly Alzheimer's disease, multiple sclerosis, migraine and amyotrophic lateral sclerosis, and processes for preparing such compounds.}, } @article {pmid38894662, year = {2024}, author = {Jacobsen, AB and Bostock, H and Howells, J and Cengiz, B and Samusyte, G and Koltzenburg, M and Pia, H and Fuglsang-Frederiksen, A and Blicher, J and Obál, I and Andersen, H and Tankisi, H}, title = {Threshold tracking transcranial magnetic stimulation and neurofilament light chain as diagnostic aids in ALS.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1887-1896}, pmid = {38894662}, issn = {2328-9503}, support = {//Sundhedsvidenskabelige Fakultet, Aarhus Universitet/ ; R290-2018-751//Lundbeck Foundation/ ; R346-2020-1946//Lundbeck Foundation/ ; //William Demant Fonden/ ; //Familien Hede Nielsens Fond/ ; //Aage og Johanne Louis-Hansens Fond/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Middle Aged ; Male ; Female ; Aged ; *Neurofilament Proteins ; *Transcranial Magnetic Stimulation/methods ; *Biomarkers ; Electromyography ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: There is a need for sensitive biomarkers in amyotrophic lateral sclerosis (ALS), to enable earlier diagnosis and to help assess potential treatments. The main objective of this study was to compare two potential biomarkers, threshold-tracking short-interval cortical inhibition (T-SICI), which has shown promise as a diagnostic aid, and neurofilament light chains (NfL).

METHODS: Ninety-seven patients with ALS (mean age 67.1 ± 11.5 years) and 53 ALS mimics (aged 62.4 ± 12.9) were included. Mean disease duration was 14 months ±14.1. Patients were evaluated with revised ALS functional rating score (ALSFRS-R), Penn upper motor neuron score (UMNS), muscle strength using the Medical Research Council (MRC) score and examined with T-SICI, quantitative electromyography (EMG), and NfL measured in spinal fluid.

RESULTS: NfL increased with increasing UMNS (rho = 0.45, p = 8.2 × 10[-6]) whereas T-SICI at 2.5 ms paradoxically increased toward normal values (rho = 0.53, p = 1.9 × 10[-7]). However, these two measures were uncorrelated. Discrimination between ALS patients and mimics was best for NfL (area under ROC curve 0.842, sensitivity 84.9%, specificity 83.5%), compared with T-SICI (0.675, 39.6%, 91.8%). For the patients with no UMN signs, NfL also discriminated best (0.884, 89.3%, 82.6%), compared with T-SICI (0.811, 71.4%, 82.6%). However, when combining NfL and T-SICI, higher AUCs of 0.854 and 0.922 and specificities of 93.8 and 100 were found when considering all patients and patients with no UMN signs, respectively.

INTERPRETATION: Both T-SICI and NfL correlated with UMN involvement and combined, they provided a strong discrimination between ALS patients and ALS mimics.}, } @article {pmid38892814, year = {2024}, author = {Barbato, F and Bombaci, A and Colacicco, G and Bruno, G and Ippolito, D and Pota, V and Dongiovanni, S and Sica, G and Bocchini, G and Valente, T and Scaglione, M and Mainenti, PP and Guarino, S}, title = {Chest Dynamic MRI as Early Biomarker of Respiratory Impairment in Amyotrophic Lateral Sclerosis Patients: A Pilot Study.}, journal = {Journal of clinical medicine}, volume = {13}, number = {11}, pages = {}, pmid = {38892814}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder characterized by limb and bulbar muscle wasting and weakness. A total of 30% of patients present a bulbar onset, while 70% have a spinal outbreak. Respiratory involvement represents one of the worst prognostic factors, and its early identification is fundamental for the early starting of non-invasive ventilation and for the stratification of patients. Due to the lack of biomarkers of early respiratory impairment, we aimed to evaluate the role of chest dynamic MRI in ALS patients. Methods: We enrolled 15 ALS patients and 11 healthy controls. We assessed the revised ALS functional rating scale, spirometry, and chest dynamic MRI. Data were analyzed by using the Mann-Whitney U test and Cox regression analysis. Results: We observed a statistically significant difference in both respiratory parameters and pulmonary measurements at MRI between ALS patients and healthy controls. Moreover, we found a close relationship between pulmonary measurements at MRI and respiratory parameters, which was statistically significant after multivariate analysis. A sub-group analysis including ALS patients without respiratory symptoms and with normal spirometry values revealed the superiority of chest dynamic MRI measurements in detecting signs of early respiratory impairment. Conclusions: Our data suggest the usefulness of chest dynamic MRI, a fast and economically affordable examination, in the evaluation of early respiratory impairment in ALS patients.}, } @article {pmid38892250, year = {2024}, author = {Cerantonio, A and Citrigno, L and Greco, BM and De Benedittis, S and Passarino, G and Maletta, R and Qualtieri, A and Montesanto, A and Spadafora, P and Cavalcanti, F}, title = {The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892250}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *DNA, Mitochondrial/genetics ; *DNA Copy Number Variations ; *Mitochondria/genetics/metabolism ; Huntington Disease/genetics/pathology ; Animals ; }, abstract = {Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.}, } @article {pmid38891895, year = {2024}, author = {Dabrowska, S and Turano, E and Scambi, I and Virla, F and Nodari, A and Pezzini, F and Galiè, M and Bonetti, B and Mariotti, R}, title = {A Cellular Model of Amyotrophic Lateral Sclerosis to Study the Therapeutic Effects of Extracellular Vesicles from Adipose Mesenchymal Stem Cells on Microglial Activation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891895}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology ; *Extracellular Vesicles/metabolism ; *Microglia/metabolism ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Cell Line ; Adipose Tissue/cytology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu[+]/Zn[+] superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.}, } @article {pmid38891791, year = {2024}, author = {Tokuda, E and Sakashita, Y and Tokoro, N and Date, A and Kosuge, Y and Miyasaka, T}, title = {MS785-MS27 Reactive Misfolded/Non-Native Zn-Deficient SOD1 Species Exhibit Cytotoxicity and Adopt Heterozygous Conformations in Motor Neurons.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891791}, issn = {1422-0067}, support = {2022-2025//The Takeda Science Foundation/ ; }, mesh = {Animals ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Motor Neurons/metabolism/pathology ; Mice ; *Zinc/metabolism/deficiency ; *Protein Folding ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Mutation ; Mice, Transgenic ; Heterozygote ; Protein Conformation ; }, abstract = {Misfolding of superoxide dismutase-1 (SOD1) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) with SOD1 mutations. The development of antibodies specific for misfolded SOD1 deepens our understanding of how the protein participates in ALS pathogenesis. Since the term "misfolding" refers to various disordered conformers other than the natively folded one, which misfolded species are recognized by specific antibodies should be determined. Here, we molecularly characterized the recognition by MS785-MS27, an antibody cocktail experimentally confirmed to recognize over 100 ALS-linked SOD1 mutants. Indirect ELISA revealed that the antibody cocktail recognized Zn-deficient wild-type and mutated SOD1 species. It also recognized conformation-disordered wild-type and mutated SOD1 species, such as unfolded and oligomeric forms, but had less affinity for the aggregated form. Antibody-reactive SOD1 exhibited cytotoxicity to a motor neuron cell model, which was blocked by Zn treatment with Zn-deficient SOD1. Immunohistochemistry revealed antibody-reactive SOD1 mainly in spinal motor neurons of SOD1[G93A] mice throughout the disease course, and the distribution after symptomatic stages differed from that of other misfolded SOD1 species. This suggests that misfolded/non-native SOD1 species exist as heterogeneous populations. In conclusion, MS785-MS27 recognizes various conformation-disordered SOD1 species lacking the Zn ion.}, } @article {pmid38891774, year = {2024}, author = {Arnold, FJ and Putka, AF and Raychaudhuri, U and Hsu, S and Bedlack, RS and Bennett, CL and La Spada, AR}, title = {Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38891774}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Glutamic Acid/metabolism ; Animals ; Motor Neurons/metabolism/pathology ; Aging/metabolism ; Receptors, AMPA/metabolism ; Endoplasmic Reticulum Stress ; Mitochondria/metabolism ; Excitatory Amino Acid Transporter 2/metabolism ; Astrocytes/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.}, } @article {pmid38891289, year = {2024}, author = {Idziak, R and Waligóra, H and Majchrzak, L and Szulc, P}, title = {Multifunctional Adjuvants Affect Sulfonylureas with Synthetic Auxin Mixture in Weed and Maize Grain Yield.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891289}, issn = {2223-7747}, abstract = {A field study in the years 2017-2019 was carried out to evaluate the impact of novel adjuvant formulations on the efficacy of sulfonylurea and synthetic auxin herbicides. Treatments included nicosulfuron + rimsulfuron + dicamba (N+R+D) at full and reduced rates with three multicomponent (TEST-1, TEST-2, TEST-3) as well as standard (MSO, S) adjuvants. In this greenhouse study, Echinochloa crus-galli seeds were planted and treated with N+R+D at 2-3 leaf stages. The water with the desired pH (4, 7, and 9) for the preparation of the spray liquid was prepared by incorporating citric acid or K3PO4 to either lower or raise the pH of the water. Adjuvant TEST-1 added to the spray liquid at pH 4 increased the effectiveness to 68%, TEST-2 to 81%, and TEST-3 to 80%, compared to 73% and 66% with the MSO and S. The efficacy of N+R+D at pH 7 with TEST-1 increased to 83%, TEST-2 to 82%, and TEST-3 to 77%, but with MSO, it increased to 81%, and 71% with S. Adjuvants TEST-1, TEST-2, and TEST-3 in the liquid at pH 9 increased efficacy to 76 and 80%, compared to 79 and 63% with MSO or S adjuvants. N+R+D applied with TEST-1, TEST-2, and TEST-3 provided greater weed control than herbicides with surfactant (S) and similar or even better than with standard methylated seed oil (MSO) adjuvants. Maize grain yield after herbicide-with-tested-adjuvant application was higher than from an untreated check, and comparable to yield from herbicide-with-MSO treatment, but higher than from S treatment.}, } @article {pmid38891112, year = {2024}, author = {Santos, JR and Park, J}, title = {MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891112}, issn = {2073-4409}, support = {n/a//Canada Research Chairs/ ; 202104PJT-462444-NSB-CEAB-275899/CAPMC/CIHR/Canada ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Nuclear Matrix-Associated Proteins/metabolism/genetics ; *Gene Expression Regulation ; *Nuclear Matrix/metabolism ; Animals ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Matrin-3 (MATR3) was initially discovered as a component of the nuclear matrix about thirty years ago. Since then, accumulating studies have provided evidence that MATR3 not only plays a structural role in the nucleus, but that it is also an active protein involved in regulating gene expression at multiple levels, including chromatin organization, DNA transcription, RNA metabolism, and protein translation in the nucleus and cytoplasm. Furthermore, MATR3 may play a critical role in various cellular processes, including DNA damage response, cell proliferation, differentiation, and survival. In addition to the revelation of its biological role, recent studies have reported MATR3's involvement in the context of various diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Moreover, sequencing studies of patients revealed a handful of disease-associated mutations in MATR3 linked to amyotrophic lateral sclerosis (ALS), which further elevated the gene's importance as a topic of study. In this review, we synthesize the current knowledge regarding the diverse functions of MATR3 in DNA- and RNA-related processes, as well as its involvement in various diseases, with a particular emphasis on ALS.}, } @article {pmid38891099, year = {2024}, author = {Hernan-Godoy, M and Rouaux, C}, title = {From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891099}, issn = {2073-4409}, support = {ANR-21-CE16-0024//Agence Nationale de la Recherche/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Epigenesis, Genetic ; *DNA Methylation/genetics ; *Carbon/metabolism ; Animals ; }, abstract = {The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.}, } @article {pmid38891059, year = {2024}, author = {Dashtmian, AR and Darvishi, FB and Arnold, WD}, title = {Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891059}, issn = {2073-4409}, support = {1R01AG067758, R01AG078129, and R01AG067758-02S2//national institute of health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; *Aging/pathology ; Senotherapeutics/pharmacology/therapeutic use ; Animals ; Cellular Senescence ; Mitochondria/metabolism/pathology ; DNA Damage ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a group of sporadic and genetic neurodegenerative disorders that result in losses of upper and lower motor neurons. Treatment of ALS is limited, and survival is 2-5 years after disease onset. While ALS can occur in younger individuals, the risk significantly increases with advancing age. Notably, both sporadic and genetic forms of ALS share pathophysiological features overlapping hallmarks of aging including genome instability/DNA damage, mitochondrial dysfunction, inflammation, proteostasis, and cellular senescence. This review explores chronological and biological aging in the context of ALS onset and progression. Age-related muscle weakness and motor unit loss mirror aspects of ALS pathology and coincide with peak ALS incidence, suggesting a potential link between aging and disease development. Hallmarks of biological aging, including DNA damage, mitochondrial dysfunction, and cellular senescence, are implicated in both aging and ALS, offering insights into shared mechanisms underlying disease pathogenesis. Furthermore, senescence-associated secretory phenotype and senolytic treatments emerge as promising avenues for ALS intervention, with the potential to mitigate neuroinflammation and modify disease progression.}, } @article {pmid38891021, year = {2024}, author = {Nguyen, L}, title = {Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {11}, pages = {}, pmid = {38891021}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/drug therapy ; Animals ; C9orf72 Protein/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for SOD1 ALS, the updated C9orf72 GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.}, } @article {pmid38891002, year = {2024}, author = {Genchi, G and Lauria, G and Catalano, A and Carocci, A and Sinicropi, MS}, title = {Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {38891002}, issn = {2304-8158}, abstract = {Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.}, } @article {pmid38890532, year = {2024}, author = {}, title = {Molecular pathology markers of FTD and ALS in blood extracellular vesicles.}, journal = {Nature medicine}, volume = {30}, number = {6}, pages = {1545-1546}, pmid = {38890532}, issn = {1546-170X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/pathology ; *Extracellular Vesicles/metabolism/genetics ; *Biomarkers/blood ; *Frontotemporal Dementia/genetics/blood/pathology ; Pathology, Molecular ; }, } @article {pmid38890531, year = {2024}, author = {Chatterjee, M and Özdemir, S and Fritz, C and Möbius, W and Kleineidam, L and Mandelkow, E and Biernat, J and Doğdu, C and Peters, O and Cosma, NC and Wang, X and Schneider, LS and Priller, J and Spruth, E and Kühn, AA and Krause, P and Klockgether, T and Vogt, IR and Kimmich, O and Spottke, A and Hoffmann, DC and Fliessbach, K and Miklitz, C and McCormick, C and Weydt, P and Falkenburger, B and Brandt, M and Guenther, R and Dinter, E and Wiltfang, J and Hansen, N and Bähr, M and Zerr, I and Flöel, A and Nestor, PJ and Düzel, E and Glanz, W and Incesoy, E and Bürger, K and Janowitz, D and Perneczky, R and Rauchmann, BS and Hopfner, F and Wagemann, O and Levin, J and Teipel, S and Kilimann, I and Goerss, D and Prudlo, J and Gasser, T and Brockmann, K and Mengel, D and Zimmermann, M and Synofzik, M and Wilke, C and Selma-González, J and Turon-Sans, J and Santos-Santos, MA and Alcolea, D and Rubio-Guerra, S and Fortea, J and Carbayo, Á and Lleó, A and Rojas-García, R and Illán-Gala, I and Wagner, M and Frommann, I and Roeske, S and Bertram, L and Heneka, MT and Brosseron, F and Ramirez, A and Schmid, M and Beschorner, R and Halle, A and Herms, J and Neumann, M and Barthélemy, NR and Bateman, RJ and Rizzu, P and Heutink, P and Dols-Icardo, O and Höglinger, G and Hermann, A and Schneider, A}, title = {Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.}, journal = {Nature medicine}, volume = {30}, number = {6}, pages = {1771-1783}, pmid = {38890531}, issn = {1546-170X}, support = {R01 AG080470/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/pathology/genetics ; *tau Proteins/blood/metabolism ; *Extracellular Vesicles/metabolism ; *Frontotemporal Dementia/blood/diagnosis/genetics/pathology ; *Biomarkers/blood ; *DNA-Binding Proteins/blood/genetics ; Female ; Male ; Aged ; Middle Aged ; Supranuclear Palsy, Progressive/blood/diagnosis ; Protein Isoforms/blood ; }, abstract = {Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.}, } @article {pmid38890465, year = {2024}, author = {Brown, AL and Wilkins, OG and Keuss, MJ and Hill, SE and Zanovello, M and Lee, WC and Bampton, A and Lee, FCY and Masino, L and Qi, YA and Bryce-Smith, S and Gatt, A and Hallegger, M and Fagegaltier, D and Phatnani, H and , and Newcombe, J and Gustavsson, EK and Seddighi, S and Reyes, JF and Coon, SL and Ramos, D and Schiavo, G and Fisher, EMC and Raj, T and Secrier, M and Lashley, T and Ule, J and Buratti, E and Humphrey, J and Ward, ME and Fratta, P}, title = {Author Correction: TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.}, journal = {Nature}, volume = {631}, number = {8020}, pages = {E7}, doi = {10.1038/s41586-024-07577-9}, pmid = {38890465}, issn = {1476-4687}, } @article {pmid38889636, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Tavakol-Afshari, J}, title = {MicroRNA (miRNA) as a biomarker for diagnosis, prognosis, and therapeutics molecules in neurodegenerative disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {177}, number = {}, pages = {116899}, doi = {10.1016/j.biopha.2024.116899}, pmid = {38889636}, issn = {1950-6007}, mesh = {Humans ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/diagnosis/genetics/therapy ; *Biomarkers/metabolism ; Animals ; Prognosis ; }, abstract = {Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) that arise due to numerous causes like protein accumulation and autoimmunity characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform an important role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. miRNA that participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative disease (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlight miRNA as therapy.}, } @article {pmid38889523, year = {2024}, author = {Müller, HP and Abrahao, A and Beaulieu, C and Benatar, M and Dionne, A and Genge, A and Frayne, R and Graham, SJ and Gibson, S and Korngut, L and Luk, C and Welsh, RC and Zinman, L and Kassubek, J and Kalra, S}, title = {Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study.}, journal = {NeuroImage. Clinical}, volume = {43}, number = {}, pages = {103633}, pmid = {38889523}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Disease Progression ; *Diffusion Tensor Imaging/methods ; Longitudinal Studies ; Aged ; *Pyramidal Tracts/diagnostic imaging/pathology ; Adult ; Cross-Sectional Studies ; Anisotropy ; Prospective Studies ; }, abstract = {OBJECTIVE: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS.

METHODS: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses.

RESULTS: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts.

CONCLUSIONS: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.}, } @article {pmid38889403, year = {2024}, author = {Zhu, Y and Wang, F and Xia, Y and Wang, L and Lin, H and Zhong, T and Wang, X}, title = {Research progress on astrocyte-derived extracellular vesicles in the pathogenesis and treatment of neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {35}, number = {8}, pages = {855-875}, pmid = {38889403}, issn = {2191-0200}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Astrocytes/metabolism ; Animals ; Cell Communication/physiology ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), pose significant global health risks and represent a substantial public health concern in the contemporary era. A primary factor in the pathophysiology of these disorders is aberrant accumulation and aggregation of pathogenic proteins within the brain and spinal cord. Recent investigations have identified extracellular vesicles (EVs) in the central nervous system (CNS) as potential carriers for intercellular transport of misfolded proteins associated with neurodegenerative diseases. EVs are involved in pathological processes that contribute to various brain disorders including neurodegenerative disorders. Proteins linked to neurodegenerative disorders are secreted and distributed from cell to cell via EVs, serving as a mechanism for direct intercellular communication through the transfer of biomolecules. Astrocytes, as active participants in CNS intercellular communication, release astrocyte-derived extracellular vesicles (ADEVs) that are capable of interacting with diverse target cells. This review primarily focuses on the involvement of ADEVs in the development of neurological disorders and explores their potential dual roles - both advantageous and disadvantageous in the context of neurological disorders. Furthermore, this review examines the current studies investigating ADEVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases. The prospects and challenges associated with the application of ADEVs in clinical settings were also comprehensively reviewed.}, } @article {pmid38888068, year = {2024}, author = {Shefner, JM and Cudkowicz, ME}, title = {Failures to Replicate: What Recent Negative Phase 3 Trials Have Taught Us about Amyotrophic Lateral Sclerosis Clinical Research.}, journal = {Annals of neurology}, volume = {96}, number = {2}, pages = {211-215}, doi = {10.1002/ana.26999}, pmid = {38888068}, issn = {1531-8249}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials, Phase III as Topic/methods ; Biomedical Research ; }, } @article {pmid38887944, year = {2024}, author = {Mendes, AE and Silva, GD and Jorge, FMH and Callegaro, D}, title = {Tongue pressure is a strong predictor of recommendation for gastrostomy in amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {409-412}, doi = {10.1002/mus.28174}, pmid = {38887944}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/therapy ; *Gastrostomy ; Female ; Male ; Middle Aged ; Aged ; Prospective Studies ; *Tongue/physiopathology ; Pressure ; ROC Curve ; Follow-Up Studies ; }, abstract = {INTRODUCTION/AIMS: Objective and practical biomarkers to determine the need for gastrostomy in patients with amyotrophic lateral sclerosis (ALS) are lacking. Tongue pressure (TP) is a promising biomarker because it is associated with bulbar dysfunction. The aims of this study were to evaluate the association of TP with the need for gastrostomy, and to determine its optimal cut-off value.

METHODS: This prospective observational study included participants with ALS taking nutrition orally. TP was evaluated using the Iowa Oral Performance Instrument. Need for gastrostomy as determined by a multidisciplinary team during a 12-month follow up period was recorded. Associations between TP and need for gastrostomy placement were performed. ROC curve analysis determined the optimal cut-off value of TP to predict gastrostomy.

RESULTS: Of 208 screened participants, 119 were included. Gastrostomy was indicated in 45% (53), in a 12-month follow up period. TP of ≤20 kPA was a strong predictor of gastrostomy indication (OR 11.8, CI 95% [4.61, 34.7], p < .001). The association persisted even after adjustment for weight loss, pneumonia, prolonged feeding duration, Revised ALS Functional Rating Scale score, and American Speech-Language-Hearing Association scale score (OR 4.51, CI 95% [1.50, 14.9], p = .009). By receiver operating characteristic curve analysis, 20 kPA represented the optimal cut-off value (sensitivity 0.75, specificity 0.89).

DISCUSSION: TP is a strong independent predictor of gastrostomy indication in the subsequent 12 months in patients with ALS, with good sensitivity and specificity at a cutoff value of ≤20 kPA, suggesting that it may be a promising biomarker in clinical practice.}, } @article {pmid38887384, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Chen, Z and Huang, Y and Pei, X and Zhao, S and Liu, Z and Guo, T and Liang, F}, title = {Immediate Efficacy of Contralateral Acupuncture on SI3 Combined with Active Exercise for Acute Lumbar Sprains: Protocol for a Randomized Controlled Trial.}, journal = {Journal of pain research}, volume = {17}, number = {}, pages = {2099-2110}, pmid = {38887384}, issn = {1178-7090}, abstract = {PURPOSE: Acute lumbar sprain (ALS) is a common clinical disease characterized by persistent intolerable low back pain and limitation of movement, and quick pain relief and restoration of mobility in a short time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of contralateral acupuncture (CAT) on SI3 combined with active exercise in treating ALS.

METHODS AND ANALYSIS: This study is a randomized controlled trial which will recruit 118 eligible participants aged 18 to 55 years with ALS at the Second Affiliated Hospital of Yunnan University of Chinese Medicine between March 2024 and December 2026. Participants will be randomly assigned to the acupuncture group or the sham-acupuncture group in a 1:1 ratio. The acupuncture group will receive a 10-minute acupuncture treatment combined with active exercise, while the sham-acupuncture group will receive a 10-minute sham acupuncture treatment combined with active exercise. Randomization will use a computer-generated sequence with allocation concealed in opaque envelopes. The primary outcome will be the pain visual analogue scale (VAS) scores after 10 minutes of treatment. Secondary outcomes will include the pain VAS scores at other time points (2, 4, 6, and 8 minutes post-treatment), the lumbar range of motion (ROM) scores at various time points, blinded assessment, the treatment effect expectancy scale, and the rescue analgesia rate. The analysis will follow the intention-to-treat principle. The primary outcome will be analyzed using ANCOVA, and secondary outcomes with repeated measures ANOVA. The rescue analgesia rate will be assessed using either the χ[2] test or Fisher's exact test.

DISCUSSION: This study is the first randomized controlled trial to assess the immediate efficacy of CAT in combination with active exercise for ALS. This study will provide a simple, rapid, and effective treatment for the clinical management of ALS.}, } @article {pmid38887187, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Zemorshidi, F and Ramezani, M and Hesami, O and Pezeshgi, S and Batouli, SAH}, title = {Volume loss in the left anterior-superior subunit of the hypothalamus in amyotrophic lateral sclerosis.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {6}, pages = {e14801}, pmid = {38887187}, issn = {1755-5949}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/pathology ; Aged ; *Magnetic Resonance Imaging ; Adult ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic lateral sclerosis (ALS) causes motor neuron loss and progressive paralysis. While traditionally viewed as motor neuron disease (MND), ALS also affects non-motor regions, such as the hypothalamus. This study aimed to quantify the hypothalamic subregion volumes in patients with ALS versus healthy controls (HCs) and examine their associations with demographic and clinical features.

METHODS: Forty-eight participants (24 ALS patients and 24 HCs) underwent structural MRI. A deep convolutional neural network was used for the automated segmentation of the hypothalamic subunits, including the anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tuberal (supTub), inferior tuberal (infTub), and posterior (posHyp). The neural network was validated using FreeSurfer v7.4.1, with individual head size variations normalized using total intracranial volume (TIV) normalization. Statistical analyses were performed for comparisons using independent sample t-tests. Correlations were calculated using Pearson's and Spearman's tests (p < 0.05). The standard mean difference (SMD) was used to compare the mean differences between parametric variables.

RESULTS: The volume of the left a-sHyp hypothalamic subunit was significantly lower in ALS patients than in HCs (p = 0.023, SMD = -0.681). No significant correlation was found between the volume of the hypothalamic subunits, body mass index (BMI), and ALSFRS-R in patients with ALS. However, right a-sHyp (r = 0.420, p = 0.041) was correlated with disease duration, whereas right supTub (r = -0.471, p = 0.020) and left postHyp (r = -0.406, p = 0.049) were negatively correlated with age. There was no significant difference in the volume of hypothalamic subunits between males and females, and no significant difference was found between patients with revised ALS Functional Rating Scale (ALSFRS-R) scores ≤41 and >41 and those with a disease duration of 9 months or less.

DISCUSSION AND CONCLUSION: The main finding suggests atrophy of the left a-sHyp hypothalamic subunit in patients with ALS, which is supported by previous research as an extra-motor neuroimaging finding for ALS.}, } @article {pmid38886938, year = {2025}, author = {Helmold, BR and Ahrens, A and Fitzgerald, Z and Ozdinler, PH}, title = {Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets.}, journal = {Neural regeneration research}, volume = {20}, number = {3}, pages = {725-739}, pmid = {38886938}, issn = {1673-5374}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; }, abstract = {Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.}, } @article {pmid38886047, year = {2024}, author = {Jiang, Q and Lin, J and Wei, Q and Yang, T and Hou, Y and Zhang, L and Ou, R and Xiao, Y and Wang, S and Zheng, X and Li, C and Shang, H}, title = {Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.}, journal = {Journal of medical genetics}, volume = {61}, number = {9}, pages = {839-846}, doi = {10.1136/jmg-2024-109909}, pmid = {38886047}, issn = {1468-6244}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality/pathology ; Male ; Female ; *C9orf72 Protein/genetics ; *Mutation ; Middle Aged ; *Phenotype ; China/epidemiology ; *Superoxide Dismutase-1/genetics ; Adult ; *Genetic Association Studies/methods ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins/genetics ; Aged ; Genotype ; Age of Onset ; Genetic Predisposition to Disease ; Proteins/genetics ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS.

METHODS: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.

RESULTS: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).

CONCLUSION: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.}, } @article {pmid38885838, year = {2024}, author = {López Sanz, P and Azaña Defez, JM}, title = {Is ILVEN a misnomer? Proposal of MALID as an accurate nomenclature. Response to Polubothu et al's "ILVEN should be genotyped to direct treatment and genetic counselling".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e107-e108}, doi = {10.1016/j.jaad.2024.05.084}, pmid = {38885838}, issn = {1097-6787}, mesh = {Humans ; *Terminology as Topic ; *Genetic Counseling ; Genotype ; }, } @article {pmid38884646, year = {2024}, author = {Mielke, JK and Klingeborn, M and Schultz, EP and Markham, EL and Reese, ED and Alam, P and Mackenzie, IR and Ly, CV and Caughey, B and Cashman, NR and Leavens, MJ}, title = {Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {100}, pmid = {38884646}, issn = {1432-0533}, support = {5P30GM140963-03/GM/NIGMS NIH HHS/United States ; P20 GM152335/GM/NIGMS NIH HHS/United States ; Sloan Scholars Mentoring Network Seed Grant//Alfred P. Sloan Foundation/ ; R21 EY033057/EY/NEI NIH HHS/United States ; P30 GM140963/GM/NIGMS NIH HHS/United States ; 1P20GM152335-01/GM/NIGMS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; C9orf72 Protein/genetics ; Motor Cortex/pathology/metabolism ; Mutation/genetics ; *Spinal Cord/pathology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; *Biomarkers/analysis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10[-5]. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.}, } @article {pmid38884572, year = {2024}, author = {Benkirane, M and Bonhomme, M and Morsy, H and Safgren, SL and Marelli, C and Chaussenot, A and Smedley, D and Cipriani, V and de Sainte-Agathe, JM and Ding, C and Larrieu, L and Vestito, L and Margot, H and Lesca, G and Ramond, F and Castrioto, A and Baux, D and Verheijen, J and Sansa, E and Giunti, P and Haetty, A and Bergougnoux, A and Pointaux, M and Ardouin, O and Van Goethem, C and Vincent, MC and Hadjivassiliou, M and Cossée, M and Rouaud, T and Bartsch, O and Freeman, WD and Wierenga, KJ and Klee, EW and Vandrovcova, J and Houlden, H and Debant, A and Koenig, M}, title = {De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {11}, pages = {3681-3689}, doi = {10.1093/brain/awae193}, pmid = {38884572}, issn = {1460-2156}, support = {//Connaître les Syndromes Cérébelleux/ ; }, mesh = {Humans ; *Tubulin/genetics ; Male ; Female ; Middle Aged ; *Muscle Spasticity/genetics ; *Mutation, Missense/genetics ; Adult ; Aged ; Cerebellar Ataxia/genetics ; Spinocerebellar Ataxias/genetics ; Pedigree ; Cohort Studies ; France ; Intellectual Disability ; Optic Atrophy ; }, abstract = {Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2-576.7); P = 4.02 ×10-7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.}, } @article {pmid38883980, year = {2024}, author = {Azam, HMH and Rößling, RI and Geithe, C and Khan, MM and Dinter, F and Hanack, K and Prüß, H and Husse, B and Roggenbuck, D and Schierack, P and Rödiger, S}, title = {MicroRNA biomarkers as next-generation diagnostic tools for neurodegenerative diseases: a comprehensive review.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1386735}, pmid = {38883980}, issn = {1662-5099}, abstract = {Neurodegenerative diseases (NDs) are characterized by abnormalities within neurons of the brain or spinal cord that gradually lose function, eventually leading to cell death. Upon examination of affected tissue, pathological changes reveal a loss of synapses, misfolded proteins, and activation of immune cells-all indicative of disease progression-before severe clinical symptoms become apparent. Early detection of NDs is crucial for potentially administering targeted medications that may delay disease advancement. Given their complex pathophysiological features and diverse clinical symptoms, there is a pressing need for sensitive and effective diagnostic methods for NDs. Biomarkers such as microRNAs (miRNAs) have been identified as potential tools for detecting these diseases. We explore the pivotal role of miRNAs in the context of NDs, focusing on Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Huntington's disease, and Amyotrophic Lateral Sclerosis. The review delves into the intricate relationship between aging and NDs, highlighting structural and functional alterations in the aging brain and their implications for disease development. It elucidates how miRNAs and RNA-binding proteins are implicated in the pathogenesis of NDs and underscores the importance of investigating their expression and function in aging. Significantly, miRNAs exert substantial influence on post-translational modifications (PTMs), impacting not just the nervous system but a wide array of tissues and cell types as well. Specific miRNAs have been found to target proteins involved in ubiquitination or de-ubiquitination processes, which play a significant role in regulating protein function and stability. We discuss the link between miRNA, PTM, and NDs. Additionally, the review discusses the significance of miRNAs as biomarkers for early disease detection, offering insights into diagnostic strategies.}, } @article {pmid38882692, year = {2024}, author = {Yang, T and Wei, Q and Li, C and Ou, R and Lin, J and Cheng, Y and Xiao, Y and Shang, H}, title = {Peripheral immunity involvement in the cognitive impairment of sporadic amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1405275}, pmid = {38882692}, issn = {1664-2295}, abstract = {BACKGROUND: Recent research has indicated the significance of immune activation in amyotrophic lateral sclerosis (ALS). However, the impact of peripheral immunity on cognitive impairment in sporadic ALS remains poorly characterized. Therefore, we aim to assess the relationship between peripheral immune parameters and cognitive impairment in patients with sporadic ALS.

METHODS: A case-control study involving 289 patients with sporadic ALS was conducted. All participants underwent cognitive assessment and measurements of blood immune parameters. The main outcomes included adjusted odds ratios (ORs) in multivariate logistic regression analysis and adjusted coefficients in a multivariate linear regression model. Sensitivity analysis was performed with stratification by the King's clinical stage.

RESULTS: Cognitive impairment was observed in 98 (33.9%) patients. Higher counts of leukocyte (OR, 0.53; 95% CI, 0.29 to 0.95; p = 0.03), neutrophil (OR, 0.48; 95% CI, 0.26 to 0.88; p = 0.02), and monocyte (OR, 0.33; 95% CI, 0.18 to 0.60; p < 0.001) were significantly associated with better cognitive preformence in sporadic ALS, particularly among patients in King's clinical stages 1 and 2. Conversely, a higher percentage of CD4+ T cells was linked to an increased risk of cognitive impairment (OR, 2.79; 95% CI, 1.52 to 5.09; p = 0.001), particularly evident in patients in King's clinical stage 3.

CONCLUSION: These results highlight the involvement of peripheral immunity in the cognitive impairment of sporadic ALS and suggest dynamic and intricate roles that vary across disease stages. Elucidating the links between immunity and ALS sheds light on the pathophysiological mechanisms underlying this fatal neurodegenerative disorder and informs potential immunotherapeutic strategies.}, } @article {pmid38879961, year = {2024}, author = {Milella, G and Zoccolella, S and Giugno, A and Filardi, M and D'Errico, E and Piccirilli, G and Nanni, AG and Urso, D and Nigro, S and Tafuri, B and Tamburrino, L and Gnoni, V and Logroscino, G}, title = {Mapping lower-limbs muscle vulnerability in patients with ALS: The role of upper and lower motor neurons.}, journal = {Journal of the neurological sciences}, volume = {462}, number = {}, pages = {123098}, doi = {10.1016/j.jns.2024.123098}, pmid = {38879961}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Muscle, Skeletal/physiopathology ; *Motor Neurons/physiology ; Aged ; *Muscle Strength/physiology ; *Lower Extremity/physiopathology ; Muscle Weakness/physiopathology/etiology ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Several studies have reported disproportionate wasting of the flexor muscles of the lower limbs (LL) compared to the extensors in patients with amyotrophic lateral sclerosis (ALS). However, these studies have involved small sample sizes (n 〈100), and their findings have been inconsistent. Thus, it remains uncertain whether a distinct pattern of LL muscle weakness is specific to ALS.

AIMS: To investigate the muscle weakness pattern in the LL at the knee, ankle, and toes in a large cohort of ALS patients and evaluate the relationship between the pattern of muscle strength and the extent of upper (UMN) and lower (LMN) motoneuron impairment.

MATERIAL AND METHODS: The strength of flexor and extensor muscle was evaluated in 1250 legs of newly diagnosed ALS patients at the knee, ankle, and foot toes. UMN and LMN burden were assessed using validated scores. Within-subjects ANOVA considering the type of muscle (flexor/extensor) and anatomical sites (knee/ankle/toes) and mixed-factorial ANOVA were conducted to explore the impact of UMN and LMN impairments on the muscle weakness pattern.

RESULTS: Muscle strength showed a significant decline from proximal to distal regions. Indeed both flexor and extensor muscles at the knee outperformed those at the ankle and toes. Within each site, extensor muscles exhibited less strength than flexor, except at the knee. Patients with heightened UMN impairment showed a more marked difference between flexors and extensors within each site, with extensor muscles being more compromised at the ankle and toes. Higher LMN impairment corresponded to a more pronounced weakness in flexor muscles at the ankle and toes compared to those at the knee.

CONCLUSIONS: The extensor muscle at the knee and the flexors at the foot and toes displayed relative resistance to ALS disease. UMN impairment amplified the differences between flexor and extensor muscles within each site, while LMN impairment demonstrated a clear distal-to-proximal vulnerability.}, } @article {pmid38879765, year = {2024}, author = {Sharma, A and Kakkar, A and Khanna, M and Devi, S}, title = {Arbutin's Potential in Neuroprotection: A Promising Role in Mitigating Neurodegenerative Diseases.}, journal = {Current drug research reviews}, volume = {}, number = {}, pages = {}, doi = {10.2174/0125899775298987240528050110}, pmid = {38879765}, issn = {2589-9783}, abstract = {Naturally occurring glycosylated hydroquinone Arbutin, has drawn interest due to its possible function in reducing the risk of neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Arbutin is well-known for its anti-inflammatory and antioxidant properties, which are essential in preventing oxidative stress and neuroinflammation. Research has shown that arbutin might alter important physiological pathways connected to protein misfolding, synapse function, and neuronal survival processes linked to the development of neurodegenerative diseases. Arbutin can also penetrate the blood- -brain barrier, which increases its therapeutic potential. Arbutin's neuroprotective properties and promise as a therapeutic agent for neurodegenerative illnesses are summarized in this review, which also emphasizes the need for further study into the molecular processes behind these effects.}, } @article {pmid38879591, year = {2024}, author = {Lambert-Smith, IA and Shephard, VK and McAlary, L and Yerbury, JJ and Saunders, DN}, title = {High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS).}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {13844}, pmid = {38879591}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Proteostasis ; Humans ; *Superoxide Dismutase-1/metabolism/genetics ; *Protein Folding ; *Mutation ; Cell Line ; Mice ; Animals ; }, abstract = {Disrupted proteome homeostasis (proteostasis) in amyotrophic lateral sclerosis (ALS) has been a major focus of research in the past two decades. However, the proteostasis processes that become disturbed in ALS are not fully understood. Obtaining more detailed knowledge of proteostasis disruption in association with different ALS-causing mutations will improve our understanding of ALS pathophysiology and may identify novel therapeutic targets and strategies for ALS patients. Here we describe the development and use of a novel high-content analysis (HCA) assay to investigate proteostasis disturbances caused by the expression of several ALS-causing gene variants. This assay involves the use of conformationally-destabilised mutants of firefly luciferase (Fluc) to examine protein folding/re-folding capacity in NSC-34 cells expressing ALS-associated mutations in the genes encoding superoxide dismutase-1 (SOD1[A4V]) and cyclin F (CCNF[S621G]). We demonstrate that these Fluc isoforms can be used in high-throughput format to report on reductions in the activity of the chaperone network that result from the expression of SOD1[A4V], providing multiplexed information at single-cell resolution. In addition to SOD1[A4V] and CCNF[S621G], NSC-34 models of ALS-associated TDP-43, FUS, UBQLN2, OPTN, VCP and VAPB mutants were generated that could be screened using this assay in future work. For ALS-associated mutant proteins that do cause reductions in protein quality control capacity, such as SOD1[A4V], this assay has potential to be applied in drug screening studies to identify candidate compounds that can ameliorate this deficiency.}, } @article {pmid38879469, year = {2024}, author = {Dai, Z and Zhou, X}, title = {Associations between allostatic load and hepatic steatosis and liver fibrosis: evidence from NHANES 2017-2020.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {1602}, pmid = {38879469}, issn = {1471-2458}, mesh = {Humans ; Female ; Male ; *Allostasis/physiology ; Middle Aged ; *Liver Cirrhosis ; *Nutrition Surveys ; *Fatty Liver/physiopathology ; Adult ; Aged ; Cross-Sectional Studies ; Risk Factors ; }, abstract = {BACKGROUND: Allostatic load, the cumulative strain resulting from chronic stress responses, has been linked to disease occurrence and progression, yet research quantifying this relationship is limited. This study aimed to explore the relationship between allostatic load score (ALS) levels and the degree of hepatic steatosis and fibrosis.

METHODS: Data from the National Health and Nutrition Examination Survey 2017-2020 were analyzed. The ALS was based on the statistical distribution, assigning one point for each biomarker if it was in the highest risk quartile, and then summing them to generate the ALS score (range, 0-8). The multivariate linear regression was employed to analyze the association between the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) with ALS. Additionally, multinomial logistic regression was used to investigate the association between ALS and the degree of hepatic steatosis and fibrosis.

RESULTS: Participants had a weighted mean age of 52.69 years and 56.14% were female. In the multivariate linear regression analysis, ALS showed a significant positive correlation with CAP (β = 15.56, 95% CI: 14.50-16.62) and LSM (β = 0.58, 95% CI: 0.48-0.67). Age, healthy dietary level, and PIR had significant interactions with this positive correlation. In the multinomial logistic regression analysis, ALS exhibited a significant positive correlation with different degrees of hepatic steatosis and fibrosis. Consistency of the results was observed in sensitivity analyses using clinical thresholds of ALS.

CONCLUSIONS: Comprehensive clinical assessment targeting load adaptation may enhance the effectiveness of risk assessment in patients with hepatic steatosis and fibrosis.}, } @article {pmid38879333, year = {2024}, author = {Han, Y and Gao, H and Sun, Y and Wang, Y and Yan, C and Ma, H and Liu, X and Huang, Z}, title = {Target gene overexpression and enhanced metabolism confer resistance to nicosulfuron in Eriochloa villosa (Thunb.).}, journal = {Pesticide biochemistry and physiology}, volume = {202}, number = {}, pages = {105946}, doi = {10.1016/j.pestbp.2024.105946}, pmid = {38879333}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; *Acetolactate Synthase/genetics/metabolism/antagonists & inhibitors ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Pyridines/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Poaceae/genetics/drug effects ; }, abstract = {Eriochloa villosa (Thunb.) Kunth is a troublesome weed widely distributed in maize (Zea mays L.) fields in Northeast China. Many populations of E. villosa have evolved resistance to nicosulfuron herbicides, which inhibit acetolactate synthase (ALS). The objectives of this research were to confirm that E. villosa is resistant to nicosulfuron and to investigate the basis of nicosulfuron resistance. Whole-plant dose-response studies revealed that the R population had not developed a high level of cross-resistance and exhibited greater resistant (25.62-fold) to nicosulfuron than that of the S population and had not yet developed a high level of cross-resistance. An in vitro ALS activity assay demonstrated that the I50 of nicosulfuron was 6.87-fold greater in the R population than the S population. However, based on ALS gene sequencing, the target ALS gene in the R population did not contain mutations. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that ALS gene expression between the R and S populations was significantly different after nicosulfuron application, but no differences were observed in the gene copy number. After the cytochrome P450 inhibitor malathion or the GST inhibitor NBD-Cl was applied, the resistant E. villosa population exhibited increased sensitivity to nicosulfuron. Based on the activities of GSTs and P450s, the activities of the R population were greater than those of the S population after nicosulfuron application. This is the first report that the resistance of E. villosa to ALS inhibitors results from increased target gene expression and increased metabolism. These findings provide a theoretical foundation for the effective control of herbicide-resistant E. villosa.}, } @article {pmid38879294, year = {2024}, author = {Xu, H and Cheng, J and Leng, Q and Liang, S and Sun, L and Su, W and Xue, F and Wu, R}, title = {Nontarget site-based resistance to nicosulfuron and identification of candidate genes in Cucumis melo L. var. agrestis Naud. via RNA-Seq transcriptome analysis.}, journal = {Pesticide biochemistry and physiology}, volume = {202}, number = {}, pages = {105912}, doi = {10.1016/j.pestbp.2024.105912}, pmid = {38879294}, issn = {1095-9939}, mesh = {*Herbicide Resistance/genetics ; *Sulfonylurea Compounds/pharmacology ; *Herbicides/pharmacology/toxicity ; *Acetolactate Synthase/genetics/metabolism ; *Cucumis melo/genetics/drug effects ; *Pyridines/pharmacology ; RNA-Seq ; Gene Expression Profiling ; Malathion/pharmacology ; Gene Expression Regulation, Plant/drug effects ; Plant Proteins/genetics/metabolism ; }, abstract = {Herbicide resistance is a worldwide concern for weed control. Cucumis melo L. var. agrestis Naud. (C. melo) is an annual trailing vine weed that is commonly controlled by nicosulfuron, acetolactate synthase (ALS)-inhibiting herbicides. However, long-term use of this herbicide has led to the emergence of resistance and several nicosulfuron resistant populations of C. melo have been found. Here we identified a resistant (R) C. melo population exhibiting 7.31-fold resistance to nicosulfuron compared with a reference sensitive (S) population. ALS gene sequencing of the target site revealed no amino acid substitution in R plants, and no difference in enzyme activity, as shown by ALS activity assays in vitro. ALS gene expression was not significantly different before and after the application of nicosulfuron. Pretreatment with the cytochrome P450 monooxygenase (P450) inhibitor malathion reduced nicosulfuron resistance in the R population. RNA-Seq transcriptome analysis was used to identify candidate genes that may confer metabolic resistance to nicosulfuron. We selected genes with annotations related to detoxification functions. A total of 20 candidate genes (7 P450 genes, 1 glutathione S-transferase (GST) gene, 2 ATP-binding cassette (ABC) transporters, and 10 glycosyltransferase (GT)) were identified; 12 of them (7 P450s, 1 GST, 2 ABC transporters, and 2 GTs) were demonstrated significantly differential expression between R and S by quantitative real-time RT-PCR (qRT-PCR). Our findings revealed that the resistance mechanism in C. melo was nontarget-site based. Our results also provide a valuable resource for studying the molecular mechanisms of weed resistance.}, } @article {pmid38879100, year = {2024}, author = {Viccaro, F and Lecci, A and Baccolini, V and Sciurti, A and Piamonti, D and Inghilleri, M and D'Antoni, L and Palange, P}, title = {Prediction of cough effectiveness in amyotrophic lateral sclerosis patients assessed by ultrasuond of the diaphragm during the cough expiration phase.}, journal = {Respiratory physiology & neurobiology}, volume = {327}, number = {}, pages = {104299}, doi = {10.1016/j.resp.2024.104299}, pmid = {38879100}, issn = {1878-1519}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnostic imaging ; *Cough/physiopathology ; Male ; *Diaphragm/physiopathology/diagnostic imaging ; Female ; Middle Aged ; Aged ; *Ultrasonography ; Exhalation/physiology ; Peak Expiratory Flow Rate/physiology ; Adult ; }, abstract = {Assessing cough effectiveness, using Cough Peak Flow, is crucial for patients with Neuromuscular Diseases, such as Amyotrophic Lateral Sclerosis. Impaired cough function can contribute to respiratory decline and failure. The goal of the study is to determine the correlation between diaphragmatic excursion and cough expiratory phase, potentially utilizing ultrasonographic indices to estimate Cough Peak Flow in these patients. Twenty-two patients were enrolled in this study. The upward displacement of the diaphragm was measured with ultrasonography during voluntary cough expiration and Cough Peak Flow was simultaneously measured. A multivariable linear regression model was built to quantify the association between Cough Peak Flow and diaphragm expiratory excursion. There is significative relationship between Cough Peak Flow and diaphragm excursion with a Pearson's r coefficient of 0.86 observed in the patients group. Multiple linear regression analysis for Cough Peak Flow (Adjusted R[2] = 0.86) revealed significant associations between Cough Peak Flow and expiratory excursion (adjusted β-coefficient: 64.78, 95 %, CI: 51.50-78.07, p<0.001) and sex (adjusted β-coefficient: -69.06; 95 % CI: -109.98 to -28.15, p=0.001). Our results predict the cough effectiveness by using M-mode diaphragmatic sonography with a potentially significant impact on therapeutic choices.}, } @article {pmid38879065, year = {2024}, author = {Ashrafzadeh-Kian, S and Figdore, D and Larson, B and Deters, R and Abou-Diwan, C and Bornhorst, J and Algeciras-Schimnich, A}, title = {Head-to-head comparison of four plasma neurofilament light chain (NfL) immunoassays.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {561}, number = {}, pages = {119817}, doi = {10.1016/j.cca.2024.119817}, pmid = {38879065}, issn = {1873-3492}, mesh = {Humans ; Immunoassay/methods ; *Neurofilament Proteins/blood ; Multiple Sclerosis/blood/diagnosis ; Biomarkers/blood ; Amyotrophic Lateral Sclerosis/blood/diagnosis ; Female ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Neurofilament Light Chain (NfL) is an emerging blood biomarker of neuro-axonal injury and neurodegeneration with the potential to be used in the clinical management of various neurological conditions. Various NfL immunoassays are in development on high-throughput automated systems, but little information is available related to the comparability between assays. In this study, we performed a head-to-head comparison of four NfL immunoassays using plasma samples from individuals with various neurological conditions.

METHODS: EDTA plasma samples in which NfL was ordered clinically were stratified according to diagnosis. NfL concentrations (pg/mL) in plasma were obtained using the Quanterix Simoa®, the Roche Elecsys, the Siemens Healthineers Atellica®IM, and the Fujirebio Lumipulse® NfL assays. Passing-Bablok regression analyses were performed to assess the correlation and bias between methods. Additionally, the distribution of NfL concentrations for each assay was assessed in three disease groups: amyotrophic lateral sclerosis (ALS) upon initial diagnosis, ALS treated, and multiple sclerosis (MS).

RESULTS: The R[2] between assays were all ≥ 0.95, however, significant proportional bias was observed between some assays. In particular, the Roche Elecsys assay NfL concentrations were significantly lower (∼85 %) when compared against the other three assays. The four assays were comparable with regards to the percentage of patients that were identified as having an elevated NfL result in the various clinical groups: ALS initial diagnoses (83-94 %), ALS untreated (93-100 %), and MS (8-18 %).

CONCLUSIONS: This is the first study describing a head-to-head comparison of four automated NfL immunoassays. We demonstrate that there is a strong correlation between assays but a lack of standardization which is evident by the bias observed between some of the evaluated methods. These analytical differences will be important to consider when using NfL as a biomarker of neurodegeneration.}, } @article {pmid38878774, year = {2024}, author = {Kumbier, K and Roth, M and Li, Z and Lazzari-Dean, J and Waters, C and Hammerlindl, S and Rinaldi, C and Huang, P and Korobeynikov, VA and , and Phatnani, H and Shneider, N and Jacobson, MP and Wu, LF and Altschuler, SJ}, title = {Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.}, journal = {Developmental cell}, volume = {59}, number = {16}, pages = {2134-2142.e6}, doi = {10.1016/j.devcel.2024.05.011}, pmid = {38878774}, issn = {1878-1551}, support = {R01 NS106236/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; Mutation/genetics ; Male ; Female ; Skin/pathology/metabolism ; Machine Learning ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.}, } @article {pmid38878554, year = {2024}, author = {Mincic, AM and Antal, M and Filip, L and Miere, D}, title = {Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {43}, number = {7}, pages = {1832-1849}, doi = {10.1016/j.clnu.2024.05.036}, pmid = {38878554}, issn = {1532-1983}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/microbiology/therapy ; *Probiotics/administration & dosage/therapeutic use ; *Prebiotics/administration & dosage ; *Dysbiosis/therapy/microbiology ; Animals ; Fecal Microbiota Transplantation ; }, abstract = {BACKGROUND AND AIMS: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles.

RESULTS: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND.

CONCLUSIONS: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND.}, } @article {pmid38878150, year = {2024}, author = {Wang, F and Wen, H and Liu, L and Aisa, HA and Xin, X}, title = {A Pair of Epimers of Lignan Alleviate Neuroinflammatory Effects by Modulating iNOS/COX-2 and MAPK/NF-κB Signaling Pathways.}, journal = {Inflammation}, volume = {}, number = {}, pages = {}, pmid = {38878150}, issn = {1573-2576}, support = {2020YFE0205600//the National Key Research and Development Program of China/ ; U1703235//the National Natural Science Foundation of China/ ; }, abstract = {Neuroinflammation is a causative factor in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Previous studies have shown that Artemisia mongolica has anti-inflammatory properties. Aschantin (AM3) has been shown to have anti-inflammatory effects. However, the mechanism of AM3 and its epimer epi-aschantin (AM2) remains controversial. Therefore, the present study explored the mechanism of neuroinflammation by AM2 and AM3 and attempted to reveal the relationship between the structure of AM2 and AM3 and anti-neuroinflammatory activity. We isolated for the first time 12 lignans from A. mongolica that inhibited NO content at 10 μM in LPS-stimulated BV2 cells. Among them, epi-aschantin (AM2) and Aschantin (AM3) showed significant inhibition in NO screening. With further studies, we found that both AM2 and AM3 effectively inhibited the overproduction of NO, PGE2, IL-6, TNF-α and MCP-1, as well as the overexpression of COX-2 and iNOS. Mechanistic studies have shown AM2 and AM3 significantly inhibited the phosphorylation of ERK, JNK and P-38 in the MAPK signaling pathway and p-IκBα,p-p65 and blocked p65 entry into the nucleus. The results suggested that the pair of epimers (AM2 and AM3) can be used as potential therapeutic agents in the treatment of various brain disorders and that structural differences do not differ in anti-neuroinflammatory effects.}, } @article {pmid38878106, year = {2024}, author = {Chourpiliadis, C and Seitz, C and Lovik, A and Joyce, EE and Pan, L and Hu, Y and Kläppe, U and Samuelsson, K and Press, R and Ingre, C and Fang, F}, title = {Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5447-5459}, pmid = {38878106}, issn = {1432-1459}, support = {R01TS000324-01-00//US Center for Disease Control and Prevention/ ; 2019-01088//Swedish Research Council/ ; 2023-02428//Swedish Research Council/ ; MegaALS 802091//European Research Council Starting Grant/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Sweden/epidemiology ; Female ; Middle Aged ; Aged ; *Life Style ; *Disease Progression ; *Body Mass Index ; Adult ; Risk Factors ; Smoking/epidemiology ; Diabetes Mellitus/epidemiology ; Hypertension/epidemiology ; Hypercholesterolemia/epidemiology ; }, abstract = {BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS).

METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022.

RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis.

CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.}, } @article {pmid38877004, year = {2024}, author = {Costa, RG and Conceição, A and Matos, CA and Nóbrega, C}, title = {The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease.}, journal = {Cell death & disease}, volume = {15}, number = {6}, pages = {415}, pmid = {38877004}, issn = {2041-4889}, mesh = {Humans ; *Ataxin-2/metabolism/genetics ; *Peptides/metabolism/genetics ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Spinocerebellar Ataxias/metabolism/genetics/pathology ; }, abstract = {A CAG repeat sequence in the ATXN2 gene encodes a polyglutamine (polyQ) tract within the ataxin-2 (ATXN2) protein, showcasing a complex landscape of functions that have been progressively unveiled over recent decades. Despite significant progresses in the field, a comprehensive overview of the mechanisms governed by ATXN2 remains elusive. This multifaceted protein emerges as a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm. The CAG overexpansion within the ATXN2 gene produces a protein with an extended poly(Q) tract, inducing consequential alterations in conformational dynamics which confer a toxic gain and/or partial loss of function. Although overexpanded ATXN2 is predominantly linked to spinocerebellar ataxia type 2 (SCA2), intermediate expansions are also implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism. While the molecular intricacies await full elucidation, SCA2 presents ATXN2-associated pathological features, encompassing autophagy impairment, RNA-mediated toxicity, heightened oxidative stress, and disruption of calcium homeostasis. Presently, SCA2 remains incurable, with patients reliant on symptomatic and supportive treatments. In the pursuit of therapeutic solutions, various studies have explored avenues ranging from pharmacological drugs to advanced therapies, including cell or gene-based approaches. These endeavours aim to address the root causes or counteract distinct pathological features of SCA2. This review is intended to provide an updated compendium of ATXN2 functions, delineate the associated pathological mechanisms, and present current perspectives on the development of innovative therapeutic strategies.}, } @article {pmid38876745, year = {2024}, author = {van Selms, MKA and van der Linden, MW and van der Meijden, C and Lobbezoo, F}, title = {A call for optimal oral care in patients with ALS.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {670}, doi = {10.1016/S1474-4422(24)00226-6}, pmid = {38876745}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Oral Hygiene ; }, } @article {pmid38876730, year = {2024}, author = {The Lancet Neurology, }, title = {Multidisciplinary care for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {649}, doi = {10.1016/S1474-4422(24)00227-8}, pmid = {38876730}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Patient Care Team ; }, } @article {pmid38876108, year = {2024}, author = {Scaber, J and Thomas-Wright, I and Clark, AJ and Xu, Y and Vahsen, BF and Carcolé, M and Dafinca, R and Farrimond, L and Isaacs, AM and Bennett, DL and Talbot, K}, title = {Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons.}, journal = {Stem cell reports}, volume = {19}, number = {7}, pages = {957-972}, pmid = {38876108}, issn = {2213-6711}, mesh = {*Induced Pluripotent Stem Cells/metabolism/cytology ; *C9orf72 Protein/genetics/metabolism ; Humans ; *Motor Neurons/metabolism ; *Sensory Receptor Cells/metabolism ; *Axonal Transport ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Phenotype ; *DNA Repeat Expansion/genetics ; }, abstract = {Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect the biology underlying the cell-specific vulnerability of ALS is uncertain. We therefore compared phenotypes due to the C9ORF72 HRE in MNs with sensory neurons (SNs), which are relatively spared in ALS. The iPSC models were able to partially reproduce the differential gene expression seen between adult SNs and MNs. We demonstrated that the typical hallmarks of C9ORF72-ALS, including RNA foci and dipeptide formation, as well as specific axonal transport defects, occurred equally in MNs and SNs, suggesting that these in vitro phenotypes are not sufficient to explain the cell-type selectivity of ALS in isolation.}, } @article {pmid38875517, year = {2024}, author = {Michielsen, A and van Veenhuijzen, K and Janse van Mantgem, MR and van Es, MA and Veldink, JH and van Eijk, RPA and van den Berg, LH and Westeneng, HJ}, title = {Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209603}, pmid = {38875517}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging/metabolism/pathology ; *Magnetic Resonance Imaging ; Aged ; Cross-Sectional Studies ; Longitudinal Studies ; Disease Progression ; Cognition/physiology ; Adult ; Energy Metabolism/physiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.

METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate.

RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029).

DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.}, } @article {pmid38875513, year = {2024}, author = {van Eijk, RPA and van den Berg, LH and Lu, Y}, title = {Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209502}, pmid = {38875513}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Patient Preference ; Reproducibility of Results ; Prognosis ; Aged ; Netherlands ; Clinical Trials as Topic ; Surveys and Questionnaires ; Registries ; }, abstract = {BACKGROUND AND OBJECTIVES: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point.

METHODS: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register.

RESULTS: In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score.

DISCUSSION: In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.}, } @article {pmid38875346, year = {2024}, author = {}, title = {Erratum for the Research Article: "Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS" by Chang et al.}, journal = {Science advances}, volume = {10}, number = {24}, pages = {eadq7259}, doi = {10.1126/sciadv.adq7259}, pmid = {38875346}, issn = {2375-2548}, } @article {pmid38874845, year = {2024}, author = {Birbaumer, N}, title = {"Your Thoughts are (were) Free!": Brain-Computer-Interfaces, Neurofeedback, Detection of Deception, and the Future of Mind-Reading.}, journal = {Applied psychophysiology and biofeedback}, volume = {}, number = {}, pages = {}, pmid = {38874845}, issn = {1573-3270}, abstract = {This review describes the historical developement and rationale of clinically relevant research on neurophysiological "mind reading" paradims: Brain- Computer-Interfaces, detection of deception, brain stimulation and neurofeedback and the clinical applications in drug resistant epilepsy, chronic stroke, and communication with paralyzed locked-in persons. The emphasis lies on completely locked-in patients with amyotrophic lateral sclerosis using non-invasive and invasive brain computer interfaces and neurofeedback to restore verbal communication with the social environment. In the second part of the article we argue that success and failure of neurophysiological "mind reading" paradigms may be explained with a motor theory of thinking and emotion in combination with learning theory. The ethical implications of brain computer interface and neurofeedback approaches, particularly for severe chronic paralysis and loss of communication diseases and decisions on hastened death and euthanasia are discussed.}, } @article {pmid38873369, year = {2024}, author = {Hong, J and Kim, GC and Cha, JG and Park, J and Park, B and Park, SY and Kim, SU}, title = {Transcholecystic Duodenal Drainage as an Alternative Decompression Method for Afferent Loop Syndrome: Two Case Reports.}, journal = {Journal of the Korean Society of Radiology}, volume = {85}, number = {3}, pages = {661-667}, pmid = {38873369}, issn = {2951-0805}, abstract = {Afferent loop syndrome (ALS) is a rare complication of gastrectomies and gastrointestinal reconstruction. This can predispose patients to fatal conditions, such as cholangitis, pancreatitis, and duodenal perforation with peritonitis. Therefore, emergency decompression is necessary to prevent these complications. Herein, we report two cases in which transcholecystic duodenal drainage, an alternative decompression treatment, was performed in ALS patients without bile duct dilatation. Two patients who underwent distal gastrectomy with Billroth II anastomosis sought consultation in an emergency department for epigastric pain and vomiting. On CT, ALS with acute pancreatitis was diagnosed. However, biliary access could not be achieved because of the absence of bile duct dilatation. To overcome this problem, a duodenal drainage catheter was placed to decompress the afferent loop after traversing the cystic duct via a transcholecystic approach. The patients were discharged without additional surgical treatment 2 weeks and 1 month after drainage.}, } @article {pmid38872308, year = {2024}, author = {Çelik, MH and Gagneur, J and Lim, RG and Wu, J and Thompson, LM and Xie, X}, title = {Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers.}, journal = {HGG advances}, volume = {5}, number = {3}, pages = {100318}, pmid = {38872308}, issn = {2666-2477}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Chromatin/metabolism/genetics ; Promoter Regions, Genetic/genetics ; Algorithms ; Gene Expression Regulation ; Chromatin Immunoprecipitation Sequencing ; Histones/metabolism/genetics ; }, abstract = {The high heritability of amyotrophic lateral sclerosis (ALS) contrasts with its low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. To aid the exploration of these factors, we introduced EpiOut, an algorithm to identify chromatin accessibility outliers that are regions exhibiting divergent accessibility from the population baseline in a single or few samples. Annotation of accessible regions with histone chromatin immunoprecipitation sequencing and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is available at github.com/uci-cbcl/EpiOut.}, } @article {pmid38872258, year = {2024}, author = {Xiong, B and Yang, C and Yang, X and Luo, S and Li, S and Chen, C and He, K and Nie, L and Li, P and Li, S and Huang, H and Liu, J and Zhang, Z and Xie, Y and Zou, L and Yang, X}, title = {Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1[G93A] transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1β/NF-κB pathways.}, journal = {CNS neuroscience & therapeutics}, volume = {30}, number = {6}, pages = {e14692}, pmid = {38872258}, issn = {1755-5949}, support = {SZSM201611090//Sanming Project of Medicine in Shenzhen/ ; 82171583//National Natural Science Foundation of China/ ; JCYJ20200109144418639//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; JCYJ20200109150717745//The Key Basic Research Program of Shenzhen Science and Technology Innovation Commission/ ; SZXK069//Shenzhen Key Medical Discipline Construction Fund/ ; }, mesh = {Animals ; *Mice, Transgenic ; *Sirtuin 1/metabolism ; Mice ; *NF-kappa B/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Furans/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Interleukin-1beta/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Lignans/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; Male ; Motor Neurons/drug effects/pathology/metabolism ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.

METHODS: A-1 at 33.3 mg/kg was administrated in SOD1[G93A] transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.

RESULTS: A-1 administration in SOD1[G93A] mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1β, pIκBα/IκBα, and pNF-κB/NF-κB.

CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1β/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.}, } @article {pmid38871941, year = {2025}, author = {Naik, B and Sasikumar, J and Das, SP}, title = {From Skin and Gut to the Brain: The Infectious Journey of the Human Commensal Fungus Malassezia and Its Neurological Consequences.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {533-556}, pmid = {38871941}, issn = {1559-1182}, support = {GIA/2019/000620/PRCGIA//Indian Council of Medical Research/ ; }, mesh = {Humans ; *Malassezia ; *Skin/microbiology/pathology ; *Brain/microbiology ; Animals ; Nervous System Diseases/microbiology ; }, abstract = {The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.}, } @article {pmid38870925, year = {2024}, author = {Hamdi, N and Ocab, O and Soliman, R and Ludolph, A and Anwar, W and Logroscino, G and Fahmy, N}, title = {Motor Neuron Disease Population-Based Registry in Egypt: Where Do We Stand?.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-13}, doi = {10.1159/000539468}, pmid = {38870925}, issn = {1423-0208}, abstract = {BACKGROUND: There is a growing body of evidence indicating that the worldwide distribution of amyotrophic lateral sclerosis (ALS) is far from uniform. This is evident through variations in the epidemiology, genetics, and phenotypical characteristics of ALS and other motor neuron diseases (MND) across different regions. However, comprehensive ALS epidemiological studies are still lacking in many parts of the world, especially in Africa. Therefore, we propose the establishment of a population-based register for ALS/MND in Egypt, an important part of Africa with a population of more than 100 millions of people.

SUMMARY: Given Egypt's distinctive social and demographic characteristics, it is highly recommended to employ specific, recently developed epidemiological techniques for assessing the prevalence and incidence of these diseases within the country. By utilizing these methods, we can gather invaluable data that will contribute to a deeper understanding of ALS and enable us to effectively address its impact on the population of Egypt.

KEY MESSAGES: Our goal with this pioneering ALS/MND population-based register in Egypt is to define the burden of ALS in this part of Africa and to increase the chances for this consanguineous population to get access to modern individualized genetic therapies. Additionally, we aspire to uncover potential environmental factors and gene-environment interactions that contribute to the development of ALS. This knowledge of MND individual and group risk in Egypt will not only open doors for interventions but also provide opportunities for future research and discovery.}, } @article {pmid38870470, year = {2024}, author = {McDool, E and Carlton, J and Powell, PA and Coates, E and Knox, L and Mayberry, E and Appleby, N and Griffiths, AW and Hobson, E and McDermott, CJ}, title = {Measuring Health-Related Quality of Life in Amyotrophic Lateral Sclerosis: A Systematic Review and Conceptual Framework.}, journal = {Neurology}, volume = {103}, number = {2}, pages = {e209549}, pmid = {38870470}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Humans ; *Quality of Life/psychology ; Patient Reported Outcome Measures ; }, abstract = {BACKGROUND AND OBJECTIVES: The assessment of health-related quality of life (HRQoL) in patients with amyotrophic lateral sclerosis (ALS) is heterogeneous and inconsistent. The objectives of this study were (1) to develop a comprehensive conceptual framework of HRQoL in ALS and (2) map the content of existing patient-reported outcome measures (PROMs) used in ALS to this novel framework.

METHODS: Our model of HRQoL in ALS (Health-related Quality of life in Amyotrophic Lateral Sclerosis, QuALS) was developed from a systematic literature review and consultative input from key stakeholders (patients, carers, and health care professionals). Five electronic databases were searched in April 2022. Primary studies of any design that assessed HRQoL in ALS by using a multi-item PROM and/or qualitative methods were identified. Using an a priori framework, HRQoL themes were extracted and iteratively modified from the content of each PROM and qualitative study quotations identified in the literature. The conceptual framework was ratified by stakeholders with lived experience and clinical experts. The QuALS framework was used to map the content of identified PROMs and qualitative studies based on thematic coverage.

RESULTS: QuALS covers 3 high-level domains of HRQoL (physical, psychological, and social functioning) and consists of 7 themes (Activities; Physical Health; Autonomy; Cognition; Feelings and Emotions; Self-identity; Relationships), characterized by 42 subthemes. Of 8,220 studies identified, 274 were included in the review that informed QuALS. In these studies, 111 PROMs were used to assess at least 1 aspect of HRQoL, and 11 studies used qualitative methods. Of the 3 high-level domains, physical functioning was the most commonly assessed, particularly within ALS-specific PROMs where almost one-quarter of PROMs exclusively assessed physical functioning. None of the PROMs or qualitative studies identified assessed all aspects of HRQoL in the QuALS framework.

DISCUSSION: This study presents a new comprehensive conceptual framework of HRQoL in ALS (QuALS), informed by a robust systematic review of existing literature and stakeholder input, incorporating lived experience. QuALS provides a valuable resource for researchers and clinicians interested in taking a holistic approach to assessing and understanding the full impact of ALS on HRQoL and how this may be affected by treatments.}, } @article {pmid38869826, year = {2024}, author = {Wang, H and Zeng, R}, title = {Aberrant protein aggregation in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {4826-4851}, pmid = {38869826}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.}, } @article {pmid38869076, year = {2024}, author = {Ye, Y and Jia, P and Miao, J and Wang, Y and Li, Z and Lin, Y and He, M and Liu, S and Zheng, BR and Wu, J and Pan, J and Li, CM and Hou, P and Guo, D}, title = {CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity.}, journal = {Autophagy}, volume = {20}, number = {11}, pages = {2529-2539}, pmid = {38869076}, issn = {1554-8635}, mesh = {Animals ; *Autophagy/physiology ; Humans ; Mice ; *Protein Aggregates ; Neurons/metabolism ; Cell Survival ; Brain/metabolism/pathology ; Proteostasis ; Neurodegenerative Diseases/metabolism/genetics ; Ubiquitination ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Protein aggregation caused by the disruption of proteostasis will lead to cellular cytotoxicity and even cell death, which is implicated in multiple neurodegenerative diseases. The elimination of aggregated proteins is mediated by selective macroautophagy receptors, which is termed aggrephagy. However, the identity and redundancy of aggrephagy receptors in recognizing substrates remain largely unexplored. Here, we find that CCDC50, a highly expressed autophagy receptor in brain, is recruited to proteotoxic stresses-induced polyubiquitinated protein aggregates and ectopically expressed aggregation-prone proteins. CCDC50 recognizes and further clears these cytotoxic aggregates through autophagy. The ectopic expression of CCDC50 increases the tolerance to stress-induced proteotoxicity and hence improved cell survival in neuron cells, whereas CCDC50 deficiency caused accumulation of lipid deposits and polyubiquitinated protein conjugates in the brain of one-year-old mice. Our study illustrates how aggrephagy receptor CCDC50 combats proteotoxic stress for the benefit of neuronal cell survival, thus suggesting a protective role in neurotoxic proteinopathy.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; BODIPY: boron-dipyrromethene; CASP3: caspase 3; CCDC50: coiled-coil domain containing 50; CCT2: chaperonin containing TCP1 subunit 2; CHX: cycloheximide; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; Cas9: CRISPR-associated system 9; DAPI: 4',6-diamidino-2-phenylindole; FK2: Anti-ubiquitinylated proteins antibody, clone FK2; FUS: FUS RNA binding protein; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; KEGG: Kyoto Encyclopedia of Genes and Genomes; LDS: LIR-docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MIU: motif interacting with ubiquitin; NBR1: NBR1, autophagy cargo receptor; OPTN: optineurin; PD: Parkinson disease; PI: propidium iodide; ROS: reactive oxygen species; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; Ub: ubiquitin; UDS: UIM-docking site; UIM: ubiquitin interacting motif; UPS: ubiquitin-proteasome system.}, } @article {pmid38868068, year = {2024}, author = {Nuredini, A and Bottignole, D and Stragliati, F and Anceschi, P and Romano, S and Pollara, I and Abramo, A and Rausa, F and Parrino, L and Zinno, L and Mutti, C}, title = {Unraveling sleep respiratory dysfunction in amyotrophic lateral sclerosis: Beyond the apnea-hypopnea index and sleep-related hypoxia.}, journal = {Heliyon}, volume = {10}, number = {11}, pages = {e32250}, pmid = {38868068}, issn = {2405-8440}, abstract = {The timely introduction of non-invasive ventilation (NIV) is extremely relevant in the multidisciplinary management of patients affected by amyotrophic lateral sclerosis (ALS) and is based on the proper identification of red flags for early diaphragmatic exhaustion. Polygraphic sleep recording may provide insightful information on the ongoing respiratory impairment; in particular, atypical breathing patterns need to be recognized, as the application of current guidelines for sleep-related hypoxemia or sleep apnea may be insufficient for detecting early signs of diaphragmatic fatigue. We report the case of a 51-year-old man affected by ALS who was asymptomatic for breathing impairment, but whose nocturnal polysomnographic recording, despite not significant for obstructive sleep apnea nor for conventional hypoventilatory patterns, strongly suggested initial respiratory failure, as lately confirmed by the pulmonary follow-up. We discuss the advantages of including sleep recording in the clinical work-up of patients affected by ALS.}, } @article {pmid38867220, year = {2024}, author = {Jia, Q and Song, Y and Zhang, C and Li, M and Feng, L and Sugimoto, K and Zhang, X and Liu, J and Gao, Y}, title = {Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study.}, journal = {BMC complementary medicine and therapies}, volume = {24}, number = {1}, pages = {231}, pmid = {38867220}, issn = {2662-7671}, support = {QN2021110001L//National Foreign Expert Project/ ; 2018, 12//Chinese Medicine Inheritance and Innovation Talent Project Leading Talent Support Program of National Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Medicine, Chinese Traditional/methods ; Female ; Male ; Middle Aged ; Surveys and Questionnaires ; Aged ; China ; Adult ; Quality of Life ; Qualitative Research ; }, abstract = {BACKGROUND AND AIM: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue.

MATERIALS AND METHODS: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes.

RESULTS: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable.

CONCLUSION: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).}, } @article {pmid38866783, year = {2024}, author = {Di Timoteo, G and Giuliani, A and Setti, A and Biagi, MC and Lisi, M and Santini, T and Grandioso, A and Mariani, D and Castagnetti, F and Perego, E and Zappone, S and Lattante, S and Sabatelli, M and Rotili, D and Vicidomini, G and Bozzoni, I}, title = {M[6]A reduction relieves FUS-associated ALS granules.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {5033}, pmid = {38866783}, issn = {2041-1723}, support = {ERC-2019-SyG 855923-ASTRA//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; ERC-2018-CoG 818669-BrightEyes//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AIRC IG 2019 Id. 23053//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; PRIN 2017 2017P352Z4//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; NextGenerationEU PNRR MUR//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "National Center for Gene Therapy and Drugbased on RNA Technology" (CN00000041)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "National Center for Gene Therapy and Drug based on RNA Technology" (CN00000041)//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; NextGenerationEU PNRR MUR//Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)/ ; "Sapienza" Ateneo Project 2021 n. RM12117A61C811CE//Sapienza Università di Roma (Sapienza University of Rome)/ ; Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020 - A0375-2020-36597//Regione Lazio (Region of Lazio)/ ; }, mesh = {*RNA-Binding Protein FUS/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Cytoplasmic Granules/metabolism ; Fibroblasts/metabolism ; Adenosine/metabolism/analogs & derivatives ; Methyltransferases/metabolism/genetics ; Mutation ; Inclusion Bodies/metabolism ; Stress Granules/metabolism ; Transcriptome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m[6]A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m[6]A downregulation. Notably, cells expressing mutant FUS were characterized by higher m[6]A levels suggesting a possible link between m[6]A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.}, } @article {pmid38865943, year = {2024}, author = {Ipek, L and Güneş Gencer, GY}, title = {Is caregiver burden of patients with amyotrophic lateral sclerosis related to caregivers' mindfulness, quality of life, and patients' functional level.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {126}, number = {}, pages = {95-100}, doi = {10.1016/j.jocn.2024.06.007}, pmid = {38865943}, issn = {1532-2653}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing/therapy ; Female ; *Quality of Life/psychology ; Male ; Middle Aged ; *Mindfulness ; *Caregiver Burden/psychology ; Adult ; Caregivers/psychology ; Aged ; Cost of Illness ; }, abstract = {BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the caregiver burden, mindfulness, and quality of life (QoL) of caregivers of ALS patients and the patient's functional level.

METHODS: This study was conducted with 57 ALS patients and their primary caregivers. The data were collected using the Zarit Burden Interview, Mindful Attention Awareness Scale (MAAS), the Short Form-36 (SF-36), and the ALS Functional Rating Scale (ALS-FRS).

RESULTS: The mean age of the caregivers was 49.7 ± 12 years; 66 % were female, and 73.7 % were spouses of the patients. Around 65 % of caregivers experienced a moderate to severe caregiver burden. A low and negative correlation was found between the caregiver burden and mindfulness of caregivers of ALS patients. As the mindfulness levels of the caregivers increased, the caregiver burden decreased, and the physical role difficulty score, one of the sub-dimensions of the QoL, increased. Also, caregivers' QoL decreased as caregiver burden increased (except physical function QoL, p < 0.05). Moreover, there was a positive correlation between the caregiver burden and ALSFRS-R scores (bulbar, motor, respiratory, and total) of the caregivers of ALS patients (p < 0.05).

DISCUSSION: Improved technology for managing ALS disease has increased patient life expectancy. However, caregivers may experience a high burden as the patient's functional level declines. Increasing caregiver mindfulness can help reduce the burden and improve their QoL.}, } @article {pmid38865034, year = {2024}, author = {Rashed, HR and Staff, NP and Milone, M and Mauermann, ML and Berini, S and Cheshire, WP and Coon, EA and Fealey, RD and Sorenson, E and Cutsforth-Gregory, J and Benarroch, EE and Sandroni, P and Low, PA and Singer, W and Shouman, K}, title = {Autonomic impairment in primary lateral sclerosis.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {34}, number = {4}, pages = {421-425}, pmid = {38865034}, issn = {1619-1560}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Autonomic Nervous System Diseases/physiopathology/diagnosis/etiology ; Adult ; Retrospective Studies ; Aged ; Sweating/physiology ; Motor Neuron Disease/physiopathology/diagnosis/complications ; Autonomic Nervous System/physiopathology ; }, abstract = {PURPOSE: Prior studies reported evidence of autonomic involvement in motor neuron disease and suggested more severe dysfunction in upper motor neuron predominant syndromes. Hence, we sought to characterize autonomic impairment in primary lateral sclerosis.

METHODS: Neurological evaluations, thermoregulatory sweat tests, and autonomic reflex screens were analyzed retrospectively in 34 primary lateral sclerosis patients (28 definite and 6 probable). Patients with other potential causes of autonomic failure and patients with autonomic testing results compromised by artifact were excluded.

RESULTS: A total of 17 patients reported autonomic symptoms. Orthostatic lightheadedness was most frequent (8 patients), followed by bladder (7), bowel (5), and erectile dysfunction (3). The autonomic reflex screens of 33 patients were reviewed; 20 patients had abnormal studies. The thermoregulatory sweat tests of 19 patients were reviewed; 11 patients had abnormal studies. Composite Autonomic Severity Score was calculated for 33 patients and found abnormal in 20/33 patients (60.6%): 15/20 patients (75%) had mild impairment, and 5/20 patients (25%) had moderate impairment. The frequencies of testing abnormalities were: sudomotor 18/20 (90%), cardiovagal 9/20 (45%), and adrenergic 6/20 (30%). Sweat loss pattern analysis showed global, regional, and mixed patterns to be more common than length-dependent and distal patterns.

CONCLUSION: We found evidence of frequent autonomic dysfunction in primary lateral sclerosis, which is generally of modest severity akin to prior reports for amyotrophic lateral sclerosis, but more commonly in a pattern consistent with preganglionic/ganglionic localization. This suggests that primary lateral sclerosis, as with amyotrophic lateral sclerosis, is a multisystem disease that affects the autonomic nervous system.}, } @article {pmid38864944, year = {2024}, author = {Wang, LY and Zhang, L and Bai, XY and Qiang, RR and Zhang, N and Hu, QQ and Cheng, JZ and Yang, YL and Xiang, Y}, title = {The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.}, journal = {Neurochemical research}, volume = {49}, number = {10}, pages = {2653-2667}, pmid = {38864944}, issn = {1573-6903}, mesh = {*Ferroptosis/drug effects/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology ; Humans ; Animals ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; Antioxidants/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.}, } @article {pmid38863235, year = {2024}, author = {Priyanka, and Raymandal, B and Mondal, S}, title = {Native State Stabilization of Amyloidogenic Proteins by Kinetic Stabilizers: Inhibition of Protein Aggregation and Clinical Relevance.}, journal = {ChemMedChem}, volume = {19}, number = {19}, pages = {e202400244}, doi = {10.1002/cmdc.202400244}, pmid = {38863235}, issn = {1860-7187}, support = {SRG/2023/000434//Science and Engineering Research Board, India/ ; }, mesh = {Humans ; Kinetics ; *Amyloidogenic Proteins/metabolism/antagonists & inhibitors/chemistry ; Protein Aggregates/drug effects ; Superoxide Dismutase-1/metabolism/chemistry/antagonists & inhibitors ; Prealbumin/metabolism/chemistry/antagonists & inhibitors ; Amyloidosis/drug therapy/metabolism ; Clinical Relevance ; }, abstract = {Proteinopathies or amyloidoses are a group of life-threatening disorders that result from misfolding of proteins and aggregation into toxic insoluble amyloid aggregates. Amyloid aggregates have low clearance from the body due to the insoluble nature, leading to their deposition in various organs and consequent organ dysfunction. While amyloid deposition in the central nervous system leads to neurodegenerative diseases that mostly cause dementia and difficulty in movement, several other organs, including heart, liver and kidney are also affected by systemic amyloidoses. Regardless of the site of amyloid deposition, misfolding and structural alteration of the precursor proteins play the central role in amyloid formation. Kinetic stabilizers are an emerging class of drugs, which act like pharmacological chaperones to stabilize the native state structure of amyloidogenic proteins and to increase the activation energy barrier that is required for adopting a misfolded structure or conformation, ultimately leading to the inhibition of protein aggregation. In this review, we discuss the kinetic stabilizers that stabilize the native quaternary structure of transthyretin, immunoglobulin light chain and superoxide dismutase 1 that cause transthyretin amyloidoses, light chain amyloidosis and familial amyotrophic lateral sclerosis, respectively.}, } @article {pmid38862967, year = {2024}, author = {Vazquez-Sanchez, S and Tilkin, B and Gasset-Rosa, F and Zhang, S and Piol, D and McAlonis-Downes, M and Artates, J and Govea-Perez, N and Verresen, Y and Guo, L and Cleveland, DW and Shorter, J and Da Cruz, S}, title = {Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {46}, pmid = {38862967}, issn = {1750-1326}, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Brain/metabolism/pathology ; Disease Models, Animal ; *Disease Progression ; *Frontotemporal Dementia/pathology/metabolism/genetics ; *Mice, Transgenic ; Protein Aggregation, Pathological/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; }, abstract = {RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.}, } @article {pmid38861223, year = {2024}, author = {Parakh, S and Perri, ER and Vidal, M and Takalloo, Z and Jagaraj, CJ and Mehta, P and Yang, S and Thomas, CJ and Blair, IP and Hong, Y and Atkin, JD}, title = {Protein Disulfide Isomerase Endoplasmic Reticulum Protein 57 (ERp57) is Protective Against ALS-Associated Mutant TDP-43 in Neuronal Cells.}, journal = {Neuromolecular medicine}, volume = {26}, number = {1}, pages = {23}, pmid = {38861223}, issn = {1559-1174}, mesh = {*Protein Disulfide-Isomerases/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Humans ; *Inclusion Bodies/metabolism/genetics ; Animals ; Mice ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Neurons/metabolism/drug effects ; Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease affecting motor neurons. Pathological forms of Tar-DNA binding protein-43 (TDP-43), involving its mislocalisation to the cytoplasm and the formation of misfolded inclusions, are present in almost all ALS cases (97%), and ~ 50% cases of the related condition, frontotemporal dementia (FTD), highlighting its importance in neurodegeneration. Previous studies have shown that endoplasmic reticulum protein 57 (ERp57), a member of the protein disulphide isomerase (PDI) family of redox chaperones, is protective against ALS-linked mutant superoxide dismutase (SOD1) in neuronal cells and transgenic SOD1[G93A] mouse models. However, it remains unclear whether ERp57 is protective against pathological TDP-43 in ALS. Here, we demonstrate that ERp57 is protective against key features of TDP-43 pathology in neuronal cells. ERp57 inhibited the mislocalisation of TDP-43[M337V] from the nucleus to the cytoplasm. In addition, ERp57 inhibited the number of inclusions formed by ALS-associated variant TDP-43[M337V] and reduced the size of these inclusions. ERp57 was also protective against ER stress and induction of apoptosis. Furthermore, ERp57 modulated the steady-state expression levels of TDP-43. This study therefore demonstrates a novel mechanism of action of ERp57 in ALS. It also implies that ERp57 may have potential as a novel therapeutic target to prevent the TDP-43 pathology associated with neurodegeneration.}, } @article {pmid38861034, year = {2024}, author = {Lehto, A and Schumacher, J and Kasper, E and Teipel, S and Hermann, A and Kurth, J and Krause, BJ and Prudlo, J}, title = {Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5290-5300}, pmid = {38861034}, issn = {1432-1459}, support = {13GW0482D//Bundesministerium für Bildung und Forschung/Verein Deutscher Ingenieure/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Fluorodeoxyglucose F18/metabolism ; Aged ; *Glucose/metabolism ; *Neuropsychological Tests ; Magnetic Resonance Imaging ; Cognition Disorders/diagnostic imaging/metabolism/etiology ; Mental Disorders/metabolism/diagnostic imaging ; Brain/diagnostic imaging/metabolism ; Cerebral Cortex/diagnostic imaging/metabolism ; }, abstract = {OBJECTIVE: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of [18]F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results.

METHODS: We analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans.

RESULTS: ALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC.

INTERPRETATION: Our study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.}, } @article {pmid38860943, year = {2024}, author = {Zhang, Y and Xia, Y and Sun, J}, title = {Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2363880}, pmid = {38860943}, issn = {1949-0984}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK105118/DK/NIDDK NIH HHS/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Disease Progression ; *DNA-Binding Proteins/metabolism/genetics ; *Gastrointestinal Microbiome ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Neuroglia/metabolism ; *Probiotics/administration & dosage/pharmacology ; Spinal Cord/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.}, } @article {pmid38860430, year = {2024}, author = {Geng, Y and Liu, C and Xu, N and Suen, MC and Miao, H and Xie, Y and Zhang, B and Chen, X and Song, Y and Wang, Z and Cai, Q and Zhu, G}, title = {Crystal structure of a tetrameric RNA G-quadruplex formed by hexanucleotide repeat expansions of C9orf72 in ALS/FTD.}, journal = {Nucleic acids research}, volume = {52}, number = {13}, pages = {7961-7970}, pmid = {38860430}, issn = {1362-4962}, support = {32071188//National Scientific Foundation of China/ ; 16101120//Research Grants Council of the Hong Kong Special Administrative Region/ ; 3502Z20214001//Hong Kong University of Science and Technology/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation/ ; }, mesh = {*C9orf72 Protein/genetics/chemistry ; *G-Quadruplexes ; *Amyotrophic Lateral Sclerosis/genetics ; *Frontotemporal Dementia/genetics ; Humans ; *RNA/chemistry/genetics ; *DNA Repeat Expansion/genetics ; Crystallography, X-Ray ; Models, Molecular ; }, abstract = {The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.}, } @article {pmid38860134, year = {2024}, author = {Levison, LS and Jepsen, P and Andersen, H}, title = {Registration of Amyotrophic Lateral Sclerosis: Validity in the Danish National Patient Registry.}, journal = {Clinical epidemiology}, volume = {16}, number = {}, pages = {409-415}, pmid = {38860134}, issn = {1179-1349}, abstract = {PURPOSE: Health care databases are a valuable source for epidemiological research on amyotrophic lateral sclerosis (ALS) if diagnosis codes are valid. We evaluated the validity of the diagnostic codes for ALS in the Danish National Patient Registry (DNPR).

PATIENTS AND METHODS: We obtained data from the DNPR for all adult (>17 years) patients registered with ALS in Denmark between 1987 and 2022 (median population of 4.2 million during the study period). We randomly selected adult patients living in the North Denmark Region and Central Denmark Region (median population 1.4 million), with a primary discharge diagnosis code of ALS, diagnosed at three departments of neurology. We retrieved and reviewed medical records and estimated the positive predictive value (PPV) of the ALS diagnosis.

RESULTS: Over 36 years, we identified 5679 patients. From the validation cohort of 300 patients, we were able to retrieve 240 (80%) medical records, and 215 ALS diagnoses were confirmed. The overall positive predictive value was 89.6% (95% confidence interval (CI): 85.1-92.8). The highest PPV was achieved for diagnoses registered for patients aged ≥70 years (93.8; 95% CI: 86.2-97.3) compared to patients <60 years (83.4; 95% CI: 73.3-90.7).

CONCLUSION: We found a high PPV of primary diagnostic codes for ALS from Danish departments of neurology, demonstrating high validity. Thus, the DNPR is a well-suited data source for large-scale epidemiological research on ALS.}, } @article {pmid38859699, year = {2024}, author = {Finsterer, J and Strobl, W}, title = {Gastrointestinal involvement in neuromuscular disorders.}, journal = {Journal of gastroenterology and hepatology}, volume = {39}, number = {10}, pages = {1982-1993}, doi = {10.1111/jgh.16650}, pmid = {38859699}, issn = {1440-1746}, mesh = {Humans ; *Neuromuscular Diseases/complications/etiology ; *Gastrointestinal Diseases/etiology/therapy/diagnosis ; Myotonic Dystrophy/complications/diagnosis/physiopathology ; Mitochondrial Diseases/complications ; }, abstract = {Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.}, } @article {pmid38859579, year = {2024}, author = {Meyer, T and Dreger, M and Grehl, T and Weyen, U and Kettemann, D and Weydt, P and Günther, R and Lingor, P and Petri, S and Koch, JC and Großkreutz, J and Rödiger, A and Baum, P and Hermann, A and Prudlo, J and Boentert, M and Weishaupt, JH and Löscher, WN and Dorst, J and Koc, Y and Bernsen, S and Cordts, I and Vidovic, M and Steinbach, R and Metelmann, M and Kleinveld, VE and Norden, J and Ludolph, A and Walter, B and Schumann, P and Münch, C and Körtvélyessy, P and Maier, A}, title = {Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16379}, pmid = {38859579}, issn = {1468-1331}, support = {//Bosis Canessa ALS Stiftung, Düsseldorf, Germany/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *Neurofilament Proteins/blood ; Male ; Female ; Middle Aged ; *Phenotype ; Aged ; Longitudinal Studies ; Disease Progression ; Biomarkers/blood ; Adult ; Germany/epidemiology ; }, abstract = {OBJECTIVE: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS).

METHODS: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival.

RESULTS: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001).

CONCLUSIONS: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.}, } @article {pmid38857767, year = {2024}, author = {Bass, J and Hill, H and Jaworsky, C}, title = {Response to Hartman et al in reply to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e103}, doi = {10.1016/j.jaad.2024.06.003}, pmid = {38857767}, issn = {1097-6787}, mesh = {Humans ; *Dermoscopy ; Skin Neoplasms/pathology ; }, } @article {pmid38856890, year = {2024}, author = {Tripathi, S and Bhawana, }, title = {Epigenetic Orchestration of Neurodegenerative Disorders: A Possible Target for Curcumin as a Therapeutic.}, journal = {Neurochemical research}, volume = {49}, number = {9}, pages = {2319-2335}, pmid = {38856890}, issn = {1573-6903}, mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Epigenesis, Genetic/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Mitochondria/metabolism/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.}, } @article {pmid38856805, year = {2024}, author = {Zhang, Z and He, X and Cui, J and Wang, J and Shi, B}, title = {Translation and reliability and validity of the Chinese version of Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {57}, pmid = {38856805}, issn = {2509-8020}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Cross-Sectional Studies ; China ; Surveys and Questionnaires ; Adult ; *Psychometrics/methods/instrumentation ; Translations ; Aged ; Translating ; }, abstract = {OBJECTIVE: To translate Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form (ALSSQOL-SF) and test its reliability and validity, so that explore feasibility in Chinese mainland and make up the gap of specific tools for measuring quality of life of patients with ALS.

METHODS: This was a cross-sectional design. The Brislin translation model was used to translate ALSSQOL-SF, and the Chinese version of ALSSQOL-SF (C-ALSSQOL-SF) was revised through cultural adaptation and pre-test. The convenience sampling method was used to investigate 138 patients with ALS in Tianjin to test the reliability and validity of the C-ALSSQOL-SF.

RESULTS: The C-ALSSQOL-SF included 20 items, covering 6 dimensions: physical symptoms, bulbar function, negative emotion, interaction with people and the environment, religiosity and intimacy. The scale-level content validity index (S-CVI) of C-ALSSQOL-SF was 0.964, and the item-level content validity index (I-CVI) was between 0.857 to 1.000. The results of Confirmatory Factor Analysis (CFA) showed that CMIN/DF = 1.161, RMSEA = 0.034, GFI = 0.892, IFI = 0.976, TLI = 0.969, CFI = 0.975, and the 6-factor model fitted well. The scores of C-ALSSQOL-SF and WHOQOL-BREF were positively correlated (r = 0.745). The Cronbach's α coefficient of the scale was 0.85, the Cronbach's α coefficient of each dimension was between 0.59 to 0.86, and the split-half reliability was 0.78.

CONCLUSION: The Chinese version of ALSSQOL-SF has good reliability and validity, and can be used as a tool to evaluate the quality of life of patients with ALS in Chinese mainland.}, } @article {pmid38856793, year = {2025}, author = {Kumari, S and Kamiya, A and Karnik, SS and Rohilla, S and Dubey, SK and Taliyan, R}, title = {Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {386-411}, pmid = {38856793}, issn = {1559-1182}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; *Nerve Growth Factors/genetics ; Gene Transfer Techniques ; Genetic Vectors ; }, abstract = {Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.}, } @article {pmid38855716, year = {2024}, author = {Morganroth, J and Bardakjian, TM and Dratch, L and Quinn, CC and Elman, LB}, title = {Enhancing Clinical Infrastructure for the Delivery of Intrathecal and Genetic Therapies: A Qalsody (Tofersen) Model for Patients With SOD1-ALS.}, journal = {Neurology. Clinical practice}, volume = {14}, number = {4}, pages = {e200303}, pmid = {38855716}, issn = {2163-0402}, abstract = {BACKGROUND: Qalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy.

RECENT FINDINGS: We predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits.

IMPLICATIONS FOR PRACTICE: As new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.}, } @article {pmid38855322, year = {2024}, author = {Tsekrekou, M and Giannakou, M and Papanikolopoulou, K and Skretas, G}, title = {Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1383453}, pmid = {38855322}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with severe socio-economic impact. A hallmark of ALS pathology is the presence of aberrant cytoplasmic inclusions composed of misfolded and aggregated proteins, including both wild-type and mutant forms. This review highlights the critical role of misfolded protein species in ALS pathogenesis, particularly focusing on Cu/Zn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43), and emphasizes the urgent need for innovative therapeutic strategies targeting these misfolded proteins directly. Despite significant advancements in understanding ALS mechanisms, the disease remains incurable, with current treatments offering limited clinical benefits. Through a comprehensive analysis, the review focuses on the direct modulation of the misfolded proteins and presents recent discoveries in small molecules and peptides that inhibit SOD1 and TDP-43 aggregation, underscoring their potential as effective treatments to modify disease progression and improve clinical outcomes.}, } @article {pmid38854008, year = {2024}, author = {Rifai, OM and Waldron, FM and O'Shaughnessy, J and Read, FL and Gilodi, M and Pastore, A and Shneider, N and Tartaglia, GG and Zacco, E and Spence, H and Gregory, JM}, title = {Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38854008}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS127186/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALSFTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43.

METHODS: Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS).

RESULTS: Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell type predominance, and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43[APT]), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron.

CONCLUSIONS: Intra-neuronal pTDP-43 and cytoplasmic TDP-43[APT] pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43[APT] staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43[APT] pathology, representing a potential region-specific imaging biomarker of early disease in ALS.}, } @article {pmid38853969, year = {2024}, author = {Bingham, IN and Norel, R and Roitberg, EG and Peller, J and Trevisan, MA and Agurto, C and Shalom, DE and Aguirre, F and Embon, I and Taitz, A and Harris, D and Wright, A and Seaver, K and Sullivan, S and Green, JR and Ostrow, LW and Fraenkel, E and Berry, JD}, title = {Listener effort quantifies clinically meaningful progression of dysarthria in people living with amyotrophic lateral sclerosis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853969}, support = {K24 DC016312/DC/NIDCD NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that causes progressive muscle weakness. Progressive bulbar dysfunction causes dysarthria and thus social isolation, reducing quality of life. The Everything ALS Speech Study obtained longitudinal clinical information and speech recordings from 292 participants. In a subset of 120 participants, we measured speaking rate (SR) and listener effort (LE), a measure of dysarthria severity rated by speech pathologists from recordings. LE intra- and inter-rater reliability was very high (ICC 0.88 to 0.92). LE correlated with other measures of dysarthria at baseline. LE changed over time in participants with ALS (slope 0.77 pts/month; p<0.001) but not controls (slope 0.005 pts/month; p=0.807). The slope of LE progression was similar in all participants with ALS who had bulbar dysfunction at baseline, regardless of ALS site of onset. LE could be a remotely collected clinically meaningful clinical outcome assessment for ALS clinical trials.}, } @article {pmid38853922, year = {2024}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, MA and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38853922}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.}, } @article {pmid38853763, year = {2024}, author = {Maranzano, A and Verde, F and Dubini, A and Torre, S and Colombo, E and Doretti, A and Gentile, F and Manini, A and Milone, I and Brusati, A and Peverelli, S and Santangelo, S and Spinelli, EG and Torresani, E and Gentilini, D and Messina, S and Morelli, C and Poletti, B and Agosta, F and Ratti, A and Filippi, M and Silani, V and Ticozzi, N}, title = {Association of APOE genotype and cerebrospinal fluid Aβ and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {9}, pages = {e16374}, pmid = {38853763}, issn = {1468-1331}, support = {RF-2021-12374238//Ministry of Health/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics ; *Apolipoproteins E/genetics/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Cognition Disorders/cerebrospinal fluid/genetics/etiology ; Genotype ; Peptide Fragments/cerebrospinal fluid ; *Phenotype ; *tau Proteins/cerebrospinal fluid ; }, abstract = {OBJECTIVE: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS.

METHODS: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype.

RESULTS: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aβ42 (-0.8 vs. 0.1, log-transformed values) and Aβ42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS-specific (β = 0.24) and ALS-nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T-tau (β = -0.29) and P-tau181 (β = -0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22).

CONCLUSIONS: APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.}, } @article {pmid38853167, year = {2024}, author = {Öijerstedt, L and Foucher, J and Lovik, A and Yazdani, S and Juto, A and Kläppe, U and Fang, F and Ingre, C}, title = {Repeated cognitive assessments show stable function over time in patients with ALS.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5267-5274}, pmid = {38853167}, issn = {1432-1459}, support = {SLS-986189//Svenska Läkaresällskapet/ ; 2023-02428//Vetenskapsrådet/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/etiology/physiopathology/diagnosis ; Longitudinal Studies ; *Neuropsychological Tests ; Disease Progression ; Executive Function/physiology ; Sweden/epidemiology ; Follow-Up Studies ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder with not only motor symptoms but also extra-motor features including cognitive impairment. The most common cognitive profile observed in patients with ALS includes deficits in executive function, language, and social cognition. However, longitudinal studies on cognitive changes over time in ALS are sparse. We aimed to investigate the presence and nature of cognitive impairment at the time of ALS diagnosis and its association with survival as well as explore longitudinal cognitive change.

METHOD: Patients (n = 216) were recruited at the Karolinska University Hospital in Stockholm, Sweden. Follow-up visits (n = 307 in total) were performed every 6 months. Cognitive impairment was assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and/or Montreal Cognitive Assessment (MoCA).

RESULTS: Cognitive impairment was observed in 38% of the patients at the time of ALS diagnosis, and the majority of these patients had deficits in executive function and/or language. Patients with cognitive impairment at the time of diagnosis had a more rapid decline in ALSFRS-R at 12- and 18-months follow-up, and a shorter survival. Cognitive function was stable during the first 2 years after diagnosis, and did not follow the trajectories of decline in motor functions.

CONCLUSION: Cognitive impairment in ALS was associated with a faster decline of motor functions, and shorter survival. However, cognitive function did not deteriorate over time. Cognitive assessment is essential for the patients and caregivers to understand the phenotypic expression of ALS.}, } @article {pmid38852806, year = {2024}, author = {Yazdani, S and Lovik, A and Seitz, C and Ingre, C and Fang, F and Andersson, J}, title = {T cell subset composition differs between blood and cerebrospinal fluid in amyotrophic lateral sclerosis.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {265}, number = {}, pages = {110270}, doi = {10.1016/j.clim.2024.110270}, pmid = {38852806}, issn = {1521-7035}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/immunology/blood ; Male ; Female ; Middle Aged ; *Flow Cytometry ; Aged ; *T-Lymphocyte Subsets/immunology ; Adult ; }, abstract = {Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.}, } @article {pmid38852741, year = {2024}, author = {Moncayo, AK and Grossman, D and Kim, CC and Hartman, RI}, title = {Response to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {4}, pages = {e101-e102}, doi = {10.1016/j.jaad.2024.05.079}, pmid = {38852741}, issn = {1097-6787}, mesh = {Humans ; *Skin Neoplasms/pathology ; Dermoscopy ; Melanoma/pathology ; }, } @article {pmid38852112, year = {2024}, author = {Leighton, DJ and Ansari, M and Newton, J and Cleary, E and Stephenson, L and Beswick, E and Carod Artal, J and Davenport, R and Duncan, C and Gorrie, GH and Morrison, I and Swingler, R and Deary, IJ and Porteous, M and Chandran, S and Pal, S and , }, title = {Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5256-5266}, pmid = {38852112}, issn = {1432-1459}, support = {CAF/MND/15/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; CAF/MND/15/01//MND Scotland/ ; CAF/MND/15/01/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; Scotland/epidemiology ; *Motor Neuron Disease/genetics/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Phenotype ; *C9orf72 Protein/genetics ; Genotype ; Adult ; DNA Repeat Expansion/genetics ; Cohort Studies ; Aged, 80 and over ; Superoxide Dismutase-1/genetics ; }, abstract = {BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.

METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.

RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.

CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.}, } @article {pmid38851229, year = {2024}, author = {Yu, Y and Zeng, L and Wu, M and Li, C and Qiu, Y and Liu, J and Yang, F and Xia, P}, title = {Exploring amyotrophic lateral sclerosis patients' experiences of psychological distress during the disease course in China: a qualitative study.}, journal = {BMJ open}, volume = {14}, number = {6}, pages = {e082398}, pmid = {38851229}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Female ; Male ; China ; Middle Aged ; *Qualitative Research ; *Psychological Distress ; *Quality of Life ; Adult ; Aged ; Stress, Psychological/psychology ; Interviews as Topic ; Social Stigma ; Adaptation, Psychological ; }, abstract = {OBJECTIVE: This study aims to explore the psychological distress course of Chinese amyotrophic lateral sclerosis (ALS) patients after the onset of the disease and to provide targeted nursing guidance.

DESIGN: The interview content was analysed qualitatively. We used seven steps of Colaizzi's method to analyse the participants' data.

SETTING: Wuhan, China, Traditional Chinese Medicine Hospital.

PARTICIPANTS: A semistructured face-to-face interview were performed among 22 people with ALS from the motor neuron disease rehabilitation centre of a tertiary Chinese medicine hospital in China.

RESULT: This study included a total of 22 participants, from whom three main themes regarding the psychological distress trajectory of ALS patients were extracted from the interview data: 'Time begins to run out' include tormented and restless waiting and shock and doubt in ALS disease confirmation, 'Family out of control' include the burden of stigma and function loss, the burden of missing family roles, the burden of marriage's emotional needs and the burden of offspring health, 'Way forward' include struggle between live and death and struggle between quality of life and the value of life.

CONCLUSION: This study outlines the psychologically distressing journey of ALS patients. Studies have pointed out the need for targeted care to address patients' various sources of psychological distress to improve their quality of life and coping ability, increase their psychological resilience and reconstruct their life beliefs.}, } @article {pmid38850875, year = {2024}, author = {Coen, M and Benyamine, A and Delmont, E and Kaplanski, G and Bouabdallah, R and Xerri, L and Attarian, S and Serratrice, J}, title = {Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.}, journal = {Pathology, research and practice}, volume = {260}, number = {}, pages = {155377}, doi = {10.1016/j.prp.2024.155377}, pmid = {38850875}, issn = {1618-0631}, mesh = {Humans ; Retrospective Studies ; Male ; Female ; Middle Aged ; *Lymphoma, B-Cell/pathology/immunology ; Aged ; Adult ; }, abstract = {INTRODUCTION: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas.

METHODS: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected.

RESULTS: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease.

CONCLUSION: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case.}, } @article {pmid38849544, year = {2024}, author = {Sun, H and Yang, B and Li, Q and Zhu, X and Song, E and Liu, C and Song, Y and Jiang, G}, title = {Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms.}, journal = {Nature nanotechnology}, volume = {19}, number = {9}, pages = {1354-1365}, pmid = {38849544}, issn = {1748-3395}, support = {22176206, 22174116 and 22241604//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {*Polystyrenes/chemistry/toxicity ; *Amyotrophic Lateral Sclerosis/metabolism/chemically induced ; *DNA-Binding Proteins/metabolism ; Humans ; *Nanoparticles/chemistry ; Animals ; Mice ; Oxidative Stress/drug effects ; Motor Neurons/metabolism/drug effects/pathology ; HSP70 Heat-Shock Proteins/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.}, } @article {pmid38849367, year = {2024}, author = {Mora, S and Stuckert, A and von Huth Friis, R and Pietersz, K and Noes-Holt, G and Montañana-Rosell, R and Wang, H and Sørensen, AT and Selvan, R and Verhaagen, J and Allodi, I}, title = {Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4867}, pmid = {38849367}, issn = {2041-1723}, support = {21-2B-9477/L102 and 18-2B-3570//Aage og Johanne Louis-Hansens Fond (Aage and Johanne Louis-Hansen Foundation)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology/metabolism/therapy ; *Interneurons/metabolism ; *Motor Neurons/metabolism ; *Disease Models, Animal ; Mice ; *Mice, Transgenic ; *Synapses/metabolism ; Phenotype ; Male ; Genetic Therapy/methods ; Humans ; Female ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1[G93A] mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1[G93A] mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.}, } @article {pmid38849340, year = {2024}, author = {Caldi Gomes, L and Hänzelmann, S and Hausmann, F and Khatri, R and Oller, S and Parvaz, M and Tzeplaeff, L and Pasetto, L and Gebelin, M and Ebbing, M and Holzapfel, C and Columbro, SF and Scozzari, S and Knöferle, J and Cordts, I and Demleitner, AF and Deschauer, M and Dufke, C and Sturm, M and Zhou, Q and Zelina, P and Sudria-Lopez, E and Haack, TB and Streb, S and Kuzma-Kozakiewicz, M and Edbauer, D and Pasterkamp, RJ and Laczko, E and Rehrauer, H and Schlapbach, R and Carapito, C and Bonetto, V and Bonn, S and Lingor, P}, title = {Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4893}, pmid = {38849340}, issn = {2041-1723}, support = {01GM1917A//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; SFB1192 PB8, and PC3//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; Humans ; Female ; Animals ; Male ; Mice ; *Mice, Transgenic ; *MAP Kinase Signaling System/drug effects ; *Disease Models, Animal ; Pyridones/pharmacology/therapeutic use ; RNA-Binding Protein FUS/metabolism/genetics ; Prefrontal Cortex/metabolism ; Transcriptome ; Superoxide Dismutase-1/genetics/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Middle Aged ; MicroRNAs/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Sex Characteristics ; Aged ; Sex Factors ; Pyrimidinones ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.}, } @article {pmid38848664, year = {2024}, author = {Morioka, D and Sagisaka, R and Nakagawa, K and Takahashi, H and Tanaka, H}, title = {Effect of timing of advanced life support on out-of-hospital cardiac arrests at home.}, journal = {The American journal of emergency medicine}, volume = {82}, number = {}, pages = {94-100}, doi = {10.1016/j.ajem.2024.05.021}, pmid = {38848664}, issn = {1532-8171}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Aged ; *Epinephrine/administration & dosage/therapeutic use ; Japan/epidemiology ; Middle Aged ; *Emergency Medical Services ; *Advanced Cardiac Life Support/methods ; Intubation, Intratracheal/statistics & numerical data ; Time-to-Treatment/statistics & numerical data ; Aged, 80 and over ; Registries ; Time Factors ; Return of Spontaneous Circulation ; Cardiopulmonary Resuscitation/methods ; }, abstract = {AIM: In cases of out-of-hospital cardiac arrests (OHCA) occurring at home, Japanese emergency medical services personnel decide whether to provide treatment on the scene or during transport based on their judgment. This study aimed to evaluate the association between the timing of advanced life support (ALS) (i.e., endotracheal intubation [ETI] or adrenaline administration) for OHCA at home and prognosis.

METHOD: This retrospective cohort study used data from the Japan Utstein Registry and emergency transport data collected from patients who underwent pre-hospital ETI (n = 6806) and received adrenaline (n = 22,636) between 2016 and 2019. The timing of ETI or adrenaline administration was determined as "on the scene" or "in the ambulance." Multiple logistic regression analysis was used to estimate the association among the timing of ALS implementation, pre-hospital return of spontaneous circulation (ROSC), and survival at 1 month.

RESULT: ETI on the scene was significantly positively associated with pre-hospital ROSC (adjusted odds ratio [AOR], 1.81; 95% confidence interval [CI], 1.57-2.09) and survival at 1 month (AOR, 1.81; 95% CI, 1.47-2.23). Adrenaline administration on the scene was significantly positively associated with pre-hospital ROSC (AOR, 2.51; 95% CI, 2.33-2.70) and survival at 1 month (AOR, 2.13; 95% CI, 1.89-2.40).

CONCLUSION: Our analysis suggests performing ALS on the scene was associated with pre-hospital ROSC and survival at 1 month. Further efforts are needed to increase the rate of ALS implementation on the scene by emergency life-saving technicians.}, } @article {pmid38848044, year = {2024}, author = {Samalia, P and Niederer, R}, title = {Letter to the Editor: Comment on Raad et al's "Adalimumab for the Treatment of Non-Infectious Uveitis: A Real Life Experience".}, journal = {Ocular immunology and inflammation}, volume = {}, number = {}, pages = {1}, doi = {10.1080/09273948.2024.2362879}, pmid = {38848044}, issn = {1744-5078}, } @article {pmid38848023, year = {2024}, author = {Fabi, JP}, title = {The connection between gut microbiota and its metabolites with neurodegenerative diseases in humans.}, journal = {Metabolic brain disease}, volume = {39}, number = {5}, pages = {967-984}, doi = {10.1007/s11011-024-01369-w}, pmid = {38848023}, issn = {1573-7365}, support = {2013/07914-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 307842/2022-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Neurodegenerative Diseases/metabolism/microbiology ; *Dysbiosis/metabolism ; *Brain-Gut Axis/physiology ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; }, abstract = {The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota.}, } @article {pmid38847583, year = {2024}, author = {Zhou, M and Sheng, Z and Ji, G and Zhang, X}, title = {Aerogel-Involved Triple-State Gels Resemble Natural Living Leaves in Structure and Multi-Functions.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {36}, number = {32}, pages = {e2406007}, doi = {10.1002/adma.202406007}, pmid = {38847583}, issn = {1521-4095}, support = {52173052//National Natural Science Foundation of China/ ; SYC2022125//Suzhou Municipal Science and Technology Bureau/ ; }, mesh = {*Plant Leaves/chemistry/metabolism ; Gels/chemistry ; Silicon Dioxide/chemistry ; Hydrogels/chemistry ; Photosynthesis ; Polyvinyl Alcohol/chemistry ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Natural plant leaves with multiple functions, for example, spectral features, transpiration, photosynthesis, etc., have played a significant role in the ecosystem, and artificial synthesis of plant leaves with multiple functions of natural ones is still a great challenge. Herein, this work presents an aerogel-involved living leaf (AL), most similar to natural ones so far, by embedding super-hydrophobic SiO2 aerogel microparticles in polyvinyl alcohol hydrogel in the presence of hygroscopic salt and chlorophyllin copper sodium to form solid-liquid-vapor triple-state gel. The AL shows a high spectral similarity with all sampled 15 species of natural leaves and exhibits ≈4-7 times transpiration speed higher than natural leaves. More importantly, AL can achieve several times higher photosynthesis than natural leaves without the energy provided by the respiratory action of natural ones. This work demonstrates the feasibility of creating ALs with natural leaf-like triple-state gel structures and multiple functions, opening up new avenues for energy conversion, environmental engineering, and biomimetic applications.}, } @article {pmid38847056, year = {2024}, author = {Michelotti, G and Egger-Sigg, M and Bornstein, MM}, title = {[Komplexes Odontom im Unterkieferfrontzahnbereich bei einer 16-jährigen Patientin - Diagnostik, Therapie und Nachsorge].}, journal = {Swiss dental journal}, volume = {134}, number = {3}, pages = {}, doi = {10.61872/sdj-2024-03-08}, pmid = {38847056}, issn = {2296-6498}, mesh = {Adolescent ; Humans ; Diagnosis, Differential ; Mandibular Neoplasms/surgery/pathology/diagnosis ; Maxillary Neoplasms/surgery/pathology/diagnosis ; *Odontoma/surgery/diagnosis/pathology ; }, abstract = {Odontome gelten zusammen mit den Amelo- blastomen als die häufigsten odontogenen Tumoren. Sie entstehen während der embryo- nalen Zahnkeimentwicklung durch fehlerhaft differenziertes Keimgewebe und werden daher auch als Hamartome bezeichnet. Somit sind sie also strenggenommen keine klassischen Neoplasien.}, } @article {pmid38846716, year = {2024}, author = {Bradford, D and Rodgers, KE}, title = {Advancements and challenges in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1401706}, pmid = {38846716}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) continues to pose a significant challenge due to the disease complexity and heterogeneous manifestations. Despite recent drug approvals, there remains a critical need for the development of more effective therapies. This review explores the underlying mechanisms involved; including neuroinflammation, glutamate mediated excitotoxicity, mitochondrial dysfunction, and hypermetabolism, and how researchers are trying to develop novel drugs to target these pathways. While progress has been made, the unmet need of ALS patients highlights the urgency for continued research and resource allocation in the pursuit of effective treatments.}, } @article {pmid38846532, year = {2024}, author = {Murage, B and Tan, H and Mashimo, T and Jackson, M and Skehel, PA}, title = {Spinal cord neurone loss and foot placement changes in a rat knock-in model of amyotrophic lateral sclerosis Type 8.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae184}, pmid = {38846532}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that amyotrophic lateral sclerosis is part of a spectrum of disorders, ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic lateral sclerosis Type 8 is a familial disease caused by mis-sense mutations in VAPB. VAPB is localized to the cytoplasmic surface of the endoplasmic reticulum, where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of amyotrophic lateral sclerosis Type 8 based on the VapB[P56S] mutation and VapB gene deletion has been generated in rats. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of amyotrophic lateral sclerosis Type 8. A loss of motor neurones in VapB[P56S/+] and VapB[P56S/P56S] animals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. VapB[-/-] animals exhibit a relative increase in cytoplasmic TDP-43 levels compared with the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies VapB[P56S/+] , VapB[P56S/P56S] and VapB[-/-] animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extramotor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of amyotrophic lateral sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.}, } @article {pmid38845371, year = {2024}, author = {Rooney, J and Murray, D and Meldrum, D and Al-Chalabi, A and Bunte, T and Chiwera, T and Choudhury, M and Chio, A and Fenton, L and Fortune, J and Maidment, L and Manera, U and McDermott, CJ and Meyjes, M and Tattersall, R and Torrieri, MC and Van Damme, P and Vanderlinden, E and Wood, C and van den Berg, LH and Hardiman, O}, title = {REVEALS-a longitudinal cohort study of multifaceted respiratory assessment in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {661-671}, pmid = {38845371}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Disease Progression ; Respiratory Function Tests/methods ; Vital Capacity/physiology ; Cohort Studies ; Cough/physiopathology/diagnosis ; }, abstract = {OBJECTIVE: To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression.

METHODS: The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model.

RESULTS: Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King's stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores.

CONCLUSION: Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King's staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements.}, } @article {pmid38845026, year = {2024}, author = {Kettunen, P and Koistinaho, J and Rolova, T}, title = {Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {152}, pmid = {38845026}, issn = {1742-2094}, support = {334525//Research Council of Finland/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Central Nervous System Infections ; Animals ; }, abstract = {Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia. This narrative review aims to bring together a broad range of data currently supporting the involvement of central nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens and subsequent pathologies.}, } @article {pmid38844617, year = {2024}, author = {Tyr, A and Heldring, N and Zilg, B}, title = {Examining the use of alternative light sources in medico-legal assessments of blunt-force trauma: a systematic review.}, journal = {International journal of legal medicine}, volume = {138}, number = {5}, pages = {1925-1938}, pmid = {38844617}, issn = {1437-1596}, mesh = {Humans ; *Contusions ; *Wounds, Nonpenetrating ; Light ; Forensic Medicine/methods ; }, abstract = {The ability to analyze blunt-force trauma is crucial for deciphering valuable clues concerning mechanisms of injury and as evidence for medico-legal investigations. The use of alternate light sources (ALS) has been studied over the past decade, and is proposed to outperform conventional white light (CWL) during bruise assessments. In response to the growing interest of the technology worldwide, a systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) to address the ability of ALS to detect and visualize bruising. From an initial 4055 records identified, ten studies met the eligibly criteria and were selected for this review. Evaluation also included a novel framework, referred to as SPICOT, to further systematically assess both scientific evidence and risk of bias in forensic literature. Analysis reveals that narrowband wavelengths within in the infrared or ultraviolet spectral ranges do not significantly outperform CWL in visualizing or detecting bruising. However, wavelengths within the visible spectrum, particularly 415 nm combined with longpass or bandpass yellow filters, are more effective. However, the majority of selected studies only address the sensitivity of ALS, and therefore, results may only be considered valid when the location of a bruise is known. Further investigation is required to understand the specificity of ALS, in particular how the use of topical cosmetic products, previous wounds/scar-tissue, tattoos, moles and freckles may affect detection. The ethical concern regarding the interpretation of enhanced visualized trauma should also be considered in prospect discussions prior to implementing ALS into routine practice. Nevertheless, this review finds that narrowband ALS within the visible spectrum demonstrates potential for improved injury documentation, outperforming CWL in the detection and visualization of bruising.}, } @article {pmid38844339, year = {2024}, author = {Robinson, G}, title = {Neuropsychological assessment in ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {692}, pmid = {38844339}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis/complications ; *Neuropsychological Tests ; Cognition Disorders/diagnosis ; }, } @article {pmid38842106, year = {2024}, author = {Neel, DV and Baselga-Garriga, C and Benson, M and Keegan, M and Chase, M and D'Agostino, D and Drake, K and Hagar, JL and Hasenoehrl, MG and Kulesa-Kelley, J and Leite, A and Mohapatra, S and Portaro, SM and Pothier, LM and Rosenthal, J and Sherman, AV and Yu, H and McCaffrey, A and Ho, D and Luppino, S and Bedlack, R and Heitzman, D and Ajroud-Driss, S and Katz, J and Felice, K and Whitaker, C and Ladha, S and Alameda, G and Locatelli, E and Qureshi, IA and Hotchkin, MT and Hayden, MR and Cudkowicz, ME and Babu, S and Berry, JD and Paganoni, S}, title = {Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {232-239}, doi = {10.1002/mus.28169}, pmid = {38842106}, issn = {1097-4598}, support = {//I AM ALS/ ; //Biohaven Pharmaceuticals, Inc/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; United States ; Male ; Female ; Middle Aged ; Aged ; Drugs, Investigational/therapeutic use ; United States Food and Drug Administration ; Adult ; Health Services Accessibility ; }, abstract = {INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers.

METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration.

RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing.

DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.}, } @article {pmid38841627, year = {2024}, author = {Picher-Martel, V and Babu, S and Amato, AA}, title = {TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.}, journal = {Neurology. Genetics}, volume = {10}, number = {3}, pages = {e200160}, pmid = {38841627}, issn = {2376-7839}, abstract = {OBJECTIVES: Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined.

METHODS: A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel.

RESULTS: The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/TARDBP). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1, are respectively absent or rare in FOSMN.

DISCUSSION: FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN.}, } @article {pmid38840222, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {32}, pmid = {38840222}, issn = {1756-6606}, support = {RF1 NS112719/NS/NINDS NIH HHS/United States ; RF1NS112719/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; *MutL Protein Homolog 1/metabolism ; *DNA Damage ; *Protein Binding/drug effects ; Cell Line, Tumor ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Neurons/metabolism ; Middle Aged ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.}, } @article {pmid38839275, year = {2024}, author = {Palumbo, F and Iazzolino, B and Callegaro, S and Canosa, A and Manera, U and Vasta, R and Grassano, M and Matteoni, E and Cabras, S and Pellegrino, G and Salamone, P and Peotta, L and Casale, F and Fuda, G and Moglia, C and Chio, A and Calvo, A}, title = {Disentangling the relationship between social cognition, executive functions and behaviour changes in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {95}, number = {8}, pages = {722-729}, doi = {10.1136/jnnp-2023-332700}, pmid = {38839275}, issn = {1468-330X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; *Executive Function ; Male ; Female ; *Social Cognition ; Middle Aged ; Cross-Sectional Studies ; *Theory of Mind/physiology ; Aged ; Neuropsychological Tests ; Cognitive Dysfunction/psychology/diagnosis ; Case-Control Studies ; }, abstract = {BACKGROUND: Social cognition (SC) deficits are included in the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTDS) revised diagnostic criteria. However, the impact of SC assessment on cognitive classification and the cognitive-behavioural correlates of SC remain unclear. This cross-sectional study aimed to assess the impact of SC assessment on ALS-FTDS categorisation and explore the relationship of SC with executive functions (EF) and behaviour changes in a cohort of ALS patients.

METHODS: 121 patients and 56 healthy controls from the Turin ALS Centre underwent cognitive/behavioural testing, including the SC subdomains of facial emotion recognition, and cognitive and affective theory of mind (ToM).

RESULTS: Patients performed significantly worse than controls in all SC explored domains, and 45% of patients exhibited a deficit in at least one SC test, dissociated from the presence of EF deficits. In 13% of cases, the SC deficit was isolated and subclinical. SC assessment contributed to the attribution of cognitive impairment in 10% of patients. Through a statistical clustering approach, we found that ToM only partially overlaps with EF while behaviour changes are associated with emotional disorders (anxiety and depression).

CONCLUSIONS: SC is overall independent of EF in ALS, with ToM only partially associated with specific EF measures, and behaviour changes associated with emotional disorders. The influence of SC on cognitive categorisation and the frequent identification of a subclinical SC impairment have implications in a clinical setting, considering the substantial impact of cognitive impairment on disease burden and therapeutic choices.}, } @article {pmid38838600, year = {2024}, author = {Ou, H and Zhang, P and Wang, X and Lin, M and Li, Y and Wang, G}, title = {Gaining insights into the responses of individual yeast cells to ethanol fermentation using Raman tweezers and chemometrics.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {319}, number = {}, pages = {124584}, doi = {10.1016/j.saa.2024.124584}, pmid = {38838600}, issn = {1873-3557}, mesh = {*Spectrum Analysis, Raman/methods ; *Ethanol/metabolism ; *Saccharomyces cerevisiae/metabolism ; *Fermentation ; *Principal Component Analysis ; Least-Squares Analysis ; Optical Tweezers ; Single-Cell Analysis/methods ; }, abstract = {Saccharomyces cerevisiae is the most common microbe used for the industrial production of bioethanol, and it encounters various stresses that inhibit cell growth and metabolism during fermentation. However, little is currently known about the physiological changes that occur in individual yeast cells during ethanol fermentation. Therefore, in this work, Raman spectroscopy and chemometric techniques were employed to monitor the metabolic changes of individual yeast cells at distinct stages during high gravity ethanol fermentation. Raman tweezers was used to acquire the Raman spectra of individual yeast cells. Multivariate curve resolution-alternating least squares (MCR-ALS) and principal component analysis were employed to analyze the Raman spectra dataset. MCR-ALS extracted the spectra of proteins, phospholipids, and triacylglycerols and their relative contents in individual cells. Changes in intracellular biomolecules showed that yeast cells undergo three distinct physiological stages during fermentation. In addition, heterogeneity among yeast cells significantly increased in the late fermentation period, and different yeast cells may respond to ethanol stress via different mechanisms. Our findings suggest that the combination of Raman tweezers and chemometrics approaches allows for characterizing the dynamics of molecular components within individual cells. This approach can serve as a valuable tool in investigating the resistance mechanism and metabolic heterogeneity of yeast cells during ethanol fermentation.}, } @article {pmid38838248, year = {2024}, author = {Liss, J and Berisha, V}, title = {Operationalizing Clinical Speech Analytics: Moving From Features to Measures for Real-World Clinical Impact.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {67}, number = {11}, pages = {4226-4232}, doi = {10.1044/2024_JSLHR-24-00039}, pmid = {38838248}, issn = {1558-9102}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; *Speech Production Measurement/methods ; Speech ; Reproducibility of Results ; }, abstract = {OBJECTIVE: This research note advocates for a methodological shift in clinical speech analytics, emphasizing the transition from high-dimensional speech feature representations to clinically validated speech measures designed to operationalize clinically relevant constructs of interest. The aim is to enhance model generalizability and clinical applicability in real-world settings.

METHOD: We outline the challenges of using conventional supervised machine learning models in clinical speech analytics, particularly their limited generalizability and interpretability. We propose a new framework focusing on speech measures that are closely tied to specific speech constructs and have undergone rigorous validation. This research note discusses a case study involving the development of a measure for articulatory precision in amyotrophic lateral sclerosis (ALS), detailing the process from ideation through Food and Drug Administration (FDA) breakthrough status designation.

RESULTS: The case study demonstrates how the operationalization of the articulatory precision construct into a quantifiable measure yields robust, clinically meaningful results. The measure's validation followed the V3 framework (verification, analytical validation, and clinical validation), showing high correlation with clinical status and speech intelligibility. The practical application of these measures is exemplified in a clinical trial and designation by the FDA as a breakthrough status device, underscoring their real-world impact.

CONCLUSIONS: Transitioning from speech features to speech measures offers a more targeted approach for developing speech analytics tools in clinical settings. This shift ensures that models are not only technically sound but also clinically relevant and interpretable, thereby bridging the gap between laboratory research and practical health care applications. We encourage further exploration and adoption of this approach for developing interpretable speech representations tailored to specific clinical needs.}, } @article {pmid38838021, year = {2024}, author = {Ho, DM and Shaban, M and Mahmood, F and Ganguly, P and Todeschini, L and Van Vactor, D and Artavanis-Tsakonas, S}, title = {cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {24}, pages = {e2400732121}, pmid = {38838021}, issn = {1091-6490}, support = {R21 NS123207/NS/NINDS NIH HHS/United States ; R21NS123207//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Cyclic AMP/metabolism ; *Drosophila melanogaster/metabolism ; *Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; *Drosophila Proteins/metabolism/genetics ; *Signal Transduction ; *DNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; Motor Neurons/metabolism ; }, abstract = {Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.}, } @article {pmid38837845, year = {2024}, author = {Huang, Q and Zhang, Q and Cao, B}, title = {Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {6}, pages = {e3543}, pmid = {38837845}, issn = {2162-3279}, support = {2022NSFSC0749 to BC//the National Natural Science Fund of Sichuan/ ; }, mesh = {Humans ; Alzheimer Disease/genetics/drug therapy ; Amyotrophic Lateral Sclerosis/genetics/drug therapy/epidemiology ; Genome-Wide Association Study ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/adverse effects ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/drug therapy/genetics ; Parkinson Disease/genetics/drug therapy ; *PCSK9 Inhibitors ; *Polymorphism, Single Nucleotide ; Proprotein Convertase 9 ; }, abstract = {BACKGROUND: In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis. However, the effects of PCSK9 inhibitors on neurodegenerative diseases are controversial. Therefore, we used drug-targeted Mendelian randomization (MR) analysis to investigate the effects of PCSK9 inhibitors on different neurodegenerative diseases.

METHODS: We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published statistics of genome-wide association studies and performed drug target MR analyses to detect a causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases. We utilized the effects of 3-Hydroxy -3- methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statin targets) for comparison with PCSK9 inhibitors. Coronary heart disease risk was used as a positive control, and primary outcomes included amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD).

RESULTS: PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%] = 0.89 [0.77 to 1.00], p = 0.048), while they increased the risk of PD (OR [95%] = 1.417 [1.178 to 1.657], p = 0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001).

CONCLUSION: PCSK9 inhibitors significantly reduce the risk of ALS but increase the risk of PD. HMGCR inhibitors may be the risk factor for PD.}, } @article {pmid38837773, year = {2024}, author = {Connaghan, KP and Green, JR and Eshghi, M and Haenssler, AE and Scheier, ZA and Clark, A and Iyer, A and Richburg, BD and Rowe, HP and Okada, J and Johnson, SA and Onnela, JP and Burke, KM and Berry, JD}, title = {The relationship of rate and pause features to the communicative participation of people living with ALS.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {217-225}, pmid = {38837773}, issn = {1097-4598}, support = {K23 DC019179/DC/NIDCD NIH HHS/United States ; DP2-MH103909/NH/NIH HHS/United States ; R15 DC018944/DC/NIDCD NIH HHS/United States ; 1R15DC018944/NH/NIH HHS/United States ; NIH-NIDCD K24DC016312/NH/NIH HHS/United States ; K23DC019179/NH/NIH HHS/United States ; DP2 MH103909/MH/NIMH NIH HHS/United States ; K24 DC016312/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology ; Female ; Male ; Middle Aged ; Aged ; Speech/physiology ; Adult ; Communication ; Self Report ; }, abstract = {INTRODUCTION/AIMS: Many people living with amyotrophic lateral sclerosis (PALS) report restrictions in their day-to-day communication (communicative participation). However, little is known about which speech features contribute to these restrictions. This study evaluated the effects of common speech symptoms in PALS (reduced overall speaking rate, slowed articulation rate, and increased pausing) on communicative participation restrictions.

METHODS: Participants completed surveys (the Communicative Participation Item Bank-short form; the self-entry version of the ALS Functional Rating Scale-Revised) and recorded themselves reading the Bamboo Passage aloud using a smartphone app. Rate and pause measures were extracted from the recordings. The association of various demographic, clinical, self-reported, and acoustic speech features with communicative participation was evaluated with bivariate correlations. The contribution of salient rate and pause measures to communicative participation was assessed using multiple linear regression.

RESULTS: Fifty seven people living with ALS participated in the study (mean age = 61.1 years). Acoustic and self-report measures of speech and bulbar function were moderately to highly associated with communicative participation (Spearman rho coefficients ranged from rs = 0.48 to rs = 0.77). A regression model including participant age, sex, articulation rate, and percent pause time accounted for 57% of the variance of communicative participation ratings.

DISCUSSION: Even though PALS with slowed articulation rate and increased pausing may convey their message clearly, these speech features predict communicative participation restrictions. The identification of quantitative speech features, such as articulation rate and percent pause time, is critical to facilitating early and targeted intervention and for monitoring bulbar decline in ALS.}, } @article {pmid38837229, year = {2024}, author = {Ó Murchú, SC and O'Halloran, KD}, title = {BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy.}, journal = {The Journal of physiology}, volume = {602}, number = {14}, pages = {3255-3272}, doi = {10.1113/JP280280}, pmid = {38837229}, issn = {1469-7793}, support = {SFI FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {*Muscular Dystrophy, Duchenne/physiopathology/therapy ; Humans ; *Hypoxia/physiopathology ; Animals ; Respiration ; }, abstract = {Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disorder, characterised by progressive decline in skeletal muscle function due to the secondary consequences of dystrophin deficiency. Weakness extends to the respiratory musculature, and cardiorespiratory failure is the leading cause of death in men with DMD. Intermittent hypoxia has emerged as a potential therapy to counteract ventilatory insufficiency by eliciting long-term facilitation of breathing. Mechanisms of sensory and motor facilitation of breathing have been well delineated in animal models. Various paradigms of intermittent hypoxia have been designed and implemented in human trials culminating in clinical trials in people with spinal cord injury and amyotrophic lateral sclerosis. Application of therapeutic intermittent hypoxia to DMD is considered together with discussion of the potential barriers to progression owing to the complexity of this devastating disease. Notwithstanding the considerable challenges and potential pitfalls of intermittent hypoxia-based therapies for DMD, we suggest it is incumbent on the research community to explore the potential benefits in pre-clinical models. Intermittent hypoxia paradigms should be implemented to explore the proclivity to express respiratory plasticity with the longer-term aim of preserving and potentiating ventilation in pre-clinical models and people with DMD.}, } @article {pmid38836336, year = {2024}, author = {Foucher, J and Öijerstedt, L and Lovik, A and Sun, J and Ismail, MA and Sennfält, S and Savitcheva, I and Estenberg, U and Pagani, M and Fang, F and Pereira, JB and Ingre, C}, title = {ECAS correlation with metabolic alterations on FDG-PET imaging in ALS.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {708-716}, doi = {10.1080/21678421.2024.2361695}, pmid = {38836336}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; *Fluorodeoxyglucose F18 ; Middle Aged ; *Positron-Emission Tomography/methods ; Aged ; Brain/metabolism/diagnostic imaging ; Cognitive Dysfunction/metabolism/diagnostic imaging ; Adult ; Neuropsychological Tests ; Glucose/metabolism ; Radiopharmaceuticals ; }, abstract = {Background: Cognitive impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is an ALS-specific multi-domain screening tool. Few studies have examined the relationship between ECAS scores and [[18]F]fluorodeoxyglucose positron emission tomography ([[18]F]FDG-PET) findings. Objective: To assess the relationship between ECAS scores and glucose metabolism patterns on [[18]F]FDG -PET images in ALS. Methods: We collected [[18]F]FDG-PET images from 65 patients with ALS and 39 healthy controls. ECAS scores were collected on all patients and we calculated the correlation to [[18]F]FDG-PET in order to investigate the potential links between cognition and glucose metabolism. Results: We observed hypometabolism in the frontal cortex, insula, and limbic system, together with hypermetabolism in the cerebellum in patients with ALS compared to controls. A lower ECAS total score was associated with lower glucose metabolism in the right orbitofrontal gyrus and higher glucose metabolism in lateral occipital, medial occipital, and cerebellar regions, among patients with ALS. Similar results, although less widespread, were observed in the analyses of ECAS ALS-specific scores. Conclusions: The metabolic patterns in [[18]F]FDG -PET show that changes in the glucose metabolism of corresponding areas are related to cognitive dysfunction in ALS, and can be detected using the ECAS.}, } @article {pmid38836001, year = {2024}, author = {Rong, P and Heidrick, L and Pattee, GL}, title = {A multimodal approach to automated hierarchical assessment of bulbar involvement in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1396002}, pmid = {38836001}, issn = {1664-2295}, abstract = {INTRODUCTION: As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement leads to progressive declines of speech and swallowing functions, significantly impacting social, emotional, and physical health, and quality of life. Standard clinical tools for bulbar assessment focus primarily on clinical symptoms and functional outcomes. However, ALS is known to have a long, clinically silent prodromal stage characterized by complex subclinical changes at various levels of the bulbar motor system. These changes accumulate over time and eventually culminate in clinical symptoms and functional declines. Detection of these subclinical changes is critical, both for mechanistic understanding of bulbar neuromuscular pathology and for optimal clinical management of bulbar dysfunction in ALS. To this end, we developed a novel multimodal measurement tool based on two clinically readily available, noninvasive instruments-facial surface electromyography (sEMG) and acoustic techniques-to hierarchically assess seven constructs of bulbar/speech motor control at the neuromuscular and acoustic levels. These constructs, including prosody, pause, functional connectivity, amplitude, rhythm, complexity, and regularity, are both mechanically and clinically relevant to bulbar involvement.

METHODS: Using a custom-developed, fully automated data analytic algorithm, a variety of features were extracted from the sEMG and acoustic recordings of a speech task performed by 13 individuals with ALS and 10 neurologically healthy controls. These features were then factorized into 10 composite outcome measures using confirmatory factor analysis. Statistical and machine learning techniques were applied to these composite outcome measures to evaluate their reliability (internal consistency), validity (concurrent and construct), and efficacy for early detection and progress monitoring of bulbar involvement in ALS.

RESULTS: The composite outcome measures were demonstrated to (1) be internally consistent and structurally valid in measuring the targeted constructs; (2) hold concurrent validity with the existing clinical and functional criteria for bulbar assessment; and (3) outperform the outcome measures obtained from each constituent modality in differentiating individuals with ALS from healthy controls. Moreover, the composite outcome measures combined demonstrated high efficacy for detecting subclinical changes in the targeted constructs, both during the prodromal stage and during the transition from prodromal to symptomatic stages.

DISCUSSION: The findings provided compelling initial evidence for the utility of the multimodal measurement tool for improving early detection and progress monitoring of bulbar involvement in ALS, which have important implications in facilitating timely access to and delivery of optimal clinical care of bulbar dysfunction.}, } @article {pmid38835240, year = {2024}, author = {McAlary, L and Nan, JR and Shyu, C and Sher, M and Plotkin, SS and Cashman, NR}, title = {Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells.}, journal = {Open biology}, volume = {14}, number = {6}, pages = {230418}, pmid = {38835240}, issn = {2046-2441}, support = {//R. Howard Webster Foundation/ ; //CIHR/ ; //Canadian Consortium for Neurodegeneration/ ; //Brain Canada/ ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics/chemistry ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Protein Aggregates ; Protein Aggregation, Pathological/genetics/metabolism ; Mutation ; Protein Conformation, beta-Strand ; Models, Molecular ; Proline/metabolism ; Amyloid/metabolism/chemistry ; Protein Folding ; }, abstract = {Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using in silico tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II ([15]QGIINF[20]) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies.}, } @article {pmid38835201, year = {2024}, author = {Tsai, CC and Tao, B and Wong, M and Suntharalingam, H and Abrahao, A and Barnett-Tapia, C}, title = {Sex, racial, and ethnic disparities in motor neuron disease: clinical trial enrolment.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {694-701}, doi = {10.1080/21678421.2024.2358793}, pmid = {38835201}, issn = {2167-9223}, mesh = {Female ; Humans ; Male ; Clinical Trials as Topic ; Ethnicity ; *Healthcare Disparities/ethnology/statistics & numerical data ; *Motor Neuron Disease/ethnology ; Sex Factors ; Racial Groups ; *Patient Selection ; }, abstract = {OBJECTIVE: Motor neuron disease (MND) is a group of neurological diseases, the majority being amyotrophic lateral sclerosis (ALS), with varying clinical presentations across demographics. Clinical trial enrollment reflecting global disease burden improves understanding of diverse presentations and aids personalized therapy development. We assessed the sex, racial, and ethnic composition of MND/ALS clinical trial participants relative to global disease burdens.

METHODS: We searched 'motor neuron disease OR amyotrophic lateral sclerosis' on ClinicalTrials.gov from 02/2000-04/2024. We extracted trial (start year, study site, sponsor location, phase, masking, intervention) and demographic data (sex, race, ethnicity) from randomized interventional studies. We obtained sex-based MND/ALS disease burden estimates from the Global Burden of Disease database. For females, we calculated pooled participation-to-prevalence ratio (PPR) with 95% confidence intervals (CIs), with PPR of 0.8-1.2 indicating adequate enrollment. We used Kruskal-Wallis tests to compare demographic groups across trial characteristics.

RESULTS: Of 85 trials, females comprised 37.47% (n = 5011) of 13,372 participants; the pooled female PPR was 0.97 (95% CI: 0.77-1.16). Of 41 trials (9340 participants) reporting race, 121 (1.30%) participants were Black or African American, 16 (0.17%) American Indian or Alaskan Native, and 6 (0.06%) Native Hawaiian or Other Pacific Islander. 24 trials (595 participants) reported ethnicity, with a minority of Hispanic participants (n = 153; 2.57%).

CONCLUSIONS: MND/ALS clinical trials had adequate female enrollment relative to global disease burdens. Race and ethnicity data were underreported. However, there were enrollment disparities of racial and ethnic groups. Increased trial leadership diversity, equitable enrollment policies, and addressing barriers to participation could improve enrollment diversity.}, } @article {pmid38835198, year = {2024}, author = {Trudel, P and Quesnel-Olivo, MH and Blais, M and Shoesmith, C and Dupré, N}, title = {ALS, MAiD and Tissue Donation: Case Reports from Six Patients' Care Journeys.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {}, number = {}, pages = {1-2}, doi = {10.1017/cjn.2024.277}, pmid = {38835198}, issn = {0317-1671}, } @article {pmid38834164, year = {2024}, author = {Griñán-Ferré, C and Bellver-Sanchis, A and Guerrero, A and Pallàs, M}, title = {Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy.}, journal = {Pharmacological research}, volume = {205}, number = {}, pages = {107247}, doi = {10.1016/j.phrs.2024.107247}, pmid = {38834164}, issn = {1096-1186}, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/drug therapy/genetics ; *Pharmacogenetics/methods ; *Epigenesis, Genetic/drug effects ; Animals ; Epigenomics/methods ; }, abstract = {About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.}, } @article {pmid38833116, year = {2024}, author = {Mubeen, H and Masood, A and Zafar, A and Khan, ZQ and Khan, MQ and Nisa, AU}, title = {Insights into AlphaFold's breakthrough in neurodegenerative diseases.}, journal = {Irish journal of medical science}, volume = {193}, number = {5}, pages = {2577-2588}, pmid = {38833116}, issn = {1863-4362}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; Artificial Intelligence ; Deep Learning ; Parkinson Disease ; Alzheimer Disease ; Algorithms ; Frontotemporal Dementia/genetics ; }, abstract = {Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-β (Aβ), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.}, } @article {pmid38832321, year = {2024}, author = {Patel, JS and McCall, NS and Thomas, M and Zhou, J and Higgins, KA and Bradley, JD and Tian, S and McDonald, MW and Kesarwala, AH and Stokes, WA}, title = {Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.}, journal = {International journal of particle therapy}, volume = {12}, number = {}, pages = {100016}, pmid = {38832321}, issn = {2331-5180}, abstract = {PURPOSE: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution.

MATERIALS AND METHODS: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans.

RESULTS: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03).

CONCLUSION: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.}, } @article {pmid38832104, year = {2024}, author = {Oh, HJ and Lee, WJ and Sung, JJ and Hong, YH and , }, title = {Individualized predictions for clinical milestone in amyotrophic lateral sclerosis: A multialgorithmic approach.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241260120}, pmid = {38832104}, issn = {2055-2076}, abstract = {OBJECTIVE: The phenotypic heterogeneity and complex disease trajectory complicate the ability to predict specific clinical milestone for individual patients with amyotrophic lateral sclerosis (ALS). Here we developed individualized prediction models to estimate the time to the loss of autonomy in swallowing function.

METHODS: Utilizing the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we built three models of distinct time-to-event prediction algorithms: accelerated failure time (AFT), cox proportional hazard (COX) and random survival forest (RSF) for an individualized risk assessment of the swallowing milestone. The target variable was defined as the time to a decline in the ALSFRS-R swallowing item score to 1 or below, indicating a need for supplementary tube feeding.

RESULTS: Internal cross-validation revealed the median concordance index (C-index) of 0.851 (IQR, 0.842-0.859) for AFT, 0.850 (0.841-0.859) for COX and 0.846 (0.839-0.854) for RSF, and all models demonstrated good distributional calibration with predicted and observed event probabilities closely matched across different time intervals. For external validation with a registry dataset with characteristics different from PRO-ACT, the discriminative power was replicated with comparable C-indices for all models, whereas the calibration revealed a left-skewed distribution suggesting a bias towards overestimation of event probabilities in real-world data. While all models were effective at stratifying patients, the results of RSF model, unlike AFT and COX, did not match well with the KM curves of the corresponding risk groups, supporting the importance of nuanced understanding of data structure and algorithmic properties.

CONCLUSION: Our models are implemented into a web application which could be applied to individualized counselling, management and clinical trial design for gastrostomy intervention. Further studies for model optimization will advance personalized care in patients with ALS.}, } @article {pmid38831349, year = {2024}, author = {López-Carbonero, JI and García-Toledo, I and Fernández-Hernández, L and Bascuñana, P and Gil-Moreno, MJ and Matías-Guiu, JA and Corrochano, S}, title = {In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {29}, pmid = {38831349}, issn = {2047-9158}, support = {2022-5A/BMD-24221//Consejería de Educación, Juventud y Deporte, Comunidad de Madrid/ ; PDI2020-1153-70RB-100/AEI/10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; CM23/00094//Instituto de Salud Carlos III/ ; INT20/00079//Instituto de Salud Carlos III/ ; INT23/00017//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *TDP-43 Proteinopathies/diagnosis/metabolism/genetics ; *Biomarkers/analysis/metabolism ; *DNA-Binding Proteins/metabolism ; Brain/metabolism/pathology ; }, abstract = {TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.}, } @article {pmid38830342, year = {2024}, author = {Li, J and Li, S and Fei, G}, title = {Potential Correlation between Tea Intake and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.}, journal = {Neuro-degenerative diseases}, volume = {24}, number = {2}, pages = {45-53}, doi = {10.1159/000539590}, pmid = {38830342}, issn = {1660-2862}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Tea ; *Mendelian Randomization Analysis/methods ; *Polymorphism, Single Nucleotide/genetics ; Risk Factors ; }, abstract = {INTRODUCTION: There were limited observation studies on the association between tea intake and amyotrophic lateral sclerosis (ALS) with inconsistent results. This study aimed to determine the potential relationship between tea intake and ALS by a two-sample Mendelian randomization (MR) analysis.

METHODS: We identified 41 independent SNPs strongly associated with tea intake from 448,060 participants of European ancestry in the UK Biobank. Summary statistics associated with ALS were also obtained from the UK Biobank including 20,806 cases and 59,804 controls. The study used MR analysis to assess the potential effect of tea consumption on ALS, and several methods such as sensitivity analyses and MR-pleiotropy residual sum and outlier method were performed to further test the robustness of our findings.

RESULTS: The F statistic was more than 10 in each SNP, which meets the first assumption for the MR study. Using the inverse variance weighted MR analysis as the primary method, we found that a one standard deviation increase in tea consumption was associated with a 14% lower risk of ALS (OR = 0.86, 95% CI = 0.74-0.99, p < 0.05). Sensitivity analyses detected no potential pleiotropy and directional heterogeneity.

CONCLUSION: Our MR study supported the potential relationship between tea intake and ALS risk, suggesting the potential advantages of tea intake for preventing ALS. Future clinical trials and research are needed to further validate the results and elucidate possible mechanisms.}, } @article {pmid38830304, year = {2024}, author = {Chin, B and Um, J and Kim, MK and Kim, HS and Yim, HS and Cho, HJ and Lim, SY and Kim, Y and Jeon, J and Park, JS}, title = {Clinical presentation, viral shedding, and neutralizing antibody responses of mpox cases in South Korea: Single center experience.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {173}, number = {}, pages = {105692}, doi = {10.1016/j.jcv.2024.105692}, pmid = {38830304}, issn = {1873-5967}, mesh = {Humans ; Male ; Female ; Adult ; Republic of Korea/epidemiology ; *Antibodies, Neutralizing/blood ; Middle Aged ; *Virus Shedding ; Young Adult ; *Antibodies, Viral/blood ; Disease Outbreaks ; DNA, Viral/blood ; Mpox (monkeypox) ; }, abstract = {BACKGROUND: A global mpox outbreak occurred in 2022, and a domestic outbreak started in South Korea in April 2023. This study aimed to evaluate the clinical characteristics, viral shedding, and immune response of mpox in South Korea.

METHODS: Patients hospitalized with mpox in the National Medical Center between September 2022 and June 2023 were included in this study. Oropharyngeal (OP), anogenital lesion (AL), and skin lesion (SL) swabs and blood samples were collected, and monkeypox virus (MPXV) DNA using real-time polymerase chain reaction (RT-PCR) and culture assays were performed. Neutralizing antibodies (NAbs) against MPXV A.2.1, B.1.1, and B.1.3 were detected using plaque reduction neutralization tests.

RESULTS: Eighteen patients were enrolled, of whom 17 (94.4 %) were male, with a median (IQR) age of 32.5 (24-51) years. While nine (50 %) were HIV-infected individuals, none of them revealed CD4+ counts less than 200 cells/μL. MPXV DNA was detected in 87.3 % and 82.7 % of patient's ALs and SLs, respectively, until 2 weeks after symptom onset. While MPXV was isolated for up to 15 days in all three sample types, the culture positivity decreased to 53.8 % and 42.9 % in ALs and SLs after 10 days, respectively, and 28.6 % and 22.2 %, respectively, after 2 weeks from symptom onset. The NAb titers against MPXV A.2.1 were significantly lower than those against B.1.1 and B.1.3.

CONCLUSIONS: Infectious MPXV was isolated from various anatomical sites up to 15 days after symptom onset. The MPXV NAb response was varied among different lineages, and this implies limited cross-lineage protection.}, } @article {pmid38830181, year = {2024}, author = {Weemering, DN and Beelen, A and Kliest, T and van Leeuwen, LAG and van den Berg, LH and van Eijk, RPA}, title = {Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.}, journal = {Neurology}, volume = {103}, number = {1}, pages = {e209503}, pmid = {38830181}, issn = {1526-632X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Clinical Trials as Topic ; *Patient Participation ; Patient Selection ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation.

METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models.

RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001).

DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.}, } @article {pmid38829866, year = {2024}, author = {Laurido-Soto, OJ and Faust, IM and Nielsen, SS and Racette, BA}, title = {Adherence to practice parameters in Medicare beneficiaries with amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {6}, pages = {e0304083}, pmid = {38829866}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Medicare ; Male ; Female ; United States ; Aged ; Retrospective Studies ; Aged, 80 and over ; Guideline Adherence/statistics & numerical data ; Middle Aged ; Practice Patterns, Physicians'/statistics & numerical data ; }, abstract = {OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence.

METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider specialty (neurologist vs. non-neurologist). Outcomes were use of practice parameters, which included feeding tubes, non-invasive ventilation (NIV), riluzole, and receiving care from a neurologist.

RESULTS: Overall, 42.9% of patients with ALS received neurologist care. Black beneficiaries (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.67), older beneficiaries (OR 0.964, 95% CI 0.961-0.968 per year), and those living in disadvantaged areas (OR 0.70, 95% CI 0.61-0.80) received less care from neurologists. Overall, only 26.7% of beneficiaries received a feeding tube, 19.2% NIV, and 15.3% riluzole. Neurologist-treated patients were more likely to receive interventions than other ALS patients: feeding tube (OR 2.80, 95% CI 2.52-3.11); NIV (OR 10.8, 95% CI 9.28-12.6); and riluzole (OR 7.67, 95% CI 6.13-9.58), after adjusting for sociodemographics. These associations remained marked and significant when we excluded ALS patients who subsequently received a code for other diseases that mimic ALS.

CONCLUSIONS: ALS patients treated by neurologists received care consistent with practice parameters more often than those not treated by a neurologist. Black, older, and disadvantaged beneficiaries received less care consistent with the practice parameters.}, } @article {pmid38829511, year = {2025}, author = {Jiang, S and Xu, R}, title = {The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {1}, pages = {221-232}, pmid = {38829511}, issn = {1559-1182}, support = {30560042//National Natural Science Foundation of China/ ; 81160161//National Natural Science Foundation of China/ ; 81360198//National Natural Science Foundation of China/ ; 82160255//National Natural Science Foundation of China/ ; GJJ13198//Education Department of Jiangxi Province/ ; GJJ170021//Education Department of Jiangxi Province/ ; 20192BAB205043//Jiangxi Provincial Department of Science and Technology/ ; 20181019//Health and Family Planning Commission of Jiangxi Province/ ; 202210002//Health and Family Planning Commission of Jiangxi Province/ ; 202310119//Health and Family Planning Commission of Jiangxi Province/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; Humans ; Animals ; Autophagy/physiology ; Mitochondria/metabolism ; Extracellular Vesicles/metabolism ; Gastrointestinal Microbiome/physiology ; Dysbiosis/complications ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.}, } @article {pmid38829431, year = {2024}, author = {Sabatelli, M and Cerri, F and Zuccarino, R and Patanella, AK and Bernardo, D and Bisogni, G and Tanel, R and Sansone, V and Filosto, M and Lattante, S and Martello, F and Doronzio, PN and Stano, S and Zanfini, BA and Coccia, M and Costantini, EM and Lizio, A and Lucioli, G and Padovani, A and Merlini, GP and Conte, A}, title = {Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5177-5186}, pmid = {38829431}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/blood ; Male ; Female ; Middle Aged ; Aged ; *Superoxide Dismutase-1/genetics ; Neurofilament Proteins/blood/cerebrospinal fluid ; Disease Progression ; Adult ; Retrospective Studies ; Treatment Outcome ; Cohort Studies ; }, abstract = {BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant.

METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients.

RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy.

CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.}, } @article {pmid38829015, year = {2024}, author = {Negri, C and Usberti, N and Contaldo, G and Bracconi, M and Nova, I and Maestri, M and Tronconi, E}, title = {Quantitative Kinetic Insights from Operando-UV/Vis Spectroscopy: An Application to NH3-SCR of NOx on Cu-CHA Catalysts.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {41}, pages = {e202408328}, doi = {10.1002/anie.202408328}, pmid = {38829015}, issn = {1521-3773}, abstract = {We employ UV/Vis Diffuse Reflectance spectroscopy directly coupled with a packed bed flow reactor to extract quantitative kinetic information. We use as a show-case the Cu[II]/Cu[I] redox dynamics during the reduction half cycle of the NH3-Selective Catalytic Reduction (SCR) on Cu-CHA catalysts. Our measurements enable quantification of the fraction of oxidized Cu, reconstructed by Multivariate Curve Resolution (MCR) together with monitoring of the gas-phase evolution during the reaction. These data both on the dynamics of the gas-phase and of the active site oxidation state have been used to assess the reduction half cycle rate equation and estimate the rate constant. Our results in terms of reaction orders and kinetic constant are in line with previous findings in the literature. Overall, our results demonstrate that the combined analysis of the UV spectra and of the gas-phase dynamics provides converging and unparalleled kinetic insight: this approach effectively resolves ambiguities concerning RHC kinetics and mechanism. More in general, this work provides evidence that operando spectroscopy can be used to extract quantitative kinetic information on catalytic cycles.}, } @article {pmid38829007, year = {2024}, author = {Foucher, J and Bunte, TM and Bertone, V and Verschoor, RL and Couillard, M and Straub, C and Genge, A and Ingre, C and van den Berg, LH}, title = {International network for ALS research and care (INARC).}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {795-796}, doi = {10.1080/21678421.2024.2362850}, pmid = {38829007}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Biomedical Research/methods/trends ; }, abstract = {The International Network for Amyotrophic Lateral Sclerosis (ALS) Research and Care (INARC) was founded in 2022. INARC's main goals are to offer a platform dedicated to staff members for ALS clinics and research teams who are not physicians. By nurturing experience and expertise exchanges to improve problem solving skills, the ultimate goal is to increase the standard ALS care and research. This brief report aims to describe the formation of INARC, the 2023 INARC meeting, as well as to report topics discussed, lessons learned and challenges raised by INARC members.}, } @article {pmid38828849, year = {2024}, author = {Mamarabadi, M and Fafoutis, E and Geronimo, A and Walsh, S and Simmons, Z}, title = {Sodium phenylbutyrate-taurursodiol access, adherence and adverse event in patients with amyotrophic lateral sclerosis: Experience at one center in the United States.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {204-209}, doi = {10.1002/mus.28175}, pmid = {38828849}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; Male ; Female ; Middle Aged ; Aged ; Adult ; *Medication Adherence ; United States ; Aged, 80 and over ; Phenylbutyrates/therapeutic use/economics ; Health Expenditures ; Retrospective Studies ; }, abstract = {INTRODUCTION/AIMS: Sodium phenylbutyrate-taurursodiol (PB-TURSO) was recently approved for treating amyotrophic lateral sclerosis (ALS). Third-party payors' coverage policies are evolving, and adverse events are just being fully assessed. The goals of this study were to evaluate patients' experiences in obtaining and continuing PB-TURSO and assess adverse events and medication adherence.

METHODS: Medical records of 109 ALS patients who were considered PB-TURSO candidates by the treating physician at a tertiary ALS clinic from October 2022 to May 2023 were reviewed. Data was recorded for demographics, clinical, and insurance information. A survey was e-mailed to patients asking about out-of-pocket expenses for PB-TURSO, financial assistance, medication start and (if applicable) stop dates, and reasons for discontinuation.

RESULTS: Insurance information was available for 91 patients [57 males (62%); mean age 64.8 years (range 25.7-88)]. Of 79 who applied for insurance approval, 71 (90%) were approved; however, 19 required 1-3 appeals. Among 73 patients with available data about medication status, 54 started PB-TURSO and 19 did not, most commonly due to personal choice or out-of-pocket expenses. About 44% of patients (24/54) stopped taking PB-TURSO, primarily due to adverse events. Monthly out-of-pocket expenses varied from $0 to $3500 and 36 patients qualified for financial assistance. Administrative and nursing staff devoted 7.2 hours/week to the insurance authorization process.

DISCUSSION: Most patients received insurance approval for PB-TURSO, but one-fourth required appeals. Some out-of-pocket costs were very high. Investment of staff time was substantial. These findings have implications for insurance coverage of, and adherence to, future ALS treatments.}, } @article {pmid38827490, year = {2024}, author = {Yotsukura, E and Torii, H and Mori, K and Ogawa, M and Hanyuda, A and Negishi, K and Kurihara, T and Tsubota, K}, title = {Slowing of Greater Axial Length Elongation Stemming from the Coronavirus Disease 2019 Pandemic with Increasing Time Outdoors: The Tokyo Myopia Study.}, journal = {Ophthalmology science}, volume = {4}, number = {5}, pages = {100491}, pmid = {38827490}, issn = {2666-9145}, abstract = {PURPOSE: To investigate the changes in axial length (AL) elongation and other ocular parameters before and during the coronavirus disease 2019 pandemic.

DESIGN: A longitudinal school-based study.

PARTICIPANTS: Public elementary schoolchildren in Tokyo (grades 1-6; age, 6-12 years) participated in this study from 2018 to 2021.

METHODS: All participants underwent eye examinations and provided written consent to measurements of the noncycloplegic refraction and ocular biometry including AL, among others. The students' parents also completed a questionnaire about the students' lifestyles. We included the right eye in our analysis and compared the changes in the ocular parameters among the periods using a linear mixed-effects model for repeated measures and examined the univariate and step-wise multiple regression analyses to evaluate the associations between myopia and other covariates.

MAIN OUTCOME MEASURES: Changes in AL elongation and other ocular parameters from 2018 to 2019 (prepandemic), that of 2019 to 2020 (immediately after the pandemic onset), and that of 2020 to 2021 (during the pandemic).

RESULTS: A total of 578 students before the pandemic period, 432 immediately after the pandemic onset, and 457 during the pandemic period were evaluated. The changes in the ALs and spherical equivalents (SEs) a year before, immediately after onset, and during the pandemic were 0.31 mm/-0.20 diopter, 0.38 mm/-0.27 diopter, and 0.28 mm/-0.47 diopter, respectively (ALs, P < 0.001; SEs, P = 0.014). The results of the questionnaire showed that time spent outdoors daily had changed during the 3 years to 79, 63, and 77 minutes/day, respectively (P < 0.001). Time spent using smartphones or tablets increased year by year to 41, 52, and 62 minutes/day (P < 0.001). The greatest AL elongation occurred during the period when the shortest amount of time was spent outdoors during the 3 years.

CONCLUSIONS: These results suggested that the school closures and decreasing time spent outdoors might have caused greater AL elongation among schoolchildren in Tokyo; however, it is possible that, although the time spent in near work still increased, the return to the time spent outdoors to the prepandemic levels may have affected the slowing of AL elongation after lockdown.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.}, } @article {pmid38826647, year = {2024}, author = {Zhao, H and Xie, J and Chen, Y and Cao, J and Liao, WH and Cao, H}, title = {Diagnosis of neurodegenerative diseases with a refined Lempel-Ziv complexity.}, journal = {Cognitive neurodynamics}, volume = {18}, number = {3}, pages = {1153-1166}, pmid = {38826647}, issn = {1871-4080}, abstract = {The investigation into the distinctive difference of gait is of significance for the clinical diagnosis of neurodegenerative diseases. However, human gait is affected by many factors like behavior, occupation and so on, and they may confuse the gait differences among Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. For the purpose of examining distinctive gait differences of neurodegenerative diseases, this study extracts various features from both vertical ground reaction force and time intervals. Moreover, refined Lempel-Ziv complexity is proposed considering the detailed distribution of signals based on the median and quartiles. Basic features (mean, coefficient of variance, and the asymmetry index), nonlinear dynamic features (Hurst exponent, correlation dimension, largest Lyapunov exponent), and refined Lempel-Ziv complexity of different neurodegenerative diseases are compared statistically by violin plot and Kruskal-Wallis test to reveal distinction and regularities. The comparative analysis results illustrate the gait differences across these neurodegenerative diseases by basic features and nonlinear dynamic features. Classification results by random forest indicate that the refined Lempel-Ziv complexity can robustly enhance the diagnosis accuracy when combined with basic features.}, } @article {pmid38826483, year = {2024}, author = {Provasek, VE and Kodavati, M and Kim, B and Mitra, J and Hegde, ML}, title = {TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {38826483}, issn = {2693-5015}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.}, } @article {pmid38826246, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.24.595817}, pmid = {38826246}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 [G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, } @article {pmid38826088, year = {2024}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Punjani, R and Larson, T and Berry, J and Mohidul, S and Horton, DK}, title = {Prevalence of ALS in all 50 states in the United States, data from the National ALS Registry, 2011-2018.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {687-693}, doi = {10.1080/21678421.2024.2358786}, pmid = {38826088}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Humans ; United States/epidemiology ; *Registries ; Male ; Prevalence ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Adult ; Risk Factors ; }, abstract = {Objective: To summarize the prevalence of ALS in all 50 states and Washington, DC in the United States from 2011 to 2018 using data collected and analyzed by the National ALS Registry. In October 2010, the federal Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated Registry to determine the incidence and prevalence of ALS within the USA, characterize the demographics of persons with ALS, and identify the potential risk factors for the disease. This is the first analysis of state-level ALS prevalence estimates. Methods: ALS is not a notifiable disease in the USA, so the Registry uses a two-pronged approach to identify cases. The first approach uses existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration). The second method uses a secure web portal to gather voluntary participant data and identify cases not included in the national administrative databases. Results: State-level age-adjusted average prevalence from 2011-2018 ranged from 2.6 per 100,000 persons (Hawaii) to 7.8 per 100,000 persons (Vermont), with an average of 4.4 per 100,000 persons in the US. New England and Midwest regions had higher prevalence rates than the national average. Conclusions: These findings summarize the prevalence of ALS for all 50 states from 2011 to 2018. This is a continuing effort to identify ALS cases on a national population basis. The establishment of the National ALS Registry has allowed for epidemiological trends of this disease and the assessment of potential risk factors that could cause ALS.}, } @article {pmid38826044, year = {2024}, author = {Rooney, JPK and Geoghegan, G and O'Reilly, F and Heverin, M and Bose-O'Reilly, S and Casale, F and Chio, A and Günther, K and Schuster, J and Klopstock, T and Ludolph, A and Hardiman, O and Rakete, S}, title = {Serum heat shock protein concentrations are not associated with amyotrophic lateral sclerosis risk or survival in three European populations.}, journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {751-759}, doi = {10.1080/21678421.2024.2358805}, pmid = {38826044}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/epidemiology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Biomarkers/blood ; Germany/epidemiology ; HSP70 Heat-Shock Proteins/blood ; Ireland/epidemiology ; Italy/epidemiology ; Heat-Shock Proteins/blood ; HSP90 Heat-Shock Proteins/blood ; Cohort Studies ; Adult ; Europe/epidemiology ; }, abstract = {Introduction: Serum heat shock protein (HSP) concentrations have been reported as potential biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigate the role of serum HSP70, HSP90, and DNAJC7 as biomarkers for ALS. Methods: Serum samples were collected from ALS patients and volunteer controls from three different clinical cohorts (in Germany, Ireland, and Italy). Serum HSP concentrations were determined using enzyme-linked immunosorbent assay. Descriptive statistics, generalized logistic regression, and Cox proportional hazards models were used to model associations between log serum HSP concentrations and ALS risk. Results: In total, 251 ALS patients and 184 healthy volunteers were included. Logistic regression models failed to find associations between ALS risk and log serum concentration of HSP70 (OR 0.43, 95% CI: 0.10-1.78, p = 0.242), HSP90 (OR 0.95, 95% CI: 0.39-2.37, p = 0.904), or DNAJC7 (OR 1.55, 95% CI: 0.90-2.68, p = 0.118). Survival of ALS patients was not associated with log serum concentration of HSP HSP70 (HR1.06, 95% CI: 0.36-3.14, p = 0.916), HSP90 (HR 1.17, 95% CI: 0.67-2.02, p = 0.584), or DNAJC7 (HR 0.83, 95% CI: 0.57-1.21, p = 0.337). Discussion: We did not replicate previous findings that serum HSP70 and HSP90 concentrations were associated with risk of ALS. DNAJC7 was not associated with ALS risk, and there were no obvious longitudinal patterns in log serum concentrations of HSP70, HSP90, or DNAJC7. In addition, serum HSP concentrations were not associated with ALS survival.}, } @article {pmid38825034, year = {2024}, author = {Fang, T and Pacut, P and Bose, A and Sun, Y and Gao, J and Sivakumar, S and Bloom, B and Nascimento Andrade, EI and Trombetta, B and Ghasemi, M}, title = {Clinical and genetic factors affecting diagnostic timeline of amyotrophic lateral sclerosis: a 15-year retrospective study.}, journal = {Neurological research}, volume = {46}, number = {9}, pages = {859-867}, doi = {10.1080/01616412.2024.2362578}, pmid = {38825034}, issn = {1743-1328}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Genetic Testing/methods ; Adult ; Delayed Diagnosis ; Time Factors ; }, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) diagnosis can take 10-16 months from symptom onset, leading to delays in treatment and patient counselling. We studied the impact of clinical and genetic risk factors on the diagnostic timeline of ALS.

METHODS: Baseline characteristics, family history, gene testing, onset location, time from symptom onset to diagnosis, and time from first doctor visit to suspected ALS was collected. We used multiple regression to assess the interaction of these factors on ALS diagnostic timeline. We analysed a subgroup of patients with genetic testing and compared positive or negative tests, sporadic or familial and ALS-related genes to time for diagnosis.

RESULTS: Four hundred and forty-eight patients diagnosed with ALS at the University of Massachusetts Chan Medical Center between January 2007 and December 2021 were analysed. The median time to ALS diagnosis was 12 months and remained unchanged from 2007 to 2021 (p = 0.20). Diagnosis was delayed in patients with sporadic compared with familial ALS (mean months [standard deviation], 16.5[13.5] and 11.2[8.5], p < 0.001); cognitive onset (41[21.26]) had longer time to diagnosis than bulbar (11.9[8.2]), limb (15.9[13.2]), respiratory (19.7[13.9]) and ALS with multiple onset locations (20.77[15.71], p < 0.001). One hundred and thirty-four patients had gene testing and 32 tested positive (23.8%). Gene testing (p = 0.23), a positive genetic test (p = 0.16), different ALS genes (p = 0.25) and sporadic (p = 0.92) or familial (p = 0.85) ALS testing positive for ALS genes did not influence time to diagnosis.

DISCUSSION: Time for ALS diagnosis remained unchanged from 2007 to 2021, bulbar-onset and familial ALS made for faster diagnosis.}, } @article {pmid38824664, year = {2024}, author = {Ahmed, Z and Shahzadi, K and Jin, Y and Li, R and Momanyi, BM and Zulfiqar, H and Ning, L and Lin, H}, title = {[Not Available].}, journal = {Proteomics}, volume = {24}, number = {21-22}, pages = {e2400044}, doi = {10.1002/pmic.202400044}, pmid = {38824664}, issn = {1615-9861}, support = {62372088//National Natural Science Foundation of China/ ; }, mesh = {*RNA/metabolism ; Humans ; *Artificial Intelligence ; Proteins/metabolism/chemistry/analysis ; Databases, Protein ; Computational Biology/methods ; Phase Separation ; }, abstract = {RNA-dependent liquid-liquid phase separation (LLPS) proteins play critical roles in cellular processes such as stress granule formation, DNA repair, RNA metabolism, germ cell development, and protein translation regulation. The abnormal behavior of these proteins is associated with various diseases, particularly neurodegenerative disorders like amyotrophic lateral sclerosis and frontotemporal dementia, making their identification crucial. However, conventional biochemistry-based methods for identifying these proteins are time-consuming and costly. Addressing this challenge, our study developed a robust computational model for their identification. We constructed a comprehensive dataset containing 137 RNA-dependent and 606 non-RNA-dependent LLPS protein sequences, which were then encoded using amino acid composition, composition of K-spaced amino acid pairs, Geary autocorrelation, and conjoined triad methods. Through a combination of correlation analysis, mutual information scoring, and incremental feature selection, we identified an optimal feature subset. This subset was used to train a random forest model, which achieved an accuracy of 90% when tested against an independent dataset. This study demonstrates the potential of computational methods as efficient alternatives for the identification of RNA-dependent LLPS proteins. To enhance the accessibility of the model, a user-centric web server has been established and can be accessed via the link: http://rpp.lin-group.cn.}, } @article {pmid38823272, year = {2024}, author = {Bijl, I and Vianen, NJ and Van Lieshout, EMM and Beekers, CHJ and Van Der Waarden, NWPL and Pekbay, B and Maissan, IM and Verhofstad, MHJ and Van Vledder, MG}, title = {Emergency reflex action drill for traumatic cardiac arrest in a simulated pre-hospital setting; a one-group pre-post intervention study.}, journal = {Intensive & critical care nursing}, volume = {84}, number = {}, pages = {103731}, doi = {10.1016/j.iccn.2024.103731}, pmid = {38823272}, issn = {1532-4036}, mesh = {Humans ; Prospective Studies ; Female ; Adult ; *Emergency Medical Services/methods/standards/statistics & numerical data ; Male ; Heart Arrest/complications/therapy ; Middle Aged ; Simulation Training/methods/standards ; Patient Simulation ; }, abstract = {BACKGROUND: Emergency Reflex Action Drills (ERADs) are meant to decrease stress-associated cognitive demand in high urgency situations. The aim of this study was to develop and test an ERAD for witnessed traumatic cardiac arrest (TCA), an event in which potentially reversible causes need to be systematically addressed and treated in a short period of time. We hypothesize that this ERAD (the TCA-Drill) helps ground Emergency Medical Services (EMS) nurses in overcoming performance decline during this specific high-pressure situation.

METHODS: This was a prospective, experimental one-group pre-post intervention study. Ground EMS nurses participated in a session of four simulated scenarios, with an in-between educational session to teach the TCA-Drill. Scenarios were video recorded, after which adherence and time differences were analyzed. Self-confidence on clinical practice was measured before and after the scenarios.

RESULTS: Twelve ground EMS nurses participated in this study. Overall median time to address reversible causes of TCA decreased significantly using the TCA-Drill (132 vs. 110 s; p = 0.030) compared with the conventional ALS strategy. More specifically, participants adhering to the TCA-Drill showed a significantly lower time needed for hemorrhage control (58 vs. 37 s; p = 0.012). Eight of 12 (67 %) ground EMS nurses performed the ERAD without protocol deviations. Reported self-confidence significantly increased on 11 of the 13 surveyed items.

CONCLUSIONS: The use of an ERAD for TCA (the TCA-Drill) significantly reduces the time to address reversible causes for TCA without delaying chest compressions in a simulated environment and can be easily taught to ground EMS nurses and increases self-confidence.

The use of an ERAD for TCA (the TCA-Drill can significantly reduce the time to address reversible causes for TCA without delaying chest compression. This drill can be easily taught to ground EMS nurses and increases their self-confidence in addressing TCA-patients.}, } @article {pmid38823229, year = {2024}, author = {Roman-Pognuz, E and Rigutti, S and Colussi, G and Lena, E and Bonsano, M and Lucangelo, U}, title = {Acute esophageal necrosis following cardiac arrest: A rare and lethal syndrome with diagnostic challenges.}, journal = {International journal of surgery case reports}, volume = {120}, number = {}, pages = {109751}, pmid = {38823229}, issn = {2210-2612}, abstract = {Acute esophageal necrosis (AEN) is a condition characterized by the necrosis of the distal portion of the esophageal mucosa. Risk factors predisposing to this condition are associated to compromised vascular perfusion (e.g. diabetes mellitus, chronic kidney disease, advanced age, and hypertension, shock states). Complications of AEN can be severe including UGI stricture, perforation and overall increased mortality. The true incidence of AEN remains uncertain due to potential subclincal presentations and early resolution.

CASE PRESENTATION: The case outlined involves a 66-years-old obese male with history of alcoholism and lymph-edema of the left leg who presented to the emergency department with hematemesis, haemodynamic instability and impaired consciousness. Shortly after initial assessment, the patient went into cardiac arrest with pulse-less electrical activity (PEA). Return of spontaneous circulation (ROSC) was achieved following instigation of ALS protocol, fluid resuscitation and the administration of a total of 5 mg of adrenaline. Following stabilization, a CT scan was performed which reported a moderately enlarged esophagus with a thickened wall, liquid hypodense material within the esophagus and stomach, and liver cirrhosis. The emergent esophagogastroduodenoscopy (EGDS) revealed extensive mucosal findings indicative of diffuse necrosis with initial scarring, which was later diagnosed as AEN. The patient unfortunately deceased in ICU after developing progression of the AEN, post-cardiac arrest syndrome and liver failure.

CLINICAL DISCUSSION: The presented case highlights several crucial clinical issues and management problems related to AEN. To diagnose AEN, EGDS is still the gold-standard since it allows direct inspection of the esophageal mucosal layer. The management of AEN necessitates a multidisciplinary approach that includes aggressive resuscitation, treatment of underlying comorbidities, and supportive care (e.g. proton pump inhibitors). The mortality rate for AEN remains high despite improvements in diagnosis and treatment highlighting the need to recognize this condition early and intervene promptly in the patients affected. Moreover, long-term sequelae like stricture formation of the esophagus and impaired esophageal motility may contribute to morbidity requiring continuos monitoring. Therefore, to optimize outcomes while reducing complications among affected patients, prompt identification associated with appropriate medical measures are essential. More research needs to be done aiming to better understand the pathophysiology of AEN thereby identifying strategies for its prevention or cure.

CONCLUSIONS: AEN is a rare syndrome characterized by upper gastrointestinal bleeding and hypoxic damage of the esophageal mucosa, often associated with ischemia, gastric outlet obstruction, and compromised protective barriers. Treatment involves aggressive resuscitation, proton pump inhibitors, and monitoring for infection or perforation. However, despite intensive efforts, the mortality rate for AEN remains high at 32 %.}, } @article {pmid38822985, year = {2024}, author = {Faysal, M and Dehbia, Z and Zehravi, M and Sweilam, SH and Haque, MA and Kumar, KP and Chakole, RD and Shelke, SP and Sirikonda, S and Nafady, MH and Khan, SL and Nainu, F and Ahmad, I and Emran, TB}, title = {Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1926-1944}, pmid = {38822985}, issn = {1573-6903}, mesh = {*Flavonoids/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use/pharmacology ; }, abstract = {Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca[2+] stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.}, } @article {pmid38822416, year = {2024}, author = {Yadav, S and Deepika, and Moar, K and Kumar, A and Khola, N and Pant, A and Kakde, GS and Maurya, PK}, title = {Reconsidering red blood cells as the diagnostic potential for neurodegenerative disorders.}, journal = {Biology of the cell}, volume = {116}, number = {7}, pages = {e2400019}, doi = {10.1111/boc.202400019}, pmid = {38822416}, issn = {1768-322X}, support = {//Council of Scientific and Industrial Research (CSIR), Government of India/ ; //University Grant Commission (UGC)/ ; HSCIT-3946//Haryana State Council for Science, Innovation, and Technology/ ; //Central University of Haryana, Mahendergarh/ ; //Indian Council of Medical Research (ICMR), Government of India/ ; }, mesh = {Humans ; *Erythrocytes/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism/blood ; *Biomarkers/metabolism/blood ; Oxidative Stress ; Animals ; Alzheimer Disease/diagnosis/metabolism/blood ; }, abstract = {BACKGROUND: Red blood cells (RBCs) are usually considered simple cells and transporters of gases to tissues.

HYPOTHESIS: However, recent research has suggested that RBCs may have diagnostic potential in major neurodegenerative disorders (NDDs).

RESULTS: This review summarizes the current knowledge on changes in RBC in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other NDDs. It discusses the deposition of neuronal proteins like amyloid-β, tau, and α-synuclein, polyamines, changes in the proteins of RBCs like band-3, membrane transporter proteins, heat shock proteins, oxidative stress biomarkers, and altered metabolic pathways in RBCs during neurodegeneration. It also highlights the comparison of RBC diagnostic markers to other in-market diagnoses and discusses the challenges in utilizing RBCs as diagnostic tools, such as the need for standardized protocols and further validation studies.

SIGNIFICANCE STATEMENT: The evidence suggests that RBCs have diagnostic potential in neurodegenerative disorders, and this study can pave the foundation for further research which may lead to the development of novel diagnostic approaches and treatments.}, } @article {pmid38821351, year = {2024}, author = {Pocock, J and Vasilopoulou, F and Svensson, E and Cosker, K}, title = {Microglia and TREM2.}, journal = {Neuropharmacology}, volume = {257}, number = {}, pages = {110020}, doi = {10.1016/j.neuropharm.2024.110020}, pmid = {38821351}, issn = {1873-7064}, mesh = {Humans ; *Microglia/metabolism ; *Receptors, Immunologic/metabolism/genetics ; *Membrane Glycoproteins/metabolism/genetics ; Animals ; Neurodegenerative Diseases/metabolism/pathology/genetics ; Induced Pluripotent Stem Cells/metabolism ; Phagocytosis/physiology ; }, abstract = {TREM2 is a membrane receptor solely expressed on microglia in normal brain. In this review we outline recent advances in TREM2 biology and its implications for microglial function, with particular emphasis on findings from iPSC-derived microglia (iMG) expressing TREM2 loss-of-function mutations. Alterations in receptor proximal and distal signalling underlie TREM2 risk variants linked to neurodegenerative disease, principally NH-linked FTD, and late-onset AD, but emerging data suggest roles for TREM2 in PD, MS and ALS. TREM2 downstream functions include phagocytosis of myelin debris, amyloid beta peptides, and phosphatidylserine-expressing cells (resulting from damage or stress). Microglial survival, migration, DAMP signalling, inflammasome activation, and intercellular signalling including tau spreading via exosomes, as well as roles for sTREM2 in protection and as a biomarker are discussed. The role of TREM2 in metabolic homeostasis, and immunometabolic switching are discussed regarding microglial responses to damage and protection. The use of iPSC models to investigate the role of TREM2 in AD, PD, MS, ALS, and other neurodegenerative diseases could prove invaluable due to their ability to recapitulate human pathology, allowing a full understanding of TREM2 and microglial involvement in the underlying disease mechanisms and progression. This article is part of the Special Issue on "Microglia".}, } @article {pmid38820331, year = {2025}, author = {Dessie, G and Li, J and Nghiem, S and Doan, T}, title = {Prevalence and Determinants of Stunting-Anemia and Wasting-Anemia Comorbidities and Micronutrient Deficiencies in Children Under 5 in the Least-Developed Countries: A Systematic Review and Meta-analysis.}, journal = {Nutrition reviews}, volume = {83}, number = {2}, pages = {e178-e194}, doi = {10.1093/nutrit/nuae063}, pmid = {38820331}, issn = {1753-4887}, support = {//Australia National University/ ; }, mesh = {Humans ; Prevalence ; *Micronutrients/deficiency ; *Growth Disorders/epidemiology ; Child, Preschool ; Infant ; *Developing Countries/statistics & numerical data ; *Comorbidity ; Wasting Syndrome/epidemiology/etiology ; Anemia/epidemiology/etiology ; Female ; }, abstract = {CONTEXT: Despite shifting from addressing isolated forms of malnutrition to recognizing its multifaceted nature, evidence on the prevalence and determinants of micronutrient deficiencies, and their coexistence with undernutrition in children under 5, remains insufficient, unsystematic, and incohesive.

OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the prevalence and determinants of stunting-anemia and wasting-anemia comorbidities and micronutrient deficiencies in children under 5 in the least-developed countries (LDCs).

DATA SOURCES: Electronic searches took place from January 15, 2023, to February 14, 2024, across multiple databases, including PubMed, Embase, Web of Science, SCOPUS, African Index Medicus (AIM), World Health Organization's Institutional Repository for Information Sharing (IRIS), and African Journals Online. The search spanned the years 2000 to 2024, yet it yielded eligible full-text English research articles from only 2005 to 2021 conducted in LDCs. Studies lacking quantitative data on malnutrition types and their determinants were excluded.

DATA EXTRACTION: Two independent authors assessed articles for bias and quality using Hoy et al's 10-item scale and Newcastle-Ottawa Scale (NOS) criteria. Prevalence and other details were extracted using a Joanna Briggs Institute Excel template. Authors extracted adjusted odds ratios (aORs) for determinant factors such as sex and vitamin A and iron supplementation.

DATA ANALYSIS: The search yielded 6248 articles from 46 LDCs. Sixty-nine articles, with a total sample size of 181 605, met inclusion criteria for the final meta-analysis. Vitamin A deficiency affected 16.32% of children, and iodine deficiency affected 43.41% of children. The pooled prevalence of wasting-anemia and stunting-anemia comorbidity was 5.44% and 19.47%, respectively. Stunting was associated with vitamin A deficiency (aOR: 1.54; 95% CI: 1.01-2.37), and not taking vitamin A supplementation was associated with iron-deficiency anemia (aOR: 1.37; 95% CI: 1.21-1.55).

CONCLUSION: A significant proportion of children under 5 in LDCs experienced stunting-anemia and wasting-anemia comorbidities and micronutrient deficiencies. This study underscores the urgent need to address factors driving these burdens.

PROSPERO registration no. CRD42023409483.}, } @article {pmid38820149, year = {2024}, author = {Montañana-Rosell, R and Selvan, R and Hernández-Varas, P and Kaminski, JM and Sidhu, SK and Ahlmark, DB and Kiehn, O and Allodi, I}, title = {Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS.}, journal = {Science advances}, volume = {10}, number = {22}, pages = {eadk3229}, pmid = {38820149}, issn = {2375-2548}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Animals ; *Motor Neurons/metabolism/pathology ; *Disease Models, Animal ; Mice ; *Interneurons/metabolism/pathology ; *Spinal Cord/pathology/metabolism ; *Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Disease Progression ; Nerve Degeneration/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1[G93A] mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.}, } @article {pmid38819717, year = {2024}, author = {Tappenden, P and Hardiman, O and Kwon, SH and Mon-Yee, M and Galvin, M and McDermott, C and , }, title = {A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies.}, journal = {PharmacoEconomics}, volume = {42}, number = {9}, pages = {1003-1016}, pmid = {38819717}, issn = {1179-2027}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy/drug therapy ; Humans ; *Cost-Benefit Analysis ; *Quality-Adjusted Life Years ; United Kingdom ; *Models, Economic ; Disease Progression ; Biomedical Technology/economics ; Technology Assessment, Biomedical ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon.

OBJECTIVES: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective.

METHODS: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness.

RESULTS: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness.

CONCLUSIONS: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.}, } @article {pmid38819491, year = {2024}, author = {Juarez, D and Handal-Silva, A and Morán-Perales, JL and Torres-Cifuentes, DM and Flores, G and Treviño, S and Moreno-Rodriguez, A and Guevara, J and Diaz, A}, title = {New insights into sodium phenylbutyrate as a pharmacotherapeutic option for neurological disorders.}, journal = {Synapse (New York, N.Y.)}, volume = {78}, number = {4}, pages = {e22301}, doi = {10.1002/syn.22301}, pmid = {38819491}, issn = {1098-2396}, support = {IN214117//PAPITT-UNAM/ ; DIFA-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; TEMS-NAT24-G//Vicerrectoría de Investigación y Estudios de Posgrado, Benemérita Universidad Autónoma de Puebla/ ; }, mesh = {Humans ; *Phenylbutyrates/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Neurological disorders (NDs) are diseases of the central and peripheral nervous systems that affect more than one billion people worldwide. The risk of developing an ND increases with age due to the vulnerability of the different organs and systems to genetic, environmental, and social changes that consequently cause motor and cognitive deficits that disable the person from their daily activities and individual and social productivity. Intrinsic factors (genetic factors, age, gender) and extrinsic factors (addictions, infections, or lifestyle) favor the persistence of systemic inflammatory processes that contribute to the evolution of NDs. Neuroinflammation is recognized as a common etiopathogenic factor of ND. The study of new pharmacological options for the treatment of ND should focus on improving the characteristic symptoms and attacking specific molecular targets that allow the delay of damage processes such as neuroinflammation, oxidative stress, cellular metabolic dysfunction, and deregulation of transcriptional processes. In this review, we describe the possible role of sodium phenylbutyrate (NaPB) in the pathogenesis of Alzheimer's disease, hepatic encephalopathy, aging, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis; in addition, we describe the mechanism of action of NaPB and its beneficial effects that have been shown in various in vivo and in vitro studies to delay the evolution of any ND.}, } @article {pmid38819416, year = {2024}, author = {Finsterer, J}, title = {Sleep Disorders Can Only be a Risk Factor for Breathing Disorders in Amyotrophic Lateral Sclerosis if All Other Risk Factors are Excluded.}, journal = {Annals of Indian Academy of Neurology}, volume = {27}, number = {4}, pages = {450-451}, pmid = {38819416}, issn = {0972-2327}, } @article {pmid38819224, year = {2024}, author = {Shen, J and Gu, X and Xiao, C and Yan, H and Feng, Y and Li, X}, title = {Genome-wide association analysis reveals potential genetic correlation and causality between circulating inflammatory proteins and amyotrophic lateral sclerosis.}, journal = {Aging}, volume = {16}, number = {11}, pages = {9470-9484}, pmid = {38819224}, issn = {1945-4589}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Mendelian Randomization Analysis ; Genetic Pleiotropy ; Inflammation/genetics/blood ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease, continues to elude complete comprehension of its pathological underpinnings. Recent focus on inflammation in ALS pathogenesis prompts this investigation into the genetic correlation and potential causal relationships between circulating inflammatory proteins and ALS.

METHODS: Genome-wide association study (GWAS) data encompassing 91 circulating inflammatory protein measures from 14,824 individuals of European ancestry, alongside records from 27,205 ALS cases and 110,881 controls, were employed. Assessment of genetic correlation and overlap utilized LD score regression (LDSC), high-definition likelihood (HDL), and genetic analysis integrating pleiotropy and annotation (GPA) methodologies. Identification of shared genetic loci involved pleiotropy analysis, functional mapping and annotation (FUMA), and co-localization analysis. Finally, Mendelian randomization was applied to probe causal relationships between inflammatory proteins and ALS.

RESULTS: Our investigation revealed significant genetic correlation and overlap between ALS and various inflammatory proteins, including C-C motif chemokine 28, Interleukin-18, C-X-C motif chemokine 1, and Leukemia inhibitory factor receptor (LIFR). Pleiotropy analysis uncovered shared variations at specific genetic loci, some of which bore potential harm. Mendelian randomization analysis suggested that alterations in specific inflammatory protein levels, notably LIFR, could impact ALS risk.

CONCLUSIONS: Our findings uncover a genetic correlation between certain circulating inflammatory proteins and ALS, suggesting their possible causal involvement in ALS pathogenesis. Moreover, the identification of LIFR as a crucial protein may yield new insights into ALS pathomechanisms and offer a promising avenue for therapeutic interventions. These discoveries provide novel perspectives for advancing the comprehension of ALS pathophysiology and exploring potential therapeutic avenues.}, } @article {pmid38818523, year = {2024}, author = {Shen, J and Wang, X and Wang, M and Zhang, H}, title = {Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1337442}, pmid = {38818523}, issn = {1664-042X}, abstract = {Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.}, } @article {pmid38817709, year = {2024}, author = {Ghaderi, S and Batouli, SAH and Kalra, S and Mohammadi, S and Fatehi, F}, title = {A 65-year-old woman with ALS and bilateral precentral motor band sign.}, journal = {Clinical case reports}, volume = {12}, number = {6}, pages = {e9014}, pmid = {38817709}, issn = {2050-0904}, abstract = {Advanced MRI techniques, including SWI, MinIP, and QSM, are instrumental in detecting the "motor band sign" in ALS, aiding in the early diagnosis and assessment of upper motor neuron involvement, which is critical for therapeutic interventions.}, } @article {pmid38817347, year = {2024}, author = {Du, R and Zhu, Y and Chen, P and Li, M and Zhang, Y and Huang, X}, title = {Causal association between obstructive sleep apnea and amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1357070}, pmid = {38817347}, issn = {1663-4365}, abstract = {BACKGROUND: Obstructive sleep apnea (OSA) had a high prevalence in the population. Whether OSA increases the risk of amyotrophic lateral sclerosis (ALS) is unknown. Our aim was to clarify this issue using two-sample Mendelian randomization (MR) analysis in a large cohort.

METHODS: Two-sample MR was used to evaluate the potential causality between OSA and ALS by selecting single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was chosen as the primary method to estimate causal association. Weighted median, weighted mode and simple mode methods were used as sensitivity analyses to ensure the robustness of the results.

RESULTS: In MR analysis, IVW mode showed genetic liability to OSA was found to be significantly associated with a higher ALS risk (OR, 1.220; 95% confidence interval, 1.031-1.443; p = 0.021). No evidence of heterogeneity and horizontal pleiotropy were suggested.

CONCLUSION: We found potential evidence for a causal effect of OSA on an increased risk of ALS.}, } @article {pmid38816946, year = {2024}, author = {Karas, M and Olsen, J and Straczkiewicz, M and Johnson, SA and Burke, KM and Iwasaki, S and Lahav, A and Scheier, ZA and Clark, AP and Iyer, AS and Huang, E and Berry, JD and Onnela, JP}, title = {Tracking amyotrophic lateral sclerosis disease progression using passively collected smartphone sensor data.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {6}, pages = {1380-1392}, pmid = {38816946}, issn = {2328-9503}, support = {//The research reported in this paper was financially supported in part by a grant from Mitsubishi Tanabe Pharma Holdings America, Inc. (MTPHA)./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Smartphone ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; *Accelerometry/instrumentation ; Mobile Applications ; Walking/physiology ; Exercise/physiology ; }, abstract = {BACKGROUND: Passively collected smartphone sensor data provide an opportunity to study physical activity and mobility unobtrusively over long periods of time and may enable disease monitoring in people with amyotrophic lateral sclerosis (PALS).

METHODS: We enrolled 63 PALS who used Beiwe mobile application that collected their smartphone accelerometer and GPS data and administered the self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey. We identified individual steps from accelerometer data and used the Activity Index to summarize activity at the minute level. Walking, Activity Index, and GPS outcomes were then aggregated into day-level measures. We used linear mixed effect models (LMMs) to estimate baseline and monthly change for ALSFRS-RSE scores (total score, subscores Q1-3, Q4-6, Q7-9, Q10-12) and smartphone sensor data measures, as well as the associations between them.

FINDINGS: The analytic sample (N = 45) was 64.4% male with a mean age of 60.1 years. The mean observation period was 292.3 days. The ALSFRS-RSE total score baseline mean was 35.8 and had a monthly rate of decline of -0.48 (p-value <0.001). We observed statistically significant change over time and association with ALSFRS-RSE total score for four smartphone sensor data-derived measures: walking cadence from top 1 min and log-transformed step count, step count from top 1 min, and Activity Index from top 1 min.

INTERPRETATION: Smartphone sensors can unobtrusively track physical changes in PALS, potentially aiding disease monitoring and future research.}, } @article {pmid38816580, year = {2024}, author = {Wu, Y and Zheng, W and Xu, G and Zhu, L and Li, Z and Chen, J and Wang, L and Chen, S}, title = {C9orf72 controls hepatic lipid metabolism by regulating SREBP1 transport.}, journal = {Cell death and differentiation}, volume = {31}, number = {8}, pages = {1070-1084}, pmid = {38816580}, issn = {1476-5403}, mesh = {Humans ; *C9orf72 Protein/metabolism/genetics ; *Lipid Metabolism ; *Sterol Regulatory Element Binding Protein 1/metabolism/genetics ; Animals ; *Endoplasmic Reticulum/metabolism ; *Liver/metabolism ; Monomeric GTP-Binding Proteins/metabolism/genetics ; Mice ; COP-Coated Vesicles/metabolism ; Vesicular Transport Proteins/metabolism/genetics ; Lipogenesis/genetics ; }, abstract = {Sterol regulatory element binding transcription factors (SREBPs) play a crucial role in lipid homeostasis. They are processed and transported to the nucleus via COPII, where they induce the expression of lipogenic genes. COPII maintains the homeostasis of organelles and plays an essential role in the protein secretion pathways in eukaryotes. The formation of COPII begins at endoplasmic reticulum exit sites (ERES), and is regulated by SEC16A, which provides a platform for the assembly of COPII. However, there have been few studies on the changes in SEC16A protein levels. The repetitive expansion of the hexanucleotide sequence GGGGCC within the chromosome 9 open reading frame 72 (C9orf72) gene is a prevalent factor in the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we found that the absence of C9orf72 leads to a decrease in SEC16A protein levels, resulting in reduced localization of the guanine nucleotide exchange factor SEC12 at the ERES. Consequently, the small GTP binding protein SAR1 is unable to bind the endoplasmic reticulum normally, impairing the assembly of COPII. Ultimately, the disruption of SREBPs transport decreases de novo lipogenesis. These results suggest that C9orf72 acts as a novel role in regulating lipid homeostasis and may serve as a potential therapeutic target for obesity.}, } @article {pmid38816479, year = {2024}, author = {Mathis, S and Beauvais, D and Duval, F and Solé, G and Le Masson, G}, title = {The various forms of hereditary motor neuron disorders and their historical descriptions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3978-3990}, pmid = {38816479}, issn = {1432-1459}, mesh = {Humans ; *Motor Neuron Disease/history/genetics ; History, 20th Century ; History, 19th Century ; Spastic Paraplegia, Hereditary/genetics/history ; }, abstract = {Motor neuron disorders comprise a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons (including both sporadic and hereditary diseases), affecting the upper motor neurons, lower motor neurons, or both. Hereditary motor neuron disorders themselves represent a vast and heterogeneous group, with numerous clinical and genetic overlaps that can be a source of error. This narrative review aims at providing an overview of the main types of inherited motor neuron disorders by recounting the stages in their historical descriptions. For practical purposes, this review of the literature sets out their various clinical characteristics and updates the list of all the genes involved in the various forms of inherited motor neuron disorders, including spinal muscular atrophy, familial amyotrophic lateral sclerosis, hereditary spastic paraplegia, distal hereditary motor neuropathies/neuronopathies, Kennedy's disease, riboflavin transporter deficiencies, VCPopathy and the neurogenic scapuloperoneal syndrome.}, } @article {pmid38814545, year = {2024}, author = {Sun, S and Chen, Y and Zhao, B and Zhu, J and Wen, T and Peng, B and Ren, Q and Sun, X and Lin, P and Zhang, D and Liu, S}, title = {Abnormal brain functional network dynamics in amyotrophic lateral sclerosis patients with depression.}, journal = {Brain imaging and behavior}, volume = {18}, number = {5}, pages = {1034-1043}, pmid = {38814545}, issn = {1931-7565}, support = {2020M672067//China postdoctoral science foundation/ ; NSFC82001354//National natural science foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/psychology/complications/diagnostic imaging ; Female ; Male ; *Magnetic Resonance Imaging/methods ; Middle Aged ; *Brain/physiopathology/diagnostic imaging ; *Depression/physiopathology/diagnostic imaging ; *Nerve Net/physiopathology/diagnostic imaging ; Adult ; Neural Pathways/physiopathology/diagnostic imaging ; Aged ; Brain Mapping/methods ; }, abstract = {Since depression is common in amyotrophic lateral sclerosis (ALS) patients, we aimed to explore the specific brain functional network dynamics in ALS patients with depression (ALS-D) compared with healthy controls (HCs) and ALS patients without depressive symptoms (ALS-ND). According to the DSM-V, 32 ALS-D patients were selected from a large and newly diagnosed ALS cohort. Then, 32 demographic- and cognitive-matched ALS-ND patients were also selected, and 64 HCs were recruited. These participants underwent resting-state fMRI scans, and functional connectivity state analysis and dynamic graph theory were applied to evaluate brain functional network dynamics. Moreover, the Hamilton Depression Rating Scale (HDRS) was used to quantify depressive symptoms in the ALS-D patients. Four distinct states were identified in the ALS-D patients and controls. Compared with that in HCs, the fraction rate (FR) in state 2 was significantly decreased in ALS-D patients, and the FR in state 4 was significantly increased in ALS-D patients. Compared with that of HCs, the dwell time in state 4 was significantly increased in the ALS-D patients. Moreover, compared with that in the ALS-D patients, the FR in state 3 was significantly decreased in the ALS-ND patients. Among the ALS-D patients, there was the suggestion of a positive association between HDRS scores and dwell time of state 4, but this association did not reach statistical significance (r = 0.354; p = 0.055). Depression is an important feature of ALS patients, and we found a special pattern of brain functional network dynamics in ALS-D patients. Our findings may play an important role in understanding the mechanism underlying depression in ALS patients and help develop therapeutic interventions for depressed ALS patients.}, } @article {pmid38814471, year = {2024}, author = {Costantino, I and Meng, A and Ravits, J}, title = {Alternatively spliced ELAVL3 cryptic exon 4a causes ELAVL3 downregulation in ALS TDP-43 proteinopathy.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {93}, pmid = {38814471}, issn = {1432-0533}, support = {T32 AG066596/AG/NIA NIH HHS/United States ; P30 NS047101/RG/CSR NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; R21 NS121805/NS/NINDS NIH HHS/United States ; T32 AG066596/RG/CSR NIH HHS/United States ; R21 NS121805/RG/CSR NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Alternative Splicing/genetics ; *Exons/genetics ; *Down-Regulation ; TDP-43 Proteinopathies/genetics/pathology/metabolism ; Male ; Female ; Middle Aged ; DNA-Binding Proteins ; }, } @article {pmid38813817, year = {2024}, author = {Sprunger, ML and Jackrel, ME}, title = {The role of Matrin-3 in physiology and its dysregulation in disease.}, journal = {Biochemical Society transactions}, volume = {52}, number = {3}, pages = {961-972}, pmid = {38813817}, issn = {1470-8752}, support = {F31 NS120512/NS/NINDS NIH HHS/United States ; R21 AG080393/AG/NIA NIH HHS/United States ; R35 GM128772/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *RNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Nuclear Matrix-Associated Proteins/metabolism ; *Frontotemporal Dementia/metabolism/genetics ; DNA-Binding Proteins/metabolism ; Animals ; DNA Damage ; RNA-Binding Protein FUS/metabolism/chemistry ; }, abstract = {The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These proteins serve many important roles in the cell, and their capacity to form biomolecular condensates (BMCs) is key to their function, but also a vulnerability that can lead to misregulation and disease. Matrin-3 (MATR3) is an intrinsically disordered RBP implicated both genetically and pathologically in ALS/FTD, though it is relatively understudied as compared with TDP-43 and FUS. In addition to binding RNA, MATR3 also binds DNA and is implicated in many cellular processes including the DNA damage response, transcription, splicing, and cell differentiation. It is unclear if MATR3 localizes to BMCs under physiological conditions, which is brought further into question due to its lack of a prion-like domain. Here, we review recent studies regarding MATR3 and its roles in numerous physiological processes, as well as its implication in a range of diseases.}, } @article {pmid38813358, year = {2024}, author = {Finsterer, J}, title = {A positive effect of Cerebrolysin on motor functions and spasticity in ALS with limb or bulbar onset is questionable.}, journal = {Journal of medicine and life}, volume = {17}, number = {2}, pages = {242}, pmid = {38813358}, issn = {1844-3117}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscle Spasticity/drug therapy ; *Amino Acids/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, } @article {pmid38813353, year = {2024}, author = {Firstenfeld, AJ}, title = {A positive effect of Cerebrolysin on motor functions and spasticity in ALS with limb or bulbar onset is questionable.}, journal = {Journal of medicine and life}, volume = {17}, number = {2}, pages = {243}, pmid = {38813353}, issn = {1844-3117}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscle Spasticity/drug therapy ; *Amino Acids/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; }, } @article {pmid38812975, year = {2024}, author = {Fu, J and Lai, X and Wei, Q and Chen, X and Shang, H}, title = {Associations of cerebrospinal fluid profiles with severity and mortality risk of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1375892}, pmid = {38812975}, issn = {1662-4548}, abstract = {BACKGROUND: The relationship between routine cerebrospinal fluid (CSF) testing and the disease phenotype of amyotrophic lateral sclerosis (ALS) is unclear, and there are some contradictions in current studies.

METHODS: This study aimed to analyze the relationship between CSF profiles and disease phenotype in ALS patients. We collected 870 ALS patients and 96 control subjects admitted to West China Hospital of Sichuan University. CSF microprotein, albumin, IgG, index of IgG (IgGindex), albumin quotient (QALB), and serum IgG were examined.

RESULTS: In ALS patients, CSF IgG, and QALB were significantly increased, while CSF IgGindex was decreased, compared with control subjects. Approximately one-third of ALS patients had higher CSF IgG levels. The multiple linear regression analysis identified that CSF IgGindex was weakly negatively associated with ALS functional rating scale revised (ALSFRS-R) scores (β = -0.062, p = 0.041). This significance was found in male ALS but not in female ALS. The Cox survival analyses found that upregulated CSF IgG was significantly associated with the increased mortality risk in ALS [HR = 1.219 (1.010-1.470), p = 0.039].

CONCLUSION: In the current study, the higher CFS IgG was associated with increased mortality risk of ALS. CSF IgGindex may be associated with the severity of ALS. These findings may be sex-specific.}, } @article {pmid38812793, year = {2024}, author = {Jadhav, SP}, title = {MicroRNAs in microglia: deciphering their role in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1391537}, pmid = {38812793}, issn = {1662-5102}, abstract = {This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia, as the resident immune cells of the central nervous system (CNS), are pivotal in maintaining neural homeostasis and responding to pathological changes. Recent studies have highlighted the significance of miRNAs, small non-coding RNA molecules, in regulating microglial functions. In neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), dysregulated miRNA expression in microglia contributes to disease progression through various mechanisms such regulation of gene expression, as modulation of cytokine response and phagocytosis. This review synthesizes current knowledge on how miRNAs influence microglial activation, cytokine production, and phagocytic activity. Specific miRNAs, such as miR-155, are explored for their roles in modulating microglial responses in the context of neuroinflammation and neurodegeneration. The study also discusses the impact of miRNA dysregulation on the transition of microglia from a neuroprotective to a neurotoxic phenotype, a critical aspect in the progression of neurodegenerative diseases.}, } @article {pmid38812789, year = {2024}, author = {Sidisky, JM and Winters, A and Caratenuto, R and Babcock, DT}, title = {Synaptic defects in a drosophila model of muscular dystrophy.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1381112}, pmid = {38812789}, issn = {1662-5102}, abstract = {Muscular dystrophies are a devastating class of diseases that result in a progressive loss of muscle integrity. Duchenne Muscular Dystrophy, the most prevalent form of Muscular Dystrophy, is due to the loss of functional Dystrophin. While much is known regarding destruction of muscle tissue in these diseases, much less is known regarding the synaptic defects that also occur in these diseases. Synaptic defects are also among the earliest hallmarks of neurodegenerative diseases, including the neuromuscular disease Amyotrophic Lateral Sclerosis (ALS). Our current study investigates synaptic defects within adult muscle tissues as well as presynaptic motor neurons in Drosophila dystrophin mutants. Here we demonstrate that the progressive, age-dependent loss of flight ability in dystrophin mutants is accompanied by disorganization of Neuromuscular Junctions (NMJs), including impaired localization of both presynaptic and postsynaptic markers. We show that these synaptic defects, including presynaptic defects within motor neurons, are due to the loss of Dystrophin specifically within muscles. These results should help to better understand the early synaptic defects preceding cell loss in neuromuscular disorders.}, } @article {pmid38811997, year = {2024}, author = {Huang, M and Liu, YU and Yao, X and Qin, D and Su, H}, title = {Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {28}, pmid = {38811997}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/epidemiology/diagnosis ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.}, } @article {pmid38811858, year = {2024}, author = {Benatar, M and Wuu, J and Huey, ED and McMillan, CT and Petersen, RC and Postuma, R and McHutchison, C and Dratch, L and Arias, JJ and Crawley, A and Houlden, H and McDermott, MP and Cai, X and Thakur, N and Boxer, A and Rosen, H and Boeve, BF and Dacks, P and Cosentino, S and Abrahams, S and Shneider, N and Lingor, P and Shefner, J and Andersen, PM and Al-Chalabi, A and Turner, MR and , }, title = {Publisher Correction: The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {6}, pages = {377}, doi = {10.1038/s41582-024-00978-4}, pmid = {38811858}, issn = {1759-4766}, support = {K01 AG057796/AG/NIA NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; U01 AG079850/AG/NIA NIH HHS/United States ; }, } @article {pmid38809826, year = {2024}, author = {Krajewski, E and Lee, J and Viswanathan, N and Olmstead, A and Simmons, Z}, title = {The Effects of Interactive Context on Acoustic Characteristics of Speech in People With Dysarthria: A Preliminary Study.}, journal = {American journal of speech-language pathology}, volume = {33}, number = {4}, pages = {1952-1964}, doi = {10.1044/2024_AJSLP-23-00372}, pmid = {38809826}, issn = {1558-9110}, mesh = {Humans ; *Dysarthria/etiology/physiopathology/diagnosis ; Male ; Female ; *Speech Acoustics ; Middle Aged ; Aged ; *Speech Production Measurement ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Phonetics ; Speech Intelligibility ; Voice Quality ; Preliminary Data ; Sound Spectrography ; Time Factors ; Aged, 80 and over ; Acoustics ; }, abstract = {PURPOSE: The current study compared temporal and spectral acoustic contrast between vowel segments produced by speakers with dysarthria across three speech tasks-interactive, solo habitual, and solo clear.

METHOD: Nine speakers with dysarthria secondary to amyotrophic lateral sclerosis participated in the study. Each speaker was paired with a typical interlocutor over videoconferencing software. The speakers produced the vowels /i, ɪ, ɛ, æ/ in /h/-vowel-/d/ words. For the solo tasks, speakers read the stimuli aloud in both their habitual and clear speaking styles. For the interactive task, speakers produced a target stimulus for their interlocutor to select among the four possibilities. We measured the duration difference between long and short vowels, as well as the F1/F2 Euclidean distance between adjacent vowels, and also determined how well the vowels could be classified based on their acoustic characteristics.

RESULTS: Temporal contrast between long and short vowels was higher in the interactive task than in both solo tasks. Spectral distance between adjacent vowel pairs was also higher for some pairs in the interactive task than the habitual speech task. Finally, vowel classification accuracy was highest in the interactive task.

CONCLUSIONS: Overall, we found evidence that individuals with dysarthria produced vowels with greater acoustic contrast in structured interactions than they did in solo tasks. Furthermore, the speech adjustments they made to the vowel segments differed from those observed in solo speech.}, } @article {pmid38809531, year = {2024}, author = {Yang, CN and Chen, WL and Yeh, HH and Chu, HS and Wu, JH and Hsieh, YT}, title = {Convolutional Neural Network-Based Prediction of Axial Length Using Color Fundus Photography.}, journal = {Translational vision science & technology}, volume = {13}, number = {5}, pages = {23}, pmid = {38809531}, issn = {2164-2591}, mesh = {Humans ; Male ; Female ; *Neural Networks, Computer ; Middle Aged ; Adult ; *Photography/methods ; Aged ; *Axial Length, Eye/diagnostic imaging ; Fundus Oculi ; Young Adult ; Aged, 80 and over ; }, abstract = {PURPOSE: To develop convolutional neural network (CNN)-based models for predicting the axial length (AL) using color fundus photography (CFP) and explore associated clinical and structural characteristics.

METHODS: This study enrolled 1105 fundus images from 467 participants with ALs ranging from 19.91 to 32.59 mm, obtained at National Taiwan University Hospital between 2020 and 2021. The AL measurements obtained from a scanning laser interferometer served as the gold standard. The accuracy of prediction was compared among CNN-based models with different inputs, including CFP, age, and/or sex. Heatmaps were interpreted by integrated gradients.

RESULTS: Using age, sex, and CFP as input, the mean ± standard deviation absolute error (MAE) for AL prediction by the model was 0.771 ± 0.128 mm, outperforming models that used age and sex alone (1.263 ± 0.115 mm; P < 0.001) and CFP alone (0.831 ± 0.216 mm; P = 0.016) by 39.0% and 7.31%, respectively. The removal of relatively poor-quality CFPs resulted in a slight MAE reduction to 0.759 ± 0.120 mm without statistical significance (P = 0.24). The inclusion of age and CFP improved prediction accuracy by 5.59% (P = 0.043), while adding sex had no significant improvement (P = 0.41). The optic disc and temporal peripapillary area were highlighted as the focused areas on the heatmaps.

CONCLUSIONS: Deep learning-based prediction of AL using CFP was fairly accurate and enhanced by age inclusion. The optic disc and temporal peripapillary area may contain crucial structural information for AL prediction in CFP.

TRANSLATIONAL RELEVANCE: This study might aid AL assessments and the understanding of the morphologic characteristics of the fundus related to AL.}, } @article {pmid38809094, year = {2024}, author = {Gafni, R and Nassar, JA and Matzrafi, M and Blank, L and Eizenberg, H}, title = {Unraveling the reasons for failure to control Amaranthus albus: insights into herbicide application at different growth stages, temperature effect, and herbicide resistance on a regional scale.}, journal = {Pest management science}, volume = {80}, number = {9}, pages = {4757-4769}, doi = {10.1002/ps.8192}, pmid = {38809094}, issn = {1526-4998}, support = {132187417//Chief Scientist, Israel Ministry of Agriculture and Rural Development/ ; }, mesh = {*Amaranthus/drug effects/growth & development/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Temperature ; *Acetolactate Synthase/metabolism/genetics ; Weed Control/methods ; Israel ; Triazines ; }, abstract = {BACKGROUND: This study investigates factors contributing Amaranthus albus control failure in processing tomato fields in northern Israel. The study region is characterized by a significant climate gradient from east to west, providing the opportunity to investigate the effect of critical elements of the agricultural environment, e.g., temperature. Eight populations were collected from commercial fields in this region. Post-emergence herbicide efficacy of metribuzin, a photosystem II inhibitor, and rimsulfuron, an acetolactate synthase (ALS) inhibitor, was assessed through dose-response analyses at various growth stages. Temperature effects on control efficacy and resistance mechanisms were also explored.

RESULTS: Standard metribuzin dose (X) was ineffective on A. albus plants with more than six true-leaves, whereas 2X dose proved effective. Rimsulfuron at 16X dose was ineffective on plants with more than four true-leaves. We report here the first case of target site resistance to ALS inhibitors in A. albus, due to point mutation in the ALS gene (Pro197 to Leu). Furthermore, our findings suggest potential involvement of CYT P450 enzymes in enhanced metabolizing of rimsulfuron. An overall decrease in dry weight was observed in response to both herbicides at 16/22 °C (P < 0.0001). Rimsulfuron was effective against only one population when applied at 28/34 °C. A possible fitness cost associated with target site-resistant biotypes was observed under low temperature conditions, leading to effective control.

CONCLUSION: This regional-scale study highlights the challenges faced by growers, emphasizes the need for adapting management practices to the local climatic conditions and lays the groundwork for implementing location-specific weed management strategies in commercial fields. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.}, } @article {pmid38808993, year = {2024}, author = {Solomon, B}, title = {Bone marrow-derived microglia confer neuroprotection to a mouse model of amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {19}, number = {12}, pages = {2586-2587}, pmid = {38808993}, issn = {1673-5374}, } @article {pmid38807398, year = {2024}, author = {Kekenadze, M and Kvirkvelia, N and Beridze, M and Vashadze, S}, title = {SEROTONIN AND AMYOTROPHIC LATERAL SCLEROSIS.}, journal = {Georgian medical news}, volume = {}, number = {348}, pages = {87-90}, pmid = {38807398}, issn = {1512-0112}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Serotonin/metabolism ; Middle Aged ; Female ; Male ; Adult ; Aged ; Aged, 80 and over ; Adolescent ; Motor Neurons/pathology ; Electromyography ; Magnetic Resonance Imaging ; }, abstract = {Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Does serotonin (5-HT) play a role in progression or development of disease is under the research. The topic of the present paper is pressing as there is no data available regarding the spread of amyotrophic lateral sclerosis. It is also noteworthy that previous studies have indicated that the pathogenesis of ALS is closely linked to 5-hydroxytryptamine (5-HT). The clinical research was conducted in Georgia. During the last five years, 60 patients from different parts of Georgia have been studied, searched, and examined by us. Including from Samegrolo, Kartli, Adjara, Abkhazia, Guria, Kakheti regions. The Georgian Neurologists Corps participated and helped us in finding patients. Brain MRI and electromyography were also performed. 60 patients with different forms of ALS participated in the study, including 34 (56.66%) men and 26 (43.33%) women. Their age ranges from 30 to 81 years. The study was conducted after obtaining the written consent of the patients, taking into account the ethical requirements for the study. We also compared the results of the serotonin level of patients with amyotrophic lateral sclerosis with a control group of 20 people (aged 18 to 50 years) who had no neurological disease in past medical history. Patients of the first group, with LMN damage, are observed with decreased amount of serotonin (61.3) %, compared to other pairs, followed by patients of the upper neuron and bulbar syndrome groups, the level of serotonin in the control group is quite high. Thus, the level of serotonin in the group of patients with bulbar events is higher than in the other groups. Low serotonin requires further investigation. According to our research, the longer the anamnesis of amyotrophic lateral sclerosis patients is, the lower the level of serotonin is observed. It should also be taken into account that a low level of serotonin may be due to the presence of depression, which requires additional research. We speculate that 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.}, } @article {pmid38807021, year = {2024}, author = {Rahimian, S and Najafi, H and Webber, CA and Jalali, H}, title = {Advances in Exosome-Based Therapies for the Repair of Peripheral Nerve Injuries.}, journal = {Neurochemical research}, volume = {49}, number = {8}, pages = {1905-1925}, pmid = {38807021}, issn = {1573-6903}, mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Peripheral Nerve Injuries/therapy/metabolism ; Animals ; Nerve Regeneration/physiology ; }, abstract = {Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.}, } @article {pmid38806659, year = {2024}, author = {Xie, C and Chen, G and Li, M and Huang, P and Chen, Z and Lei, K and Li, D and Wang, Y and Cleetus, A and Mohamed, MA and Sonar, P and Feng, W and Ökten, Z and Ou, G}, title = {Neurons dispose of hyperactive kinesin into glial cells for clearance.}, journal = {The EMBO journal}, volume = {43}, number = {13}, pages = {2606-2635}, pmid = {38806659}, issn = {1460-2075}, support = {31991191//MOST | National Natural Science Foundation of China (NSFC)/ ; 32200612//MOST | National Natural Science Foundation of China (NSFC)/ ; 32071191//MOST | National Natural Science Foundation of China (NSFC)/ ; 31971160//MOST | National Natural Science Foundation of China (NSFC)/ ; 2019YFA0508401//MOST | National Key Research and Development Program of China (NKPs)/ ; XDB37020302//Strategic Priority Research Program of CAS/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Kinesins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Neuroglia/metabolism ; *Cilia/metabolism ; Neurons/metabolism ; Mutation ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; }, abstract = {Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins.}, } @article {pmid38806131, year = {2024}, author = {Oliveira, D and Assoni, AF and Alves, LM and Sakugawa, A and Melo, US and Teles E Silva, AL and Sertie, AL and Caires, LC and Goulart, E and Ghirotto, B and Carvalho, VM and Ferrari, MR and Zatz, M}, title = {ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons.}, journal = {Neurobiology of disease}, volume = {198}, number = {}, pages = {106540}, doi = {10.1016/j.nbd.2024.106540}, pmid = {38806131}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Mitochondria/metabolism/genetics/pathology ; Male ; *Protein Serine-Threonine Kinases/genetics/metabolism ; Female ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Proteostasis/genetics ; Middle Aged ; Mutation, Missense ; Adult ; }, abstract = {Vaccinia-related kinase 1 (VRK1) is a gene which has been implicated in the pathological process of a broad range of neurodevelopmental disorders as well as neuropathies, such as Amyotrophic Lateral Sclerosis (ALS). Here we report a family presenting ALS in an autosomal recessive mode of inheritance, segregating with a homozygous missense mutation located in VRK1 gene (p.R321C; Arg321Cys). Proteomic analyses from iPSC-derived motor neurons identified 720 proteins eligible for subsequent investigation, and our exploration of protein profiles revealed significant enrichments in pathways such as mTOR signaling, E2F, MYC targets, DNA repair response, cell proliferation and energetic metabolism. Functional studies further validated such alterations, showing that affected motor neurons presented decreased levels of global protein output, ER stress and downregulation of mTOR signaling. Mitochondrial alterations also pointed to decreased reserve capacity and increased non-mitochondrial oxygen consumption. Taken together, our results present the main pathological alterations associated with VRK1 mutation in ALS.}, } @article {pmid38805448, year = {2024}, author = {Fernandes, APM and Holanda, LJ and Lucena, LC and Silva, KERD and Lopes, ACSM and Borges, DT and Nagem, DAP and Valentim, RAM and Bougrain, L and Rodrigues Lindquist, AR}, title = {Electromyography as a tool to motion analysis for people with Amyotrophic Lateral Sclerosis: A protocol for a systematic review.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0302479}, pmid = {38805448}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; *Electromyography/methods ; Systematic Reviews as Topic ; Muscle, Skeletal/physiopathology ; Movement/physiology ; Biomechanical Phenomena ; }, abstract = {Biomechanical analysis of human movement plays an essential role in understanding functional changes in people with Amyotrophic Lateral Sclerosis (ALS), providing information on muscle impairment. Studies suggest that surface electromyography (sEMG) may be able to quantify muscle activity, identify levels of fatigue, assess muscle strength, and monitor variation in limb movement. In this article, a systematic review protocol will analyze the psychometric properties of the sEMG regarding the clinical data on the skeletal muscles of people with ALS. This protocol uses the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodological tool. A specific field structure was defined to reach each phase. Nine scientific databases (PubMed, Web of Science, Embase, Elsevier, IEEE, Google Scholar, SciELO, PEDro, LILACS E CENTRAL) were searched. The framework developed will extract data (i.e. study information, sample information, sEMG information, intervention, and outcomes) from the selected studies using a rigorous approach. The data will be described quantitatively using frequency and trend analysis methods, and heterogeneity between the included studies will be assessed using the I2 test. The risk of bias will be summarized using the most recent prediction model risk of bias assessment tool. Be sure to include relevant statistics here, such as sample sizes, response rates, P values or Confidence Intervals. Be specific (by stating the value) rather than general (eg, "there were differences between the groups"). This protocol will map out the construction of a systematic review that will identify and synthesize the advances in movement analysis of people with ALS through sEMG, using data extracted from articles.}, } @article {pmid38805282, year = {2024}, author = {Bell, AM and Utting, C and Dickie, AC and Kucharczyk, MW and Quillet, R and Gutierrez-Mecinas, M and Razlan, ANB and Cooper, AH and Lan, Y and Hachisuka, J and Weir, GA and Bannister, K and Watanabe, M and Kania, A and Hoon, MA and Macaulay, IC and Denk, F and Todd, AJ}, title = {Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {23}, pages = {e2314213121}, pmid = {38805282}, issn = {1091-6490}, support = {BB/S017178/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; 204820/Z/16/Z//Wellcome Trust (WT)/ ; MR/W004739/1//UKRI | Medical Research Council (MRC)/ ; MR/T01072X/1/MRC_/Medical Research Council/United Kingdom ; BBS/E/T/000PR9816//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; MR/V033638/1//UKRI | Medical Research Council (MRC)/ ; 219433/Z/19/Z//Wellcome Trust (WT)/ ; MR/V033638/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; SGL025\1079//Academy of Medical Sciences (The Academy of Medical Sciences)/ ; BB/CCG1720/1//UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; MR/W002426/1//UKRI | Medical Research Council (MRC)/ ; MR/T01072X/1//UKRI | Medical Research Council (MRC)/ ; ZIADE000721-22//HHS | NIH | National Institute of Dental and Craniofacial Research (NIDCR)/ ; MRF-160-0015-ELP-DENK-C0844//UKRI | MRC | Medical Research Foundation/ ; }, mesh = {Animals ; Mice ; *Homeodomain Proteins/genetics/metabolism ; Spinal Cord/cytology/metabolism ; Neurons/metabolism ; High-Throughput Nucleotide Sequencing ; Male ; Cell Nucleus/metabolism/genetics ; Transcription Factors/genetics/metabolism ; }, abstract = {The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch, and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here, we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify three clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 and ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons.}, } @article {pmid38805054, year = {2024}, author = {Beswick, E and Christides, A and Symonds, A and Johnson, M and Fawcett, T and Newton, J and Lyle, D and Weaver, C and Chandran, S and Pal, S}, title = {Exploratory study to evaluate the acceptability of a wearable accelerometer to assess motor progression in motor neuron disease.}, journal = {Journal of neurology}, volume = {271}, number = {8}, pages = {5083-5101}, pmid = {38805054}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Motor Neuron Disease/physiopathology/diagnosis ; Aged ; *Wearable Electronic Devices ; *Accelerometry/instrumentation ; *Disease Progression ; Patient Acceptance of Health Care ; Surveys and Questionnaires/standards ; }, abstract = {Motor neuron disease (MND) is a rapidly progressive condition traditionally assessed using a questionnaire to evaluate physical function, the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Its use can be associated with poor sensitivity in detecting subtle changes over time and there is an urgent need for more sensitive and specific outcome measures. The ActiGraph GT9X is a wearable device containing multiple sensors that can be used to provide metrics that represent physical activity. The primary aim of this study was to investigate the initial suitability and acceptability of limb-worn wearable devices to group of people with MND in Scotland. A secondary aim was to explore the preliminary associations between the accelerometer sensor data within the ActiGraph GT9X and established measures of physical function. 10 participants with MND completed a 12-week schedule of assessments including fortnightly study visits, both in-person and over videoconferencing software. Participants wore the device on their right wrist and right ankle for a series of movements, during a 6-min walking test and for a period of 24-h wear, including overnight. Participants also completed an ALSFRS-R and questionnaires on their experience with the devices. 80% of the participants found wearing these devices to be a positive experience and no one reported interference with daily living or added burden. However, 30% of the participants experienced technical issues with their devices. Data from the wearable devices correlated with established measures of physical function.}, } @article {pmid38805053, year = {2024}, author = {Bjelica, B and Bartels, MB and Hesebeck-Brinckmann, J and Petri, S}, title = {Non-motor symptoms in patients with amyotrophic lateral sclerosis: current state and future directions.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {3953-3977}, pmid = {38805053}, issn = {1432-1459}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/complications ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of both upper and lower motor neurons. A defining histopathological feature in approximately 97% of all ALS cases is the accumulation of phosphorylated trans-activation response (TAR) DNA-binding protein 43 protein (pTDP-43) aggregates in the cytoplasm of neurons and glial cells within the central nervous system. Traditionally, it was believed that the accumulation of TDP-43 aggregates and subsequent neurodegeneration primarily occurs in motor neurons. However, contemporary evidence suggests that as the disease progresses, other systems and brain regions are also affected. Despite this, there has been a limited number of clinical studies assessing the non-motor symptoms in ALS patients. These studies often employ various outcome measures, resulting in a wide range of reported frequencies of non-motor symptoms in ALS patients. The importance of assessing the non-motor symptoms reflects in a fact that they have a significant impact on patients' quality of life, yet they frequently go underdiagnosed and unreported during clinical evaluations. This review aims to provide an up-to-date overview of the current knowledge concerning non-motor symptoms in ALS. Furthermore, we address their diagnosis and treatment in everyday clinical practice.}, } @article {pmid38802624, year = {2024}, author = {Riva, N and Domi, T and Pozzi, L and Lunetta, C and Schito, P and Spinelli, EG and Cabras, S and Matteoni, E and Consonni, M and Bella, ED and Agosta, F and Filippi, M and Calvo, A and Quattrini, A}, title = {Update on recent advances in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4693-4723}, pmid = {38802624}, issn = {1432-1459}, support = {IDEALS//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; Marazzina Project//Marazzina Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; }, abstract = {In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients.}, } @article {pmid38802492, year = {2024}, author = {Watanabe, S and Amporndanai, K and Awais, R and Latham, C and Awais, M and O'Neill, PM and Yamanaka, K and Hasnain, SS}, title = {Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {12118}, pmid = {38802492}, issn = {2045-2322}, support = {WA1198//ALS Association/ ; }, mesh = {*Superoxide Dismutase-1/genetics/metabolism ; Animals ; *Organoselenium Compounds/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism ; *Isoindoles/pharmacology ; Mice ; *Azoles/pharmacology ; Humans ; Mice, Transgenic ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1[G93A] mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1[G93A] mice clearly indicating functional improvement.}, } @article {pmid38802184, year = {2024}, author = {Vucic, S and de Carvalho, M and Bashford, J and Alix, JJP}, title = {Contribution of neurophysiology to the diagnosis and monitoring of ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {87-118}, doi = {10.1016/bs.irn.2024.04.001}, pmid = {38802184}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Transcranial Magnetic Stimulation/methods ; *Electromyography/methods ; *Neurophysiology/methods ; Disease Progression ; Motor Cortex/physiopathology ; }, abstract = {This chapter describes the role of neurophysiological techniques in diagnosing and monitoring amyotrophic lateral sclerosis (ALS). Despite many advances, electromyography (EMG) remains a keystone investigation from which to build support for a diagnosis of ALS, demonstrating the pathophysiological processes of motor unit hyperexcitability, denervation and reinnervation. We consider development of the different diagnostic criteria and the role of EMG therein. While not formally recognised by established diagnostic criteria, we discuss the pioneering studies that have demonstrated the diagnostic potential of transcranial magnetic stimulation (TMS) of the motor cortex and highlight the growing evidence for TMS in the diagnostic process. Finally, accurately monitoring disease progression is crucial for the successful implementation of clinical trials. Neurophysiological measures of disease state have been incorporated into clinical trials for over 20 years and we review prominent techniques for assessing disease progression.}, } @article {pmid38802183, year = {2024}, author = {Moll, T and Harvey, C and Alhathli, E and Gornall, S and O'Brien, D and Cooper-Knock, J}, title = {Non-coding genome contribution to ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {75-86}, doi = {10.1016/bs.irn.2024.04.002}, pmid = {38802183}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; Animals ; Genetic Predisposition to Disease/genetics ; }, abstract = {The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. This limits the development of targeted genetic therapies which require an understanding of patient-specific genetic drivers. There is good evidence that the majority of these missing genetic risk factors are likely to be found within the non-coding genome. However, a major challenge in the discovery of non-coding risk variants is determining which variants are functional in which specific CNS cell type. We summarise current discoveries of ALS-associated genetic drivers within the non-coding genome and we make the case that improved cell-specific annotation of genomic function is required to advance this field, particularly via single-cell epigenetic profiling and spatial transcriptomics. We highlight the example of TBK1 where an apparent paradox exists between pathogenic coding variants which cause loss of protein function, and protective non-coding variants which cause reduced gene expression; the paradox is resolved when it is understood that the non-coding variants are acting primarily via change in gene expression within microglia, and the effect of coding variants is most prominent in neurons. We propose that cell-specific functional annotation of ALS-associated genetic variants will accelerate discovery of the genetic architecture underpinning disease in the vast majority of patients.}, } @article {pmid38802182, year = {2024}, author = {Al-Chalabi, A and Andrews, J and Farhan, S}, title = {Recent advances in the genetics of familial and sporadic ALS.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {49-74}, doi = {10.1016/bs.irn.2024.04.007}, pmid = {38802182}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease/genetics ; }, abstract = {ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.}, } @article {pmid38802181, year = {2024}, author = {De Cock, L and Bercier, V and Van Den Bosch, L}, title = {New developments in pre-clinical models of ALS to guide translation.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {477-524}, doi = {10.1016/bs.irn.2024.04.008}, pmid = {38802181}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/therapy ; Animals ; *Disease Models, Animal ; Humans ; Translational Research, Biomedical/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder in which selective death of motor neurons leads to muscle weakness and paralysis. Most research has focused on understanding and treating monogenic familial forms, most frequently caused by mutations in SOD1, FUS, TARDBP and C9orf72, although ALS is mostly sporadic and without a clear genetic cause. Rodent models have been developed to study monogenic ALS, but despite numerous pre-clinical studies and clinical trials, few disease-modifying therapies are available. ALS is a heterogeneous disease with complex underlying mechanisms where several genes and molecular pathways appear to play a role. One reason for the high failure rate of clinical translation from the current models could be oversimplification in pre-clinical studies. Here, we review advances in pre-clinical models to better capture the heterogeneous nature of ALS and discuss the value of novel model systems to guide translation and aid in the development of precision medicine.}, } @article {pmid38802180, year = {2024}, author = {Shelkovnikova, TA and Hautbergue, GM}, title = {RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {455-479}, doi = {10.1016/bs.irn.2024.04.009}, pmid = {38802180}, issn = {2162-5514}, support = {MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Ribonucleoproteins/metabolism ; Animals ; *Cytoplasmic Granules/metabolism ; Neurodegenerative Diseases/metabolism ; Organelles/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase-separated complexes, ribonucleoprotein (RNP) granules, have come into the limelight as "crucibles" of neuronal pathology in ALS. RNP granules are indispensable for the multitude of regulatory processes underlying cellular RNA metabolism and serve as critical organisers of cellular biochemistry. Neurons, highly specialised cells, heavily rely on RNP granules for efficient trafficking, signalling and stress responses. Multiple RNP granule components, primarily RBPs such as TDP-43 and FUS, are affected by ALS mutations. However, even in the absence of mutations, RBP proteinopathies represent pathophysiological hallmarks of ALS. Given the high local concentrations of RBPs and RNAs, their weakened or enhanced interactions within RNP granules disrupt their homeostasis. Thus, the physiological process of phase separation and RNP granule formation, vital for maintaining the high-functioning state of neuronal cells, becomes their Achilles heel. Here, we will review the recent literature on the causes and consequences of abnormal RNP granule functioning in ALS and related disorders. In particular, we will summarise the evidence for the network-level dysfunction of RNP granules in these conditions and discuss considerations for therapeutic interventions to target RBPs, RNP granules and their network as a whole.}, } @article {pmid38802179, year = {2024}, author = {Pandya, VA and Patani, R}, title = {The role of glial cells in amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {381-450}, doi = {10.1016/bs.irn.2024.04.005}, pmid = {38802179}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/therapy ; Humans ; *Neuroglia/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.}, } @article {pmid38802177, year = {2024}, author = {Lee, J and Pye, N and Ellis, L and Vos, K and Mortiboys, H}, title = {Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {269-325}, doi = {10.1016/bs.irn.2024.04.006}, pmid = {38802177}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Mitochondria/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Oxidative Stress/physiology ; }, abstract = {Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable of utilising a multitude of cellular substrates in an array of ATP-generating reactions. With reactive oxygen species (ROS) production occurring during some of these reactions, mitochondria can contribute considerably to oxidative stress. Mitochondria are also very dynamic organelles, interacting with other organelles, undergoing fusion/fission in response to changing metabolic states and being turned over by the cell regularly. Disruptions to many of these mitochondrial functions and processes have been reported in ALS models, largely indicating compromised mitochondrial function, increased ROS production by mitochondria, disrupted interactions with the endoplasmic reticulum and reduced turnover. This chapter summarises methods routinely used to assess mitochondria in ALS models and the alterations that have been reported in these models.}, } @article {pmid38802176, year = {2024}, author = {Castelli, L and Vasta, R and Allen, SP and Waller, R and Chiò, A and Traynor, BJ and Kirby, J}, title = {From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {209-268}, doi = {10.1016/bs.irn.2024.02.001}, pmid = {38802176}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/therapy ; *Systems Biology/methods ; *Genomics/methods ; Proteomics/methods ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.}, } @article {pmid38802175, year = {2024}, author = {Malaspina, A}, title = {Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {171-207}, doi = {10.1016/bs.irn.2024.04.010}, pmid = {38802175}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis/genetics/metabolism/drug therapy ; *Biomarkers ; *Clinical Trials as Topic/methods ; }, abstract = {Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.}, } @article {pmid38802174, year = {2024}, author = {Hobson, E and McDermott, C}, title = {Advances in symptom management and in monitoring disease progression in motor neuron disease.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {119-169}, doi = {10.1016/bs.irn.2024.04.004}, pmid = {38802174}, issn = {2162-5514}, mesh = {Humans ; *Motor Neuron Disease/therapy/physiopathology ; *Disease Progression ; Disease Management ; Quality of Life ; }, abstract = {The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.}, } @article {pmid38802173, year = {2024}, author = {Van Es, MA}, title = {Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.}, journal = {International review of neurobiology}, volume = {176}, number = {}, pages = {1-47}, doi = {10.1016/bs.irn.2024.04.011}, pmid = {38802173}, issn = {2162-5514}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/pathology/physiopathology ; Diagnosis, Differential ; Frontotemporal Dementia/diagnosis/genetics/physiopathology/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.}, } @article {pmid38799643, year = {2024}, author = {Xu, S and Ma, Q and Shen, J and Li, N and Sun, S and Wang, N and Chen, Y and Dong, C and Tam, KY and Prehn, JHM and Wang, H and Ying, Z}, title = {ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.}, journal = {Acta pharmaceutica Sinica. B}, volume = {14}, number = {5}, pages = {2026-2038}, pmid = {38799643}, issn = {2211-3835}, abstract = {Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.}, } @article {pmid38798695, year = {2024}, author = {Conforti, FL and Renton, AE and Houlden, H}, title = {Editorial: Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia volume II.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1420029}, doi = {10.3389/fgene.2024.1420029}, pmid = {38798695}, issn = {1664-8021}, } @article {pmid38798645, year = {2024}, author = {Landry, C and Costanzo, J and Mitne-Neto, M and Zatz, M and Schaffer, A and Hatzoglou, M and Muotri, A and Miranda, HC}, title = {Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.13.594000}, pmid = {38798645}, issn = {2692-8205}, abstract = {Vesicle-associated membrane protein-associated protein-B (VAPB) is an ER membrane bound protein. VAPB P56S causes a dominant, familial form of amyotrophic lateral sclerosis (ALS), however, the mechanism through which this mutation causes motor neuron (MN) disease remains unknown. Using inducible wild type (WT) and VAPB P56S expressing iPSC-derived MNs we show that VAPB P56S, but not WT, protein decreased neuronal firing and mitochondrial-ER contact (MERC) with an associated age-dependent decrease in mitochondrial membrane potential (MMP); all typical characteristics of MN-disease. We further show that VAPB P56S expressing iPSC-derived MNs have enhanced age-dependent sensitivity to ER stress. We identified elevated expression of the master regulator of the Integrated Stress Response (ISR) marker ATF4 and decreased protein synthesis in the VAPB P56S iPSC-derived MNs. Chemical inhibition of ISR with the compound, ISRIB, rescued all MN disease phenotype in VAPB P56S MNs. Thus, our results not only support ISR inhibition as a potential therapeutic target for ALS patients, but also provides evidence to pathogenesis.}, } @article {pmid38798341, year = {2024}, author = {Provasek, VE and Bacolla, A and Rangaswamy, S and Mitra, J and Kodavati, M and Yusuf, IO and Malojirao, VH and Vasquez, V and Britz, GW and Li, GM and Xu, Z and Mitra, S and Garruto, RM and Tainer, JA and Hegde, ML}, title = {RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38798341}, issn = {2692-8205}, support = {R35 CA220430/CA/NCI NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; P01 CA092584/CA/NCI NIH HHS/United States ; R01 NS088645/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {TAR DNA-binding protein 43 (TDP43) is increasingly recognized for its involvement in neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 proteinopathy, characterized by dysregulated nuclear export and cytoplasmic aggregation, is present in most ALS/FTD cases and is associated with a loss of nuclear function and genomic instability in neurons. Building on prior evidence linking TDP43 pathology to DNA double-strand breaks (DSBs), this study identifies a novel regulatory role for TDP43 in the DNA mismatch repair (MMR) pathway. We demonstrate that depletion or overexpression of TDP43 affects the expression of key MMR genes, including MLH1, MSH6, MSH2, MSH3, and PMS2. Specifically, TDP43 modulates the expression of MLH1 and MSH6 proteins through alternative splicing and transcript stability. These findings are validated in ALS mice models, patient-derived neural progenitor cells and autopsied brain tissues from ALS patients. Furthermore, MMR depletion showed a partial rescue of TDP43-induced DNA damage in neuronal cells. Bioinformatics analysis of TCGA cancer database reveals significant correlations between TDP43 and MMR gene expressions and mutational burden across various cancer subtypes. These results collectively establish TDP43 as a critical regulator of the MMR pathway, with broad implications for understanding the genomic instability underlying neurodegenerative and neoplastic diseases.}, } @article {pmid38796984, year = {2024}, author = {Jiang, L and Tracey, TJ and Gill, MK and Howe, SL and Power, DT and Bharti, V and McCombe, PA and Henderson, RD and Steyn, FJ and Ngo, ST}, title = {Generation of human induced pluripotent stem cell lines from sporadic, sporadic frontotemporal dementia, familial SOD1, and familial C9orf72 amyotrophic lateral sclerosis (ALS) patients.}, journal = {Stem cell research}, volume = {78}, number = {}, pages = {103447}, doi = {10.1016/j.scr.2024.103447}, pmid = {38796984}, issn = {1876-7753}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Female ; Male ; Cell Line ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics.}, } @article {pmid38796647, year = {2024}, author = {Chong, NF and Van de Wouw, AP and Idnurm, A}, title = {The ilv2 gene, encoding acetolactate synthase for branched chain amino acid biosynthesis, is required for plant pathogenicity by Leptosphaeria maculans.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {682}, pmid = {38796647}, issn = {1573-4978}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Plant Diseases/microbiology ; *Herbicides/pharmacology ; *Amino Acids, Branched-Chain/biosynthesis/metabolism ; *Leptosphaeria/genetics/pathogenicity ; Mutation/genetics ; Fungal Proteins/genetics/metabolism ; Gene Editing/methods ; Plant Leaves/microbiology ; CRISPR-Cas Systems/genetics ; Brassica/microbiology ; Ascomycota/pathogenicity/genetics ; }, abstract = {BACKGROUND: Control of blackleg disease of canola caused by the fungus Leptosphaeria maculans relies on strategies such as the inhibition of growth with fungicides. However, other chemicals are used during canola cultivation, including fertilizers and herbicides. There is widespread use of herbicides that target the acetolactate synthase (ALS) enzyme involved in branched chain amino acid synthesis and low levels of these amino acids within leaves of Brassica species. In L. maculans the ilv2 gene encodes ALS and thus ALS-inhibiting herbicides may inadvertently impact the fungus.

METHODS AND RESULTS: Here, the impact of a commercial herbicide targeting ALS and mutation of the homologous ilv2 gene in L. maculans was explored. Exposure to herbicide had limited impact on growth in vitro but reduced lesion sizes in plant disease experiments. Furthermore, the mutation of the ilv2 gene via CRISPR-Cas9 gene editing rendered the fungus non-pathogenic.

CONCLUSION: Herbicide applications can influence disease outcome, but likely to a minor extent.}, } @article {pmid38795957, year = {2024}, author = {Bhushan, NL and Romano, CD and Gras-Najjar, J and Reno, J and Rockwood, N and Quattrone, W and Adams, ET and Kelly, B and McLeod, L and Bhavnani, SP and Bocell, FD and Campbell, M and Kontson, K and Reasner, D and Zhang, C and Retzky, S}, title = {Remote-Use Applications of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Clinical Outcome Assessment Tool: A Scoping Review.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {27}, number = {10}, pages = {1454-1465}, doi = {10.1016/j.jval.2024.05.005}, pmid = {38795957}, issn = {1524-4733}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Humans ; *Outcome Assessment, Health Care/methods ; Telemedicine ; Severity of Illness Index ; Videoconferencing ; }, abstract = {OBJECTIVES: In 2021, the US Congress passed the Accelerating Access to Critical Therapies for Amyotrophic Lateral Sclerosis Act. The law encourages development of "tools, methods, and processes" to improve clinical trial efficiency for neurodegenerative diseases. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is an outcome measure administered during in-person clinic visits and used to support investigational studies for persons living with amyotrophic lateral sclerosis. Availability of a standardized, remote-use version of the ALSFRS-R may promote more inclusive, decentralized clinical trials. A scoping literature review was conducted to identify existing remote-use ALSFRS-R tools, synthesize feasibility and comparability of administration modes, and summarize barriers and facilitators to inform development of a standardized remote-use ALSFRS-R tool.

METHODS: Included studies reported comparisons between remote and in-person, clinician-reported, ALSFRS-R administration and were published in English (2002-2022). References were identified by searching peer-reviewed and gray literature. Twelve studies met the inclusion criteria and were analyzed to compare findings within and across modes of administration.

RESULTS: Remote modes of ALSFRS-R administration were categorized into 4 nonmutually exclusive categories: telephone (n = 6), videoconferencing (n = 3), computer or online platforms (n = 3), mobile applications and wearables (n = 2), and 1 unspecified telemedicine modality (n = 1). Studies comparing in-person to telephone or videoconferencing administration reported high ALSFRS-R rating correlations and nonsignificant between-mode differences.

CONCLUSIONS: There is insufficient information in the ALSFRS-R literature to support remote clinician administration for collecting high quality data. Future research should engage persons living with amyotrophic lateral sclerosis, care partners, and providers to develop a standardized remote-use ALSFRS-R version.}, } @article {pmid38795892, year = {2024}, author = {Ridho, MR and Lubis, MAR and Nawawi, DS and Fatriasari, W}, title = {Optimization of areca leaf sheath nanolignin synthesis by a mechanical method for in situ modification of ultra-low molar ratio urea-formaldehyde adhesives.}, journal = {International journal of biological macromolecules}, volume = {271}, number = {Pt 1}, pages = {132614}, doi = {10.1016/j.ijbiomac.2024.132614}, pmid = {38795892}, issn = {1879-0003}, mesh = {*Formaldehyde/chemistry ; *Adhesives/chemistry ; *Urea/chemistry ; Plant Leaves/chemistry ; Particle Size ; Lignin/chemistry ; }, abstract = {This study addresses the optimization of the nanolignin preparation method from the areca leaf sheath (ALS) by a mechanical process using a high shear homogenizer at 13,000-16,000 rpm for 1-4 h and its application in enhancing the performance of ultralow molar ratio urea-formaldehyde (UF) adhesive. Response surface methodology (RSM) with a central composite design (CCD) model was used to determine the optimum nanolignin preparation method. The mathematical model obtained was quadratic for the particle size response and linear for the zeta potential response. Under the optimum conditions, a speed of 16,000 rpm for 4 h resulted in a particle size of 227.7 nm and a zeta potential of -18.57 mV with a high desirability value of 0.970. FE-SEM revealed that the characteristic changes of lignin to nanolignin occur from an irregular or nonuniform shape to an oval shape with uniform particles. Nanolignin was introduced during the addition reaction of UF resin synthesis. UF modified with nanolignin (UF-NL) was analyzed for its adhesive characteristics, functional groups, crystallinity, and thermomechanical properties. The UF-NL adhesive had a slightly greater solid content (73.23 %) than the UF adhesive, a gelation time of 4.10 min, and a viscosity of 1066 mPa[.]s. The UF-NL adhesive had similar functional groups as the UF adhesive, with a lower crystallinity of 59.73 %. Compared with the control plywood which has a tensile shear strength value of 0.79 MPa, the plywood bonded with UF-NL had a greater tensile shear strength of 1.07 MPa, with a lower formaldehyde emission of 0.065 mg/L.}, } @article {pmid38795640, year = {2024}, author = {Li, Z and Zhang, Y and Ji, M and Wu, C and Zhang, Y and Ji, S}, title = {Targeting ferroptosis in neuroimmune and neurodegenerative disorders for the development of novel therapeutics.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {176}, number = {}, pages = {116777}, doi = {10.1016/j.biopha.2024.116777}, pmid = {38795640}, issn = {1950-6007}, mesh = {*Ferroptosis/drug effects/physiology ; Humans ; *Neurodegenerative Diseases/drug therapy/immunology/metabolism/pathology ; Animals ; Neuroimmunomodulation ; }, abstract = {Neuroimmune and neurodegenerative ailments impose a substantial societal burden. Neuroimmune disorders involve the intricate regulatory interactions between the immune system and the central nervous system. Prominent examples of neuroimmune disorders encompass multiple sclerosis and neuromyelitis optica. Neurodegenerative diseases result from neuronal degeneration or demyelination in the brain or spinal cord, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The precise underlying pathogenesis of these conditions remains incompletely understood. Ferroptosis, a programmed form of cell death characterised by lipid peroxidation and iron overload, plays a pivotal role in neuroimmune and neurodegenerative diseases. In this review, we provide a detailed overview of ferroptosis, its mechanisms, pathways, and regulation during the progression of neuroimmune and neurodegenerative diseases. Furthermore, we summarise the impact of ferroptosis on neuroimmune-related cells (T cells, B cells, neutrophils, and macrophages) and neural cells (glial cells and neurons). Finally, we explore the potential therapeutic implications of ferroptosis inhibitors in diverse neuroimmune and neurodegenerative diseases.}, } @article {pmid38795036, year = {2024}, author = {Chen, X and Cao, Z and Wang, Y}, title = {Amyotrophic Lateral Sclerosis-Associated Mutants of SOD1 Perturb mRNA Splicing through Aberrant Interactions with SRSF2.}, journal = {Analytical chemistry}, volume = {96}, number = {23}, pages = {9713-9720}, pmid = {38795036}, issn = {1520-6882}, support = {R35 ES031707/ES/NIEHS NIH HHS/United States ; }, mesh = {*Serine-Arginine Splicing Factors/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; *RNA Splicing ; *Mutation ; RNA, Messenger/genetics/metabolism ; HEK293 Cells ; Biotinylation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results in the degeneration of neurons in the brain and spinal cord. Although a substantial number of studies have been conducted, much remains to be learned about the cellular mechanisms underlying ALS. In this study, we employed an engineered ascorbate peroxidase (APEX)-based proximity biotinylation, together with affinity pull-down of the ensuing biotinylated peptides, to investigate the proximity proteomes of human SOD1 and its two ALS-linked mutants, G85R and G93A. We were able to identify 25 common biotinylated peptides with preferential enrichment in the proximity proteomes of SOD1[G85R] and SOD1[G93A] over wild-type SOD1. Our coimmunoprecipitation followed by Western blot analyses revealed that one of these proteins, SRSF2, binds more strongly with the two SOD1 mutants than its wild-type counterpart. We also observed aberrant splicing of mRNAs in cells with ectopic expression of the two SOD1 mutants relative to cells expressing the wild-type protein. In addition, the aberrations in splicing elicited by the SOD1 variants were markedly attenuated upon knockdown of SRSF2. Collectively, we uncovered that ALS-liked SOD1[G85R] and SOD1[G93A] mutants interact more strongly with SRSF2, where the aberrant interactions perturbed mRNA splicing. Thus, our work offered novel mechanistic insights into the contributions of the ALS-linked SOD1 mutants to disease etiology.}, } @article {pmid38791160, year = {2024}, author = {Bocheva, G and Bakalov, D and Iliev, P and Tafradjiiska-Hadjiolova, R}, title = {The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791160}, issn = {1422-0067}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Brain/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroprotection/drug effects ; *Neuroprotective Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Kynuramine/metabolism/analogs & derivatives ; }, abstract = {While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.}, } @article {pmid38791099, year = {2024}, author = {Moțățăianu, A and Mănescu, IB and Șerban, G and Bărcuțean, L and Ion, V and Bălașa, R and Andone, S}, title = {Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791099}, issn = {1422-0067}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI, Romania/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; *Islet Amyloid Polypeptide/metabolism/blood ; Cross-Sectional Studies ; *Biomarkers/blood ; *Insulin/metabolism/blood ; Disease Progression ; Leptin/blood/metabolism ; Glucagon-Like Peptide 1/metabolism/blood ; C-Peptide/blood/metabolism ; Ghrelin/metabolism/blood ; Glucagon/blood/metabolism ; Adult ; Hormones/metabolism/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.}, } @article {pmid38790984, year = {2024}, author = {Zhdanov, DD and Gladilina, YA and Blinova, VG and Abramova, AA and Shishparenok, AN and Eliseeva, DD}, title = {Induction of FoxP3 Pre-mRNA Alternative Splicing to Enhance the Suppressive Activity of Regulatory T Cells from Amyotrophic Lateral Sclerosis Patients.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790984}, issn = {2227-9059}, support = {23-24-00326//Russian Science Foundation/ ; }, abstract = {Forkhead box protein 3 (FoxP3) is a key transcription factor responsible for the development, maturation, and function of regulatory T cells (Tregs). The FoxP3 pre-mRNA is subject to alternative splicing, resulting in the translation of multiple splice variants. We have shown that Tregs from patients with amyotrophic lateral sclerosis (ALS) have reduced expression of full-length (FL) FoxP3, while other truncated splice variants are expressed predominantly. A correlation was observed between the reduced number of Tregs in the peripheral blood of ALS patients, reduced total FoxP3 mRNA, and reduced mRNA of its FL splice variant. Induction of FL FoxP3 was achieved using splice-switching oligonucleotides capable of base pairing with FoxP3 pre-mRNA and selectively modulating the inclusion of exons 2 and 7 in the mature mRNA. Selective expression of FL FoxP3 resulted in the induction of CD127[low], CD152, and Helios-positive cells, while the cell markers CD4 and CD25 were not altered. Such Tregs had an increased proliferative activity and a higher frequency of cell divisions per day. The increased suppressive activity of Tregs with the induced FL FoxP3 splice variant was associated with the increased synthesis of the pro-apoptotic granzymes A and B, and perforin, IL-10, and IL-35, which are responsible for contact-independent suppression, and with the increased ability to suppress telomerase in target cells. The upregulation of Treg suppressive and proliferative activity using splice-switching oligonucleotides to induce the predominant expression of the FoxP3 FL variant is a promising approach for regenerative cell therapy in Treg-associated diseases.}, } @article {pmid38790979, year = {2024}, author = {Mishra, PS and Phaneuf, D and Boutej, H and Picher-Martel, V and Dupre, N and Kriz, J and Julien, JP}, title = {Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS.}, journal = {Biomedicines}, volume = {12}, number = {5}, pages = {}, pmid = {38790979}, issn = {2227-9059}, support = {143275/CAPMC/CIHR/Canada ; 231575//Canada Research Chairs/ ; }, abstract = {The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.}, } @article {pmid38790450, year = {2024}, author = {Eisen, A and Pioro, EP and Goutman, SA and Kiernan, MC}, title = {Nanoplastics and Neurodegeneration in ALS.}, journal = {Brain sciences}, volume = {14}, number = {5}, pages = {}, pmid = {38790450}, issn = {2076-3425}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, abstract = {Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood-brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut-brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.}, } @article {pmid38788983, year = {2024}, author = {de Holanda Paranhos, L and Magalhães, RSS and de Araújo Brasil, A and Neto, JRM and Ribeiro, GD and Queiroz, DD and Dos Santos, VM and Eleutherio, ECA}, title = {The familial amyotrophic lateral sclerosis-associated A4V SOD1 mutant is not able to regulate aerobic glycolysis.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1868}, number = {8}, pages = {130634}, doi = {10.1016/j.bbagen.2024.130634}, pmid = {38788983}, issn = {1872-8006}, mesh = {*Glycolysis ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Superoxide Dismutase-1/genetics/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Glucose/metabolism ; Mutation ; }, abstract = {Under certain stress conditions, astrocytes operate in aerobic glycolysis, a process controlled by pyruvate dehydrogenase (PDH) inhibition through its E1 α subunit (Pda1) phosphorylation. This supplies lactate to neurons, which save glucose to obtain NADPH to, among other roles, counteract reactive oxygen species. A failure in this metabolic cooperation causes severe damage to neurons. In this work, using humanized Saccharomyces cerevisiae cells in which its endogenous Cu/Zn Superoxide Dismutase (SOD1) was replaced by human ortholog, we investigated the role of human SOD1 (hSOD1) in aerobic glycolysis regulation and its implications to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. Yeast cells ferment glucose even in the presence of oxygen and switch to respiratory metabolism after glucose exhaustion. However, like cells of SOD1-knockout strain, cells expressing A4V mutant of hSOD1 growing on glucose showed a respiratory phenotype, i.e., low glucose and high oxygen consumptions and low intracellular oxidation levels in response to peroxide stress, contrary to cells expressing wild-type (WT) SOD1 (yeast or human). The A4V mutation in hSOD1 is linked to ALS. In contrast to WT SOD1 strains, PDH activity of both sod1Δ and A4V hSOD1 cells did not change in response to a metabolic shift toward oxidative metabolism, which was associated to lower Pda1 phosphorylation levels under growth on glucose. Taken together, our results suggest that A4V mutant cannot regulate aerobic glycolysis via Pda1 phosphorylation the same way WT hSOD1, which might be linked to problems observed in the motor neurons of ALS patients with the SOD1 A4V mutation.}, } @article {pmid38788796, year = {2024}, author = {Togawa, N and Ayaki, T and Yoshii, D and Maki, T and Sawamoto, N and Takahashi, R}, title = {TMEM119-positive microglia were increased in the brains of patients with amyotrophic lateral sclerosis.}, journal = {Neuroscience letters}, volume = {833}, number = {}, pages = {137829}, doi = {10.1016/j.neulet.2024.137829}, pmid = {38788796}, issn = {1872-7972}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Microglia/metabolism/pathology ; Male ; Female ; Aged ; Middle Aged ; *Membrane Proteins/metabolism ; *Brain/pathology/metabolism ; Macrophages/metabolism/pathology ; Receptors, CCR2/metabolism ; White Matter/pathology/metabolism ; Spinal Cord/metabolism/pathology ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has been reported to be affected by inflammatory cells, such as microglia and macrophages, through the concept of non-cell autonomous neuronal death. Resident microglia in the human brain and monocyte-derived macrophages (MoDM) infiltrating in tissues are difficult to distinguish. Therefore, the effects of microglia and MoDMs in ALS remain poorly understood. This study aimed to investigate the role of resident microglia and MoDMs in the pathogenesis of ALS using postmortem brain and spinal cord samples. The samples used for immunohistochemical analysis included 11 cases of sporadic ALS and 11 age-matched controls. We stained the cells with TMEM119 to detect resident microglia and CCR2 to detect MoDMs. In ALS cases, TMEM119-immunopositive resident microglia were abundant in the motor cortex and subcortical white matter (SWM) of the motor area, whereas CCR2-immunopositive MoDM was similar to control cases. In addition, the mean density of CD68-immunopositive cells in the SWM significantly correlated with the mean density of pTDP-43-positive GCIs. These results suggest that resident microglial activation plays an important role in the cerebral pathogenesis of ALS and may provide novel therapeutic strategies to target excessive activation of resident microglia in ALS.}, } @article {pmid38788509, year = {2024}, author = {Valeriano, MC and Neto, AM and Batista, ACF and Mamián-López, MB}, title = {Raman spectra soft modeling of the biodiesel oxidation through evolving factor analysis & multivariate curve resolution.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {318}, number = {}, pages = {124498}, doi = {10.1016/j.saa.2024.124498}, pmid = {38788509}, issn = {1873-3557}, abstract = {The oxidative stability of biodiesel is defined by its relative resistance to the action of oxygen at room temperature. Its determination is an essential reference to the quality of biofuel and a significant parameter to be determined. This parameter concerns the quality of the biodiesel to be supplied to the consumer, and its determination is fundamental to maintaining the engine's proper functioning. Raman spectroscopy allows the rapid obtaining of structural information regarding biodiesel quality and, when aided by multivariate analysis methods, allows a quantitative determination of specific properties. This work uses Raman spectroscopy, Multivariate Curve Resolution with Alternative Least Squares (MCR-ALS) method, and Evolving Factor Analysis (EFA) to study biodiesel's oxidation kinetics. Also, the vibrational modes C = C, CH2, and CH3 were identified as the main structural groups involved in this process, corroborating previous studies. The MCR-ALS & EFA combination allowed modeling of the degradation kinetics following an A → B → C mechanism, where A corresponds to the biodiesel (starting material), B is related to the hydroperoxide mixture, and C is the final product. The results also suggested that this process follows a first-order reaction, with kinetic constant values of k1 = 0.0056 min[-1] and k2 = 0.0031 min[-1].}, } @article {pmid38788288, year = {2024}, author = {van Neerven, GJL and Schelling, WJ and van den Borne, K and Bijleveld, K and Baars, A and Flink, H and Gilissen, LPL}, title = {The periprocedural respiratory safety of propofol sedation in patients with a motor neuron disease undergoing percutaneous endoscopic gastrostomy insertion.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123049}, doi = {10.1016/j.jns.2024.123049}, pmid = {38788288}, issn = {1878-5883}, mesh = {Humans ; Male ; Female ; Aged ; *Gastrostomy/adverse effects/methods ; *Propofol/adverse effects/administration & dosage/therapeutic use ; Retrospective Studies ; *Motor Neuron Disease ; Middle Aged ; *Hypnotics and Sedatives/adverse effects ; Pneumonia, Aspiration/etiology ; Aged, 80 and over ; Enteral Nutrition/methods/adverse effects ; }, abstract = {Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS), may cause swallowing and respiratory problems, due to muscle weakness. Chronic enteral feeding via percutaneous endoscopic gastrostomy (PEG) is often indicated in these patients. PEG insertion is normally performed with sedation. Some guidelines withhold sedation in MND patients, due to the risk of respiratory complications. These guidelines seem to be defensive however and evidence is lacking. Our aim was to examine periprocedural respiratory complications occurring in MND patients undergoing PEG insertion with propofol sedation. A retrospective monocentre study was conducted in a referral hospital with an experienced PEG team. Patients with MND who underwent PEG insertion with propofol sedation between January 1. 2016 to January 1. 2023 were analysed to identify periprocedural respiratory complications. 46 patients were included. In five patients (10.9%) respiratory adverse events (AE) occurred, of which two serious (4.3%) and four AE (8.7%). Serious AE (SAE) were fatal in both cases: aspiration pneumonia (2.2%) and hypercapnia (2.2%) a few days after insertion. Sedation may have influenced the first case. Respiratory AE consisted of desaturation in two (4.3%), mild aspiration pneumonia in one (2.2%), and apnea in one patient (2.2%). Compared to previous studies respiratory complications and mortality had comparable prevalences.}, } @article {pmid38788085, year = {2024}, author = {Mohassel, P and Abdullah, M and Eichler, FS and Dunn, TM}, title = {Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {4}, pages = {735-747}, pmid = {38788085}, issn = {2214-3602}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Hereditary Sensory and Autonomic Neuropathies/genetics/metabolism/physiopathology ; *Neurodegenerative Diseases/metabolism ; *Neurodevelopmental Disorders ; *Serine C-Palmitoyltransferase/metabolism/genetics ; Spastic Paraplegia, Hereditary/genetics/metabolism ; Sphingolipids/metabolism ; }, abstract = {Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.}, } @article {pmid38787599, year = {2024}, author = {Wong, JPH and Blazev, R and Ng, YK and Goodman, CA and Montgomery, MK and Watt, KI and Carl, CS and Watt, MJ and Voldstedlund, CT and Richter, EA and Crouch, PJ and Steyn, FJ and Ngo, ST and Parker, BL}, title = {Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {10}, pages = {e23647}, doi = {10.1096/fj.202400045R}, pmid = {38787599}, issn = {1530-6860}, support = {APP2009642//DHAC | National Health and Medical Research Council (NHMRC)/ ; 1185427//DHAC | National Health and Medical Research Council (NHMRC)/ ; //University of Melbourne Driving Research Momentum/ ; //Motor Neurone Disease Research Australia Charcot/ ; //Department of Anatomy and Physiology (The University of Melbourne) ECR Seeding Grant/ ; }, mesh = {*Muscle, Skeletal/metabolism/pathology ; *Arginine/metabolism/analogs & derivatives ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Mice ; *Protein-Arginine N-Methyltransferases/metabolism/genetics ; Male ; Methylation ; Female ; Protein Processing, Post-Translational ; Mice, Inbred C57BL ; Proteome/metabolism ; }, abstract = {Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.}, } @article {pmid38786016, year = {2024}, author = {Salzinger, A and Ramesh, V and Das Sharma, S and Chandran, S and Thangaraj Selvaraj, B}, title = {Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {13}, number = {10}, pages = {}, pmid = {38786016}, issn = {2073-4409}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; *Motor Neurons/pathology/physiology ; Animals ; Nerve Net/physiopathology/pathology ; Neuromuscular Junction/physiopathology/pathology ; Disease Models, Animal ; Motor Cortex/physiopathology/pathology ; }, abstract = {The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.}, } @article {pmid38785754, year = {2024}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Tavakol-Afshari, J}, title = {Evaluation of the Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantations in ALS Patients by Investigating Patients' Specific Immunological and Biochemical Biomarkers.}, journal = {Diseases (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {38785754}, issn = {2079-9721}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors.

METHODS: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 × 106 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-α), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF).

RESULTS: Our study indicated that, in the case of immunological biomarkers, TNF-α levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05.

CONCLUSIONS: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.}, } @article {pmid38785539, year = {2024}, author = {Pribac, M and Motataianu, A and Andone, S and Mardale, E and Nemeth, S}, title = {Bridging the Gap: Harnessing Plant Bioactive Molecules to Target Gut Microbiome Dysfunctions in Amyotrophic Lateral Sclerosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4471-4488}, pmid = {38785539}, issn = {1467-3045}, abstract = {The correlation between neurodegenerative diseases and the gut microbiome is increasingly evident, with amyotrophic lateral sclerosis (ALS) being particularly notable for its severity and lack of therapeutic options. The gut microbiota, implicated in the pathogenesis and development of ALS, plays a crucial role in the disease. Bioactive plant molecules, specifically volatile compounds in essential oils, offer a promising therapeutic avenue due to their anti-inflammatory properties and gut-modulating effects. Our narrative review aimed to identify microbiota-associated bacteria in ALS and analyze the benefits of administering bioactive plant molecules as much-needed therapeutic options in the management of this disease. A comprehensive search of PubMed database articles published before December 2023, encompassing research on cell, human, and animal ALS models, was conducted. After selecting, analyzing, and discussing key articles, bacteria linked to ALS pathogenesis and physiopathology were identified. Notably, positively highlighted bacteria included Akkermansia muciniphila (Verrucomicrobia phylum), Faecalibacterium prausnitzii, and Butyrivibrio spp. (Firmicutes phylum). Conversely, members of the Escherichia coli spp. (Proteobacteria phylum) and Ruminococcus spp. (Firmicutes phylum) stood out negatively in respect to ALS development. These bacteria were associated with molecular changes linked to ALS pathogenesis and evolution. Bioactive plant molecules can be directly associated with improvements in the microbiome, due to their role in reducing inflammation and oxidative stress, emerging as one of the most promising natural agents for enriching present-day ALS treatments.}, } @article {pmid38785530, year = {2024}, author = {Serrano, PL and Rodrigues, TPV and Pinto, LD and Pereira, IC and Farias, IB and Cavalheiro, RBR and Mendes, PM and Peixoto, KO and Barile, JP and Seneor, DD and Correa Silva, EG and Oliveira, ASB and Pinto, WBVR and Sgobbi, P}, title = {Assessing Chitinases and Neurofilament Light Chain as Biomarkers for Adult-Onset Leukodystrophies.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4309-4323}, pmid = {38785530}, issn = {1467-3045}, abstract = {Leukodystrophies represent a large and complex group of inherited disorders affecting the white matter of the central nervous system. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare leukodystrophy which still needs the proper identification of diagnostic, prognostic, and monitoring biomarkers. The aim of this study was to determine the diagnostic and prognostic value of chitinases and neurofilament light chain as biomarkers for ALSP. A cross-sectional study was performed to analyze cerebrospinal fluid levels of chitinases (chitotriosidase and chitinase 3-like 2) and neurofilament light chain in five different groups: (i) normal health individuals; (ii) patients with definitive diagnosis of ALSP and genetic confirmation; (iii) asymptomatic patients with CSF1R variants; (iv) patients with other adult-onset leukodystrophies; and (v) patients with amyotrophic lateral sclerosis (external control group). Chitinase levels showed a statistical correlation with clinical assessment parameters in ALSP patients. Chitinase levels were also distinct between ALSP and the other leukodystrophies. Significant differences were noted in the levels of chitinases and neurofilament light chain comparing symptomatic (ALSP) and asymptomatic individuals with CSF1R variants. This study is the first to establish chitinases as a potential biomarker for ALSP and confirms neurofilament light chain as a good biomarker for primary microgliopathies.}, } @article {pmid38784406, year = {2024}, author = {Keselica, M and Peřan, D and Renza, M and Duška, F and Omáčka, D and Schnaubelt, S and Lulic, I and Sýkora, R}, title = {Efficiency of two-member crews in delivering prehospital advanced life support cardiopulmonary resuscitation: A scoping review.}, journal = {Resuscitation plus}, volume = {18}, number = {}, pages = {100661}, pmid = {38784406}, issn = {2666-5204}, abstract = {BACKGROUND: Advanced Life Support (ALS) during cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) is frequently administered by two-member crews. However, ALS CPR is mostly designed for larger crews, and the feasibility and efficacy of implementing ALS guidelines for only two rescuers remain unclear.

OBJECTIVE: This scoping review aims to examine the existing evidence and identify knowledge gaps in the efficiency of pre-hospital ALS CPR performed by two-member teams.

DESIGN: A comprehensive search was undertaken across the following databases: PubMed, Web of Science, SCOPUS, Cochrane Library Trials, and ClinicalTrials.gov. The search covered publications in English or German from January 1, 2005, to November 30, 2023. The review included studies that focused on ALS CPR procedures carried out by two-member teams in adult patients in either simulated or clinical settings.

RESULTS: A total of 22 articles were included in the qualitative synthesis. Seven topics in two-person prehospital ALS/CPR delivery were identified: 1) effect of team configuration on clinical outcome and CPR quality, 2) early airway management and ventilation techniques, 3) mechanical chest compressions, 4) prefilled syringes, 5) additional equipment, 6) adaptation of recommended ALS/CPR protocols, and 7) human factors.

CONCLUSION: There is a lack of comprehensive data regarding the adaptation of the recommended ALS algorithm in CPR for two-member crews. Although simulation studies indicate potential benefits arising from the employment of mechanical chest compression devices, prefilled syringes, and automation-assisted protocols, the current evidence is too limited to support specific modifications to existing guidelines.}, } @article {pmid38784093, year = {2024}, author = {Chen, W and Liu, X and Wan, P and Chen, Z and Chen, Y}, title = {Anti-artifacts techniques for neural recording front-ends in closed-loop brain-machine interface ICs.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1393206}, pmid = {38784093}, issn = {1662-4548}, abstract = {In recent years, thanks to the development of integrated circuits, clinical medicine has witnessed significant advancements, enabling more efficient and intelligent treatment approaches. Particularly in the field of neuromedical, the utilization of brain-machine interfaces (BMI) has revolutionized the treatment of neurological diseases such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. The BMI acquires neural signals via recording circuits and analyze them to regulate neural stimulator circuits for effective neurological treatment. However, traditional BMI designs, which are often isolated, have given way to closed-loop brain-machine interfaces (CL-BMI) as a contemporary development trend. CL-BMI offers increased integration and accelerated response speed, marking a significant leap forward in neuromedicine. Nonetheless, this advancement comes with its challenges, notably the stimulation artifacts (SA) problem inherent to the structural characteristics of CL-BMI, which poses significant challenges on the neural recording front-ends (NRFE) site. This paper aims to provide a comprehensive overview of technologies addressing artifacts in the NRFE site within CL-BMI. Topics covered will include: (1) understanding and assessing artifacts; (2) exploring the impact of artifacts on traditional neural recording front-ends; (3) reviewing recent technological advancements aimed at addressing artifact-related issues; (4) summarizing and classifying the aforementioned technologies, along with an analysis of future trends.}, } @article {pmid38782644, year = {2024}, author = {Corcia, P and Couratier, P and Ingre, C}, title = {Could PLS represent a UMN-predominant ALS syndrome?.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2024.04.006}, pmid = {38782644}, issn = {0035-3787}, abstract = {Primary lateral sclerosis (PLS) is a motor neuron condition marked by pure upper motor neuron (UMN) degeneration. PLS represents around 3% of all motor neuron diseases. Classically the prognosis of PLS is less severe than those of amyotrophic lateral sclerosis (ALS). This explains the necessity to distinguish both conditions as early as possible. The key hallmark between the two diseases is the involvement of the lower motor neuron (LMN) system which is classically considered spared in PLS contrary to ALS. Although it seemed clinically easy to distinguish PLS from ALS with the aid of clinical and complementary examinations, there is a large body of evidence highlighting that the LMN system might be impaired in PLS. This led us to suggest that PLS might be considered as an almost pure UMN ALS phenotype.}, } @article {pmid38782052, year = {2024}, author = {Bass, J and Hill, H and Jaworsky, C}, title = {Response to Green et al in reply to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {3}, pages = {e81}, doi = {10.1016/j.jaad.2024.05.038}, pmid = {38782052}, issn = {1097-6787}, mesh = {Humans ; *Dermoscopy ; Skin Neoplasms/pathology ; }, } @article {pmid38782041, year = {2024}, author = {Hogan, DB and Maxwell, CJ and Dampf, H and McGrail, K and Estabrooks, CA and Poss, JW and Bakal, JA and Hoben, M}, title = {Excess Deaths in Assisted Living and Nursing Homes during the COVID-19 Pandemic in Alberta, Canada.}, journal = {Journal of the American Medical Directors Association}, volume = {25}, number = {7}, pages = {105032}, doi = {10.1016/j.jamda.2024.105032}, pmid = {38782041}, issn = {1538-9375}, mesh = {Humans ; *COVID-19/mortality/epidemiology ; *Nursing Homes ; Alberta/epidemiology ; *Assisted Living Facilities ; Male ; Female ; Aged ; Retrospective Studies ; Aged, 80 and over ; SARS-CoV-2 ; Pandemics ; Dementia/mortality/epidemiology ; Homes for the Aged/statistics & numerical data ; Cognitive Dysfunction/mortality/epidemiology ; Mortality/trends ; }, abstract = {OBJECTIVES: Assisted living (AL) is a significant and growing congregate care option for vulnerable older adults designed to reduce the use of nursing homes (NHs). However, work on excess mortality in congregate care during the COVID-19 pandemic has primarily focused on NHs with only a few US studies examining AL. The objective of this study was to assess excess mortality among AL and NH residents with and without dementia or significant cognitive impairment in Alberta, Canada, during the first 2 years of the COVID-19 pandemic, relative to the 3 years before.

DESIGN: Population-based, retrospective cohort study.

SETTING AND PARTICIPANTS: Residents who lived in an AL or NH facility operated or contracted by the Provincial health care system to provide publicly funded care in Alberta between January 1, 2017, and December 31, 2021.

METHODS: We used administrative health care data, including Resident Assessment Instrument - Home Care (RAI-HC, AL) and Minimum Data Set 2.0 (RAI-MDS 2.0, NHs) records, linked with data on residents' vital statistics, COVID-19 testing, emergency room registrations, and hospital stays. The outcome was excess deaths during COVID-19 (ie, the number of deaths beyond that expected based on pre-pandemic data), estimated, using overdispersed Poisson generalized linear models.

RESULTS: Overall, the risk of excess mortality [adjusted incidence rate ratio (95% confidence interval)] was higher in ALs than in NHs [1.20 (1.14-1.26) vs 1.10 (1.07-1.13)]. Weekly peaks in excess deaths coincided with COVID-19 pandemic waves and were higher among those with diagnosed dementia or significant cognitive impairment in both, AL and NHs.

CONCLUSIONS AND IMPLICATIONS: Finding excess mortality within both AL and NH facilities should lead to greater focus on infection prevention and control measures across all forms of congregate housing for vulnerable older adults. The specific needs of residents with dementia in particular will have to be addressed.}, } @article {pmid38782015, year = {2024}, author = {Benatar, M and Hansen, T and Rom, D and Geist, MA and Blaettler, T and Camu, W and Kuzma-Kozakiewicz, M and van den Berg, LH and Morales, RJ and Chio, A and Andersen, PM and Pradat, PF and Lange, D and Van Damme, P and Mora, G and Grudniak, M and Elliott, M and Petri, S and Olney, N and Ladha, S and Goyal, NA and Meyer, T and Hanna, MG and Quinn, C and Genge, A and Zinman, L and Jabari, D and Shoesmith, C and Ludolph, AC and Neuwirth, C and Nations, S and Shefner, JM and Turner, MR and Wuu, J and Bennett, R and Dang, H and Sundgreen, C and , }, title = {Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {687-699}, doi = {10.1016/S1474-4422(24)00134-0}, pmid = {38782015}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; *Neuroprotective Agents/therapeutic use/adverse effects ; Treatment Outcome ; Adult ; Hydroxylamines/therapeutic use/adverse effects/pharmacology ; Oxadiazoles/therapeutic use/adverse effects ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.

METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.

FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).

INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.

FUNDING: Orphazyme.}, } @article {pmid38782014, year = {2024}, author = {Hardiman, O}, title = {Amyotrophic lateral sclerosis: a lesson in translation.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {651-653}, doi = {10.1016/S1474-4422(24)00223-0}, pmid = {38782014}, issn = {1474-4465}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Translational Research, Biomedical ; }, } @article {pmid38781481, year = {2025}, author = {Zeng, Y and Guo, R and Cao, S and Chavarria Gonzalez, S and Pang, K and Liu, C and Yang, H}, title = {Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis.}, journal = {Nutritional neuroscience}, volume = {28}, number = {1}, pages = {116-124}, doi = {10.1080/1028415X.2024.2352196}, pmid = {38781481}, issn = {1476-8305}, support = {G9815508/MRC_/Medical Research Council/United Kingdom ; MC_PC_15018/MRC_/Medical Research Council/United Kingdom ; MC_PC_19009/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Mendelian Randomization Analysis ; *Dietary Carbohydrates/administration & dosage ; Risk Factors ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Diet ; Dietary Fats/administration & dosage ; Dietary Proteins/administration & dosage ; }, abstract = {OBJECTIVES: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk.

METHODS: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses.

RESULTS: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy.

DISCUSSION: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required.}, } @article {pmid38780855, year = {2024}, author = {Burgio, F and Danesin, L and Wennberg, A and Tonini, E and Galetto, V and Sivieri, S and Giustiniani, A and Palmer, K and Meneghello, F and Sorarù, G and Zettin, M and Arcara, G and Benavides-Varela, S and Semenza, C}, title = {Financial and numerical abilities: patterns of dissociation in neurological and psychiatric diseases.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {10}, pages = {4779-4787}, pmid = {38780855}, issn = {1590-3478}, support = {GR-2018-12367927//Ministero della Salute/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Neuropsychological Tests ; Adult ; Aged ; Cognitive Dysfunction/etiology/physiopathology ; Mental Disorders/economics ; Schizophrenia/physiopathology/complications ; Brain Injuries, Traumatic/complications/psychology ; }, abstract = {The present work investigates whether financial abilities can be associated with numerical abilities and with general cognitive abilities. We compared performance on numerical and financial tests, and on tests routinely used to measure general cognitive performance, in healthy controls and in a group of people with heterogeneous pathological conditions including mild cognitive impairment, amyotrophic lateral sclerosis, traumatic brain injury, and schizophrenia. Patients showed lower performances in both numerical and financial abilities compared to controls. Numerical and financial skills were positively correlated in both groups, but they correlated poorly with measures of general cognitive functioning. Crucially, only basic financial tasks -such as counting currencies- but not advanced ones -like financial judgments- were associated with numerical or general cognitive functioning in logistic regression analyses. Conversely, advanced financial abilities, but not basic ones, were associated with abstract reasoning. At a qualitative analysis, we found that deficits in numerical and financial abilities might double dissociate. Similarly, we observed double dissociations between difficulties in financial abilities and cognitive deficits. In conclusion, financial abilities may be independent of numerical skills, and financial deficits are not always related to the presence of cognitive difficulties. These findings are important for both clinical and legal practice.}, } @article {pmid38780595, year = {2024}, author = {da Gama, NAS and Queiroz, GAMC and de Alcântara, C and Cruzeiro, MM and Alencar, MA and Martins de Araújo, C and Gomide, GFD and de Souza, LC and Jaeger, A}, title = {Memory for emotional information in sporadic and Type 8 amyotrophic lateral sclerosis.}, journal = {Neuropsychology}, volume = {38}, number = {5}, pages = {465-474}, doi = {10.1037/neu0000957}, pmid = {38780595}, issn = {1931-1559}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/physiopathology ; Male ; Female ; Middle Aged ; *Emotions/physiology ; Aged ; *Recognition, Psychology/physiology ; Memory Disorders/etiology/diagnosis ; Adult ; Memory, Episodic ; Neuropsychological Tests ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is often shown to cause episodic memory deficits. Here, we investigated whether such memory deficits are differentially expressed according to the emotional valence of stimuli and whether they are similarly reproduced in both individuals with sporadic ALS (sALS) and familial Type 8 ALS (ALS8).

METHOD: Twenty individuals with sALS, 18 individuals with ALS8, and 19 healthy controls were recruited for the study. After a neuropsychological and psychopathological assessment, all participants responded to a recognition memory test wherein images varying in terms of valence were initially shown. After a short interval, the images were shown again intermixed with new images, and the participants' task was to indicate whether each image was "old" or "new" and to estimate the confidence in their responses.

RESULTS: Both the sALS and the ALS8 groups showed significantly lower recognition of positive relative to negative valence images (d = 0.92 and d = 0.74, respectively), an effect that was completely absent for healthy controls (d = 0.17). These effects were qualified by a significant interaction involving the factors of valence and group (ηp² = 0.12).

CONCLUSIONS: The current findings demonstrate that sALS and ALS8 are associated with decreased recognition of emotional information, an effect that is nonetheless restricted to positive valence stimuli. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, } @article {pmid38779803, year = {2024}, author = {Zhu, L and Bai, D and Wang, X and Ou, K and Li, B and Jia, Q and Tan, Z and Liang, J and He, D and Yan, S and Wang, L and Li, S and Li, XJ and Yin, P}, title = {Pathologic TDP-43 downregulates myelin gene expression in the monkey brain.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {34}, number = {6}, pages = {e13277}, pmid = {38779803}, issn = {1750-3639}, support = {32270564//National Natural Science Foundation of China/ ; 81830032//National Natural Science Foundation of China/ ; 82071421//National Natural Science Foundation of China/ ; 82394422//National Natural Science Foundation of China/ ; 2021ZT09Y007//Department of Science and Technology of Guangdong Province/ ; 2018B030337001//Department of Science and Technology of Guangdong Province/ ; 2022A1515011205//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010811//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, mesh = {Animals ; Male ; *Brain/metabolism/pathology ; Corpus Callosum/metabolism/pathology ; Demyelinating Diseases/pathology/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; Down-Regulation ; Myelin Sheath/metabolism/pathology/genetics ; Oligodendroglia/metabolism/pathology ; Macaca fascicularis ; }, abstract = {Growing evidence indicates that non-neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP-43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP-43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate-specific cleavage of truncated TDP-43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP-43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP-35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP-35 in cytoplasm, the downstream myelin-associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP-43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP-43 related diseases.}, } @article {pmid38779353, year = {2024}, author = {Trubshaw, M and Gohil, C and Yoganathan, K and Kohl, O and Edmond, E and Proudfoot, M and Thompson, AG and Talbot, K and Stagg, CJ and Nobre, AC and Woolrich, M and Turner, MR}, title = {The cortical neurophysiological signature of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {3}, pages = {fcae164}, pmid = {38779353}, issn = {2632-1297}, abstract = {The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterize the cortical oscillatory signature of amyotrophic lateral sclerosis for having potential as a pharmacodynamic biomarker. Eight to ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n = 36) and healthy age-matched controls (n = 51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutation-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a random forest regression model was trained and evaluated using nested leave-one-out cross-validation. Amyotrophic lateral sclerosis was characterized by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The random forest model achieved a coefficient of determination (R[2]) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have a wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.}, } @article {pmid38778614, year = {2024}, author = {Zhou, H and Xia, Y and Zhu, R and Zhang, Y and Zhang, X and Zhang, Y and Wang, J}, title = {Ribosomal DNA and Neurological Disorders.}, journal = {Current molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665240292079240513093708}, pmid = {38778614}, issn = {1875-5666}, abstract = {Ribosomal DNA (rDNA) is important in the nucleolus and nuclear organization of human cells. Defective rDNA repeat maintenance has been reported to be closely associated with neurological disorders, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, depression, suicide, etc. However, there has not been a comprehensive review on the role of rDNA in these disorders. In this review, we have summarized the role of rDNA in major neurological disorders to sort out the correlation between rDNA and neurological diseases and provided insights for therapy with rDNA as a target.}, } @article {pmid38778595, year = {2025}, author = {Jayaprakash, B and Savira, M and Mahmood, AAR and Prasanna, M}, title = {The Role of Stem Cell Therapies in the Treatment of Neurodegenerative Diseases.}, journal = {Current stem cell research & therapy}, volume = {20}, number = {2}, pages = {146-165}, doi = {10.2174/011574888X313112240510160102}, pmid = {38778595}, issn = {2212-3946}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; Animals ; Neural Stem Cells/transplantation ; Parkinson Disease/therapy ; }, abstract = {Cellular replacement therapy and genetic transfer in injured brains provide new pathways for treating human neurological illnesses. Current progress in the field focuses on the production of neurons and glial cells from many types of stem cells, such as embryonic, induced pluripotent, mesenchymal, and neural stem cells. This has led to a significant increase in research on brain transplantation treatments. Extended neurodegeneration results in the progressive decline of certain neuronal subtypes or whole neuronal cells. An analysis of the progress made in induced pluripotent and mesenchymal stem cells reveals their significant promise in disease modeling, regeneration, and medication screening. The requirement for stem cells in neurodegenerative disease studies has been crucial in recent years. Stem cells provide the potential for replacing impaired neurons, comprehending disease needs modeling, and creating efficient treatments, but they have many challenges in culturing and acceptability to the host immune cells. The need to use their potential in discovering novel therapies for diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis leads to promising therapy. This review examines the function of stem cells in the pathogenesis and treatment of Huntington's disease, Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review further examines hurdles such as immunological reactions and delivery systems intending to overcome these problems. This article offers a detailed viewpoint on the use of stem cell-based nanotherapies as revolutionary treatments for various neurological illnesses.}, } @article {pmid38778483, year = {2024}, author = {Yan, J and Chen, H and Zhang, Y and Peng, L and Wang, Z and Lan, X and Yu, S and Yang, Y}, title = {Fecal microbiota transplantation significantly improved respiratory failure of amyotrophic lateral sclerosis.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2353396}, pmid = {38778483}, issn = {1949-0984}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/microbiology ; Bacteroides ; Faecalibacterium prausnitzii ; *Fecal Microbiota Transplantation ; Feces/microbiology ; Gastrointestinal Microbiome ; Respiration, Artificial ; *Respiratory Insufficiency/therapy/microbiology ; Treatment Outcome ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.}, } @article {pmid38777640, year = {2024}, author = {Zhu, J and Yan, Y and Jiang, W and Zhang, S and Niu, X and Wan, S and Cong, Y and Hu, X and Zheng, B and Yang, Y}, title = {A Deep Learning Model for Automatically Quantifying the Anterior Segment in Ultrasound Biomicroscopy Images of Implantable Collamer Lens Candidates.}, journal = {Ultrasound in medicine & biology}, volume = {50}, number = {8}, pages = {1262-1272}, doi = {10.1016/j.ultrasmedbio.2024.05.004}, pmid = {38777640}, issn = {1879-291X}, mesh = {Humans ; *Microscopy, Acoustic/methods ; *Deep Learning ; *Anterior Eye Segment/diagnostic imaging ; Male ; Female ; Adult ; Phakic Intraocular Lenses ; Lens Implantation, Intraocular ; Young Adult ; Middle Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {OBJECTIVE: This study aimed to develop and evaluate a deep learning-based model that could automatically measure anterior segment (AS) parameters on preoperative ultrasound biomicroscopy (UBM) images of implantable Collamer lens (ICL) surgery candidates.

METHODS: A total of 1164 panoramic UBM images were preoperatively obtained from 321 patients who received ICL surgery in the Eye Center of Renmin Hospital of Wuhan University (Wuhan, China) to develop an imaging database. First, the UNet++ network was utilized to segment AS tissues automatically, such as corneal lens and iris. In addition, image processing techniques and geometric localization algorithms were developed to automatically identify the anatomical landmarks (ALs) of pupil diameter (PD), anterior chamber depth (ACD), angle-to-angle distance (ATA), and sulcus-to-sulcus distance (STS). Based on the results of the latter two processes, PD, ACD, ATA, and STS can be measured. Meanwhile, an external dataset of 294 images from Huangshi Aier Eye Hospital was employed to further assess the model's performance in other center. Lastly, a subset of 100 random images from the external test set was chosen to compare the performance of the model with senior experts.

RESULTS: Whether in the internal test dataset or external test dataset, using manual labeling as the reference standard, the models achieved a mean Dice coefficient exceeding 0.880. Additionally, the intra-class correlation coefficients (ICCs) of ALs' coordinates were all greater than 0.947, and the percentage of Euclidean distance distribution of ALs within 250 μm was over 95.24%.While the ICCs for PD, ACD, ATA, and STS were greater than 0.957, furthermore, the average relative error (ARE) of PD, ACD, ATA, and STS were below 2.41%. In terms of human versus machine performance, the ICCs between the measurements performed by the model and those by senior experts were all greater than 0.931.

CONCLUSION: A deep learning-based model could measure AS parameters using UBM images of ICL candidates, and exhibited a performance similar to that of a senior ophthalmologist.}, } @article {pmid38777186, year = {2024}, author = {Green, LJ and Brouha, B and Bhatia, N}, title = {Response to Bass et al's "Significant discordance in DermTech test results when paired with histopathology: Caveat emptor".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {3}, pages = {e79}, doi = {10.1016/j.jaad.2024.02.067}, pmid = {38777186}, issn = {1097-6787}, mesh = {Humans ; *Skin Neoplasms/pathology ; Dermoscopy ; Melanoma/pathology ; }, } @article {pmid38776614, year = {2024}, author = {López-Figueroa, C and Domingo, M and Duignan, PJ and Cuvertoret-Sanz, M and Martí-García, B and Pintado, E and Martinez, M and Martínez, J}, title = {Air leak syndrome in animals: definition and pathogenesis.}, journal = {Journal of comparative pathology}, volume = {211}, number = {}, pages = {42-51}, doi = {10.1016/j.jcpa.2024.04.005}, pmid = {38776614}, issn = {1532-3129}, mesh = {Animals ; Cats ; *Pneumothorax/veterinary/etiology ; Dogs ; Mediastinal Emphysema/veterinary ; Retrospective Studies ; Cat Diseases/pathology ; Dog Diseases/pathology ; Female ; Male ; Subcutaneous Emphysema/veterinary/etiology ; Pneumoperitoneum/veterinary ; }, abstract = {Air leak syndrome (ALS) is described in human medicine as a constellation of clinical disorders including pneumomediastinum, pneumopericardium, pulmonary interstitial emphysema, pneumothorax, pneumoperitoneum, pneumoretroperitoneum and subcutaneous emphysema. The pathogenesis of ALS depends on the anatomy of the mediastinum and its associations with thoracic, abdominal and cervical connective tissues, as well as a physical phenomenon referred to as the Macklin effect. Various animal species develop diverse combinations of these lesions, although ALS has not been recognized in animals. However, this term aids pathologists in addressing this disease compilation. The aim of this retrospective study is to illustrate examples of ALS in animals by arbitrarily selecting 13 cases in dogs, cats, pinnipeds, sea otters and harbour porpoises. ALS can be classified into three groups based on aetiology: iatrogenic, secondary or spontaneous. Iatrogenic ALS was diagnosed in two cats with tracheal laceration following endotracheal intubation. Secondary ALS was identified in two dogs, one with acute respiratory distress syndrome and the other due to grass awn migration. Secondary ALS in pinnipeds was diagnosed following severe pulmonary parasitism, uraemic pneumonia and oesophageal perforation. The other marine mammals developed ALS following trauma. Spontaneous ALS was also diagnosed in one cat and one dog without any apparent predisposing causes.}, } @article {pmid38776297, year = {2024}, author = {Issa, NP and Aydin, S and Polley, E and Carberry, N and Garret, MA and Smith, S and Habib, AA and Baumgartner, NW and Soliven, B and Rezania, K}, title = {Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0303053}, pmid = {38776297}, issn = {1932-6203}, support = {R01 NS116262/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Biomarkers/analysis ; *Electromyography/methods ; Motor Neurons/pathology ; Muscle, Skeletal/physiopathology/pathology ; Prospective Studies ; Multicenter Studies as Topic ; }, abstract = {OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment.

RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities.

SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.}, } @article {pmid38775852, year = {2024}, author = {Ebrahimi, P and Davoudi, E and Sadeghian, R and Zadeh, AZ and Razmi, E and Heidari, R and Morowvat, MH and Sadeghian, I}, title = {In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {10}, pages = {7501-7530}, pmid = {38775852}, issn = {1432-1912}, support = {29849//Shiraz University of Medical Sciences/ ; }, mesh = {Humans ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/therapy/genetics ; Gene Editing/methods ; }, abstract = {Neurodegenerative diseases (NDDs), including AD, PD, HD, and ALS, represent a growing public health concern linked to aging and lifestyle factors, characterized by progressive nervous system damage leading to motor and cognitive deficits. Current therapeutics offer only symptomatic management, highlighting the urgent need for disease-modifying treatments. Gene therapy has emerged as a promising approach, targeting the underlying pathology of diseases with diverse strategies including gene replacement, gene silencing, and gene editing. This innovative therapeutic approach involves introducing functional genetic material to combat disease mechanisms, potentially offering long-term efficacy and disease modification. With advancements in genomics, structural biology, and gene editing tools such as CRISPR/Cas9, gene therapy holds significant promise for addressing the root causes of NDDs. Significant progress in preclinical and clinical studies has demonstrated the potential of in vivo and ex vivo gene therapy to treat various NDDs, offering a versatile and precise approach in comparison to conventional treatments. The current review describes various gene therapy approaches employed in preclinical and clinical studies for the treatment of NDDs, including AD, PD, HD, and ALS, and addresses some of the key translational challenges in this therapeutic approach.}, } @article {pmid38775303, year = {2024}, author = {Zhang, J and Yang, F and Li, M and Zhu, Y and Huang, X}, title = {Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.}, journal = {Muscle & nerve}, volume = {70}, number = {2}, pages = {194-203}, doi = {10.1002/mus.28165}, pmid = {38775303}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Adult ; Electric Stimulation/methods ; Neuromuscular Junction/physiopathology ; Electromyography/methods ; }, abstract = {INTRODUCTION/AIMS: Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice.

METHODS: A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building.

RESULTS: Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset.

DISCUSSION: In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.}, } @article {pmid38775192, year = {2024}, author = {Ju, W and Ban, JJ and Im, HR and Ko, SH and Seo, J and Min, YG and Hong, YH and Choi, SJ and Sung, JJ}, title = {Association of serum Spp1 levels with disease progression in ALS and SBMA.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1809-1818}, pmid = {38775192}, issn = {2328-9503}, support = {2018R1A5A2025964//National Research Foundation of Korea/ ; 2020R1C1C1005122//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/physiopathology/diagnosis ; *Osteopontin/blood ; Male ; Female ; Middle Aged ; *Disease Progression ; Aged ; Biomarkers/blood ; Adult ; Neuroinflammatory Diseases/blood ; Cytokines/blood ; }, abstract = {OBJECTIVE: In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1).

METHODS: This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels.

RESULTS: In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01).

INTERPRETATION: Neuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.}, } @article {pmid38775181, year = {2024}, author = {Marriott, H and Spargo, TP and Al Khleifat, A and Andersen, PM and Başak, NA and Cooper-Knock, J and Corcia, P and Couratier, P and de Carvalho, M and Drory, V and Gotkine, M and Landers, JE and McLaughlin, R and Pardina, JSM and Morrison, KE and Pinto, S and Shaw, CE and Shaw, PJ and Silani, V and Ticozzi, N and van Damme, P and van den Berg, LH and Vourc'h, P and Weber, M and Veldink, JH and , and Dobson, RJ and Schwab, P and Al-Chalabi, A and Iacoangeli, A}, title = {Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {7}, pages = {1775-1786}, pmid = {38775181}, issn = {2328-9503}, support = {//Maudsley NHS Foundation Trust/ ; 22-PDF-609//ALS Association Milton Safenowitz Research/ ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; //BHF British Heart Foundation/ ; //Darby Rimmer MND Foundation/ ; NIHR202421//National Institute for Health Research/ ; Al Khleifat/Oct21/975-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; //MND Scotland/ ; ES/L008238/1//Economic and Social Research Council/ ; //Alan Davidson Foundation/ ; /WT_/Wellcome Trust/United Kingdom ; //Alzheimer's Research UK/ ; //Rosetrees Trust/ ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; //My Name'5 Doddie Foundation/ ; //GlaxoSmithKline/ ; //MRC Medical Research Council/ ; //The NIHR Maudsley Biomedical Research Centre/ ; //Spastic Paraplegia Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Genetic Predisposition to Disease/genetics ; Mutation ; Mutation, Missense ; *Neurofilament Proteins/genetics ; Protein Domains/genetics ; }, abstract = {OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.

METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data.

RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation.

INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.}, } @article {pmid38775138, year = {2024}, author = {Calma, AD and Pavey, N and Menon, P and Vucic, S}, title = {Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {585-592}, pmid = {38775138}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/therapy/genetics ; Humans ; *Neuroinflammatory Diseases/immunology ; Animals ; Immunity, Innate/immunology ; Inflammation/immunology ; }, abstract = {PURPOSE OF REVIEW: Neuroinflammation appears to be an important pathogenic process in amyotrophic lateral sclerosis (ALS). Dysfunction of central immune pathways, including activation of microglia and astrocytes, and peripherally derived immune cells, initiate noncell autonomous inflammatory mechanisms leading to degeneration. Cell autonomous pathways linked to ALS genetic mutations have been recently identified as contributing mechanism for neurodegeneration. The current review provides insights into the pathogenic importance of central and peripheral inflammatory processes in ALS pathogenesis and appraises their potential as therapeutic targets.

RECENT FINDINGS: ALS is a multistep process mediated by a complex interaction of genetic, epigenetic, and environmental factors. Noncell autonomous inflammatory pathways contribute to neurodegeneration in ALS. Activation of microglia and astrocytes, along with central nervous system infiltration of peripherally derived pro-inflammatory innate (NK-cells/monocytes) and adaptive (cell-mediated/humoral) immune cells, are characteristic of ALS. Dysfunction of regulatory T-cells, elevation of pro-inflammatory cytokines and dysbiosis of gut microbiome towards a pro-inflammatory phenotype, have been reported as pathogenic mechanisms in ALS.

SUMMARY: Dysregulation of adaptive and innate immunity is pathogenic in ALS, being associated with greater disease burden, more rapid disease course and reduced survival. Strategies aimed at modulating the pro-inflammatory immune components could be of therapeutic utility.}, } @article {pmid38775034, year = {2024}, author = {Brooks, BR}, title = {Letter to the Editor: Glycemic Index/Load Effect on Amyotrophic Lateral Sclerosis Progression: Potential Interaction with Riluzole.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {208}, doi = {10.1002/ana.26970}, pmid = {38775034}, issn = {1531-8249}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Riluzole/therapeutic use ; *Disease Progression ; *Glycemic Index/drug effects ; Neuroprotective Agents/therapeutic use ; Blood Glucose/metabolism/drug effects ; }, } @article {pmid38774156, year = {2024}, author = {Canella, C and Braun, C and Witt, CM}, title = {Developing a digital mind body medicine supportive care intervention for people with amyotrophic lateral sclerosis using stakeholder engagement and design thinking.}, journal = {Digital health}, volume = {10}, number = {}, pages = {20552076241255928}, pmid = {38774156}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis disease (ALS) is also called the disease of a thousand farewells. Consequently, it is important to offer supportive care interventions that can be applied continuously during the whole course of the disease. People with ALS are interested in complementary and integrative medicine. Due to ALS' progressive nature, digital solutions might be most feasible and accessible for people with ALS in the long-term.

OBJECTIVES: In our study, we explored with stakeholders which digital complementary and integrative medicine interventions and formats are considered as supportive for people with ALS, and which settings are needed by the people with ALS to incorporate the interventions in everyday life.

METHODS: We used a participatory research approach and conducted a stakeholder engagement process, applying a design thinking process with qualitative research methods (interviews, workshops).

RESULTS: Due to the unpredictable course of the disease on their loss of abilities, people with ALS welcome online settings because they are accessible and easy to implement in their daily life. Stakeholders considered the following implementation factors for a complementary and integrative medicine intervention as essential: short-term realization of planned interventions, short duration of interventions, and user-friendliness in terms of accessibility and applicability. Concerning the complementary and integrative medicine interventions, the people with ALS preferred mind body medicine interventions, such as breathing, mindfulness and relaxation exercises.

CONCLUSIONS: Short-term treatment intervals and short online mind body medicine interventions align with the needs of people with ALS. The complementary and integrative medicine interventions as well as the digital infrastructure must meet the special accessibility and applicability needs of people with ALS.}, } @article {pmid38772930, year = {2024}, author = {Kherbek, H and Itoh, CY and Daley, C and Eggers, SD and Hinson, S and Sarker, P and Staff, NP and Pittock, SJ and Dubey, D}, title = {Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.}, journal = {Journal of neurology}, volume = {271}, number = {7}, pages = {4620-4627}, pmid = {38772930}, issn = {1432-1459}, support = {238183//State of Minnesota's David J. Tomassoni ALS Research Grant Program/ ; }, mesh = {Humans ; Male ; Middle Aged ; Retrospective Studies ; Aged ; Female ; *Paraneoplastic Syndromes, Nervous System/immunology/diagnosis/blood ; Adult ; Autoantibodies/blood ; Brachial Plexus Neuropathies/etiology/diagnosis/physiopathology ; Carrier Proteins ; }, abstract = {BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited.

METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared.

RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement.

DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.}, } @article {pmid38772669, year = {2024}, author = {Martínez Bilesio, AR and Puig-Castellví, F and Tauler, R and Sciara, M and Fay, F and Rasia, RM and Burdisso, P and García-Reiriz, AG}, title = {Multivariate curve resolution-based data fusion approaches applied in [1]H NMR metabolomic analysis of healthy cohorts.}, journal = {Analytica chimica acta}, volume = {1309}, number = {}, pages = {342689}, doi = {10.1016/j.aca.2024.342689}, pmid = {38772669}, issn = {1873-4324}, mesh = {Humans ; *Metabolomics/methods ; Male ; Female ; Multivariate Analysis ; Healthy Volunteers ; Adult ; Proton Magnetic Resonance Spectroscopy ; Cohort Studies ; Middle Aged ; Least-Squares Analysis ; Young Adult ; }, abstract = {BACKGROUND: Metabolomics plays a critical role in deciphering metabolic alterations within individuals, demanding the use of sophisticated analytical methodologies to navigate its intricate complexity. While many studies focus on single biofluid types, simultaneous analysis of multiple matrices enhances understanding of complex biological mechanisms. Consequently, the development of data fusion methods enabling multiblock analysis becomes essential for comprehensive insights into metabolic dynamics.

RESULTS: This study introduces a novel guideline for jointly analyzing diverse metabolomic datasets (serum, urine, metadata) with a focus on metabolic differences between groups within a healthy cohort. The guideline presents two fusion strategies, 'Low-Level data fusion' (LLDF) and 'Mid-Level data fusion' (MLDF), employing a sequential application of Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS), linking the outcomes of successive analyses. MCR-ALS is a versatile method for analyzing mixed data, adaptable at various stages of data processing-encompassing resonance integration, data compression, and exploratory analysis. The LLDF and MLDF strategies were applied to [1]H NMR spectral data extracted from urine and serum samples, coupled with biochemical metadata sourced from 145 healthy volunteers.

SIGNIFICANCE: Both methodologies effectively integrated and analysed multiblock datasets, unveiling the inherent data structure and variables associated with discernible factors among healthy cohorts. While both approaches successfully detected sex-related differences, the MLDF strategy uniquely revealed components linked to age. By applying this analysis, we aim to enhance the interpretation of intricate biological mechanisms and uncover variations that may not be easily discernible through individual data analysis.}, } @article {pmid38771698, year = {2024}, author = {Alarcan, H and Bruno, C and Emond, P and Raoul, C and Vourc'h, P and Corcia, P and Camu, W and Veyrune, JL and Garlanda, C and Locati, M and Juntas-Morales, R and Saker, S and Suehs, C and Masseguin, C and Kirby, J and Shaw, P and Malaspina, A and De Vos, J and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G and Blasco, H}, title = {Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.}, journal = {Annals of the New York Academy of Sciences}, volume = {1536}, number = {1}, pages = {82-91}, doi = {10.1111/nyas.15147}, pmid = {38771698}, issn = {1749-6632}, support = {//National Institute of Health and Medical Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Humans ; *Interleukin-2/administration & dosage/metabolism ; *Metabolomics/methods ; *T-Lymphocytes, Regulatory/metabolism/drug effects/immunology ; Male ; Middle Aged ; Female ; Kynurenine/metabolism ; Aged ; Metabolome/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.}, } @article {pmid38771230, year = {2024}, author = {Maccabeo, A and Salustro, E and Sanna, M and Garau, P and Maioli, MA and Coa, R and Puligheddu, M and Borghero, G}, title = {Scleroderma-Polymyositis Overlap Syndrome as a Potential Bulbar Amyotrophic Lateral Sclerosis Mimic.}, journal = {Journal of clinical neuromuscular disease}, volume = {25}, number = {4}, pages = {199-200}, doi = {10.1097/CND.0000000000000467}, pmid = {38771230}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis ; Diagnosis, Differential ; *Polymyositis/complications ; Scleroderma, Systemic/complications ; }, } @article {pmid38770222, year = {2024}, author = {Lagrange, E and Loriot, MA and Chaudhary, NK and Schultz, P and Dirks, AC and Guissart, C and James, TY and Vernoux, JP and Camu, W and Tripathi, A and Spencer, PS}, title = {Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes.}, journal = {eNeurologicalSci}, volume = {35}, number = {}, pages = {100502}, pmid = {38770222}, issn = {2405-6502}, abstract = {A case-control study of sporadic amyotrophic lateral sclerosis (ALS) in a mountainous village in the French Alps discovered an association of cases with a history of eating wild fungi (false morels) collected locally and initially identified and erroneously reported as Gyromitra gigas. Specialist re-examination of dried specimens of the ALS-associated fungi demonstrated they were members of the G. esculenta group, namely G. venenata and G. esculenta, species that have been reported to contain substantially higher concentrations of gyromitrin than present in G. gigas. Gyromitrin is metabolized to monomethylhydrazine, which is responsible not only for the acute oral toxic and neurotoxic properties of false morels but also has genotoxic potential with proposed mechanistic relevance to the etiology of neurodegenerative disease. Most ALS patients had a slow- or intermediate-acetylator phenotype predicted by N-acetyltransferase-2 (NAT2) genotyping, which would increase the risk for neurotoxic and genotoxic effects of gyromitrin metabolites.}, } @article {pmid38769202, year = {2024}, author = {Benatar, M and Wuu, J and Huey, ED and McMillan, CT and Petersen, RC and Postuma, R and McHutchison, C and Dratch, L and Arias, JJ and Crawley, A and Houlden, H and McDermott, MP and Cai, X and Thakur, N and Boxer, A and Rosen, H and Boeve, BF and Dacks, P and Cosentino, S and Abrahams, S and Shneider, N and Lingor, P and Shefner, J and Andersen, PM and Al-Chalabi, A and Turner, MR and , }, title = {The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {6}, pages = {364-376}, pmid = {38769202}, issn = {1759-4766}, support = {U01 AG079850/AG/NIA NIH HHS/United States ; R01 MH120794/MH/NIMH NIH HHS/United States ; K01 AG057796/AG/NIA NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; R01 AG062268/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism/pathology ; *Phenotype ; *Frontotemporal Dementia/genetics/diagnosis/metabolism ; Neurodegenerative Diseases/diagnosis/metabolism/genetics ; Biomarkers/metabolism ; }, abstract = {Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.}, } @article {pmid38768217, year = {2024}, author = {Petrauskas, A and Fortunati, DL and Kandi, AR and Pothapragada, SS and Agrawal, K and Singh, A and Huelsmeier, J and Hillebrand, J and Brown, G and Chaturvedi, D and Lee, J and Lim, C and Auburger, G and VijayRaghavan, K and Ramaswami, M and Bakthavachalu, B}, title = {Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation.}, journal = {PLoS genetics}, volume = {20}, number = {5}, pages = {e1011251}, pmid = {38768217}, issn = {1553-7404}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Ataxin-2/genetics/metabolism ; Animals ; Humans ; *Ribonucleoproteins/genetics/metabolism ; *Drosophila Proteins/genetics/metabolism ; *Drosophila melanogaster/genetics/metabolism ; *RNA, Messenger/genetics/metabolism ; Poly(A)-Binding Proteins/metabolism/genetics ; Animals, Genetically Modified ; Cytoplasmic Granules/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Protein Biosynthesis ; RNA-Binding Proteins/genetics/metabolism ; Intrinsically Disordered Proteins/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; DNA-Binding Proteins ; }, abstract = {Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.}, } @article {pmid38767564, year = {2024}, author = {Natung, T and Pandey, I and Nongrum, B and Sekhose, EK}, title = {Comparison of Hill-RBF 3.0 with Barrett Universal II, SRK/T, Hoffer Q, Haigis, and Holladay 1 to predict the accuracy of post-cataract surgery refractive outcomes in Indian eyes.}, journal = {Indian journal of ophthalmology}, volume = {72}, number = {9}, pages = {1261-1266}, pmid = {38767564}, issn = {1998-3689}, mesh = {Humans ; Prospective Studies ; Male ; Female ; India/epidemiology ; *Refraction, Ocular/physiology ; Middle Aged ; *Visual Acuity/physiology ; Aged ; Follow-Up Studies ; Lenses, Intraocular ; Phacoemulsification ; Postoperative Period ; Lens Implantation, Intraocular ; Refractive Errors/physiopathology/diagnosis/epidemiology ; }, abstract = {PURPOSE: To compare Hill-RBF 3.0 with Barrett Universal II (BU II), SRK/T, Hoffer Q, Haigis, and Holladay 1 in predicting the accuracy of post-cataract surgery refractive outcomes in Indian eyes.

METHODS: In this prospective, comparative, observational study, consecutive patients with uncomplicated age-related cataracts undergoing uneventful phacoemulsification with posterior chamber intraocular lens (IOL) implantation were included. The mean absolute errors (MAEs) and median absolute errors were used to determine the accuracy of predicted postoperative target refractions.

RESULTS: A total of 219 eyes of 173 patients were enrolled. Based on the axial lengths (AL), the patients were classified into: AL <22 mm (short), 22-24.5 mm (normal), and >24.5 mm (long). BU II exhibited the lowest MAE for normal ALs (0.2683 ± 0.2790 D) as well as for the entire population (0.2764 ± 0.2764 D). For the short ALs, Hill RBF 3.0 exhibited the lowest MAE (0.3268 ± 0.3268 D), while for the long ALs, SRK/T showed the lowest MAE (0.2823 ± 0.2642 D). BU II exhibited the highest percentage of eyes of 57.5%, 95.4%, and 98.6% within ±0.25, ±0.75, and ±1.0 D of postoperative target refractions respectively, whereas Hill RBF 3.0 had the highest percentages of eyes (88.1%) within ±0.5 D of postoperative target refraction.

CONCLUSION: Hill-RBF 3.0 exhibited the least MAE for patients with short ALs, while BU II showed the least MAE for normal ALs as well as for the entire population and SRK/T for long ALs. This study is likely to aid surgeons in selecting the most appropriate IOL power formula, which thereby improves the refractive outcomes with utmost accuracy.}, } @article {pmid38767482, year = {2025}, author = {Martinelli, I and Mandrioli, J and Ghezzi, A and Zucchi, E and Gianferrari, G and Simonini, C and Cavallieri, F and Valzania, F}, title = {Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients: a rare occurrence?.}, journal = {Neural regeneration research}, volume = {20}, number = {1}, pages = {130-138}, pmid = {38767482}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. While the typical clinical phenotype of ALS involves both upper and lower motor neurons, human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions, expanding the phenotype of ALS. Although superoxide dismutase 1 (SOD1) mutations represent a minority of ALS cases, the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies. Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1 (SOD1-ALS), no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation. In this narrative review, we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS. The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms, pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.}, } @article {pmid38767073, year = {2024}, author = {Napoletano, G and Circosta, F and Basile, G}, title = {Access to medically-assisted procreation: the withdrawal of paternal consent in the maze of law n. 40/2004.}, journal = {La Clinica terapeutica}, volume = {175}, number = {3}, pages = {163-167}, doi = {10.7417/CT.2024.5057}, pmid = {38767073}, issn = {1972-6007}, mesh = {Humans ; *Reproductive Techniques, Assisted/legislation & jurisprudence/ethics ; Italy ; Female ; Male ; Health Services Accessibility/legislation & jurisprudence ; Cryopreservation ; Parental Consent/legislation & jurisprudence ; Informed Consent/legislation & jurisprudence ; }, abstract = {The law (No.40/2004) stipulates that consent to Medically Assisted Procreation (MAP) remains irrevocable post ovum fertilization. Cryo-preservation introduces complexities, enabling embryo implantation requests after a couple's separation and the dissolution of the original parenthood plan. Constitutional Court Ruling No.161 in 2023 affirmed that the prohibition of revoking consent to MAP aligns with the Italian Constitution and the jurisprudence of the European Court of Human Rights. This delicate equilibrium of conflicting interests upholds human freedom, allowing consent revocation prior to ovocyte fertilization. Permitting revocation until implantation could inflict more significant harm: the infertile woman can in fact miss the opportunity to become a mother, impacting her psychophysical well-being and freedom of self-determination. Moreover, the embryo loses the chance to live, remaining in cryopreservation, which violates its dignity. Addressing this issue requires thorough communication by medical profession-als to inform couples about the limitations on consent revocation. An element of objectivity in terms of standards and evidence-based guidelines, from which norms must originate, is of utmost importance. Relying on broadly shared rules, especially at the international level, is vital in light of the unremitting scientific advances in MAP, as in other areas of medicine, which will open up new opportunities for which current legal/regulatory frameworks are inadequate.}, } @article {pmid38766825, year = {2024}, author = {Tedeschi, V and Sapienza, S and Ciancio, R and Canzoniero, LMT and Pannaccione, A and Secondo, A}, title = {Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X22666240517101846}, pmid = {38766825}, issn = {1875-6190}, abstract = {Besides controlling several organellar functions, lysosomal channels also guide the catabolic "self-eating" process named autophagy, which is mainly involved in protein and organelle quality control. Neuronal cells are particularly sensitive to the rate of autophagic flux either under physiological conditions or during the degenerative process. Accordingly, neurodegeneration occurring in Parkinson's (PD), Alzheimer's (AD), and Huntington's Diseases (HD), and Amyotrophic Lateral Sclerosis (ALS) as well as Lysosomal Storage Diseases (LSD) is partially due to defective autophagy and accumulation of toxic aggregates. In this regard, dysfunction of lysosomal ionic homeostasis has been identified as a putative cause of aberrant autophagy. From a therapeutic perspective, Transient Receptor Potential Channel Mucolipin 1 (TRPML1) and Two-Pore Channel isoform 2 (TPC2), regulating lysosomal homeostasis, are now considered promising druggable targets in neurodegenerative diseases. Compelling evidence suggests that pharmacological modulation of TRPML1 and TPC2 may rescue the pathological phenotype associated with autophagy dysfunction in AD, PD, HD, ALS, and LSD. Although pharmacological repurposing has identified several already used drugs with the ability to modulate TPC2, and several tools are already available for the modulation of TRPML1, many efforts are necessary to design and test new entities with much higher specificity in order to reduce dysfunctional autophagy during neurodegeneration.}, } @article {pmid38765269, year = {2024}, author = {Cheng, J and Niu, X and Li, H and Yang, Q and Du, K}, title = {Evaluation of the therapeutic effects of rehabilitation therapy on patients with amyotrophic lateral sclerosis-a meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1389146}, pmid = {38765269}, issn = {1664-2295}, abstract = {OBJECTIVE: To investigate the effect of rehabilitation therapy on the global function, respiratory function, and quality of life in patients with amyotrophic lateral sclerosis (ALS).

METHODS: PubMed, Web of Science, and The National Library of Medicine (NLM) were systematically searched and the search period was between the date of database establishment and December 31, 2023. The outcome measures finally analyzed included the ALS functional rating scale/revised (ALSFRS/ALSFRS-R), forced vital capacity percentage predicted (FVC%), fatigue severity scale (FSS), and maximal expiratory pressure (MEP).

RESULTS: A total of 13 randomized controlled trials (RCTs) were included, and 5 outcome measures were pooled and analyzed. A total of 657 patients with ALS were enrolled, with 299 in the experimental group (rehabilitation therapy, such as resistance training, endurance training, aerobic training, respiratory muscle training, and standard rehabilitation therapy) and 358 in the control group (conventional interventions, such as simple joint movements or daily stretching). The ALSFRS scores were better in the experimental group than in the control group at 0-4 months (MD = 3.36, 95% CI: 0.82, 5.91, Z = 2.59, p = 0.009) and at 5-8 months (MD = 5.00, 95% CI: -2.42, 7.58, Z = 3.80, p < 0.001). Moreover, the ALSFRS-R scores of the experimental group was better than that of the control group at 5-8 months (MD = 2.83, 95% CI: 1.21, 4.45, Z = 3.42, p < 0.001) and 9-12 months (MD = 1.87, 95% CI: -0.37, 4.11, Z = 1.63, p = 0.10). It was also found that the MEP value of the experimental group was significantly better than that of the control group after intervention (MD = 18.49, 95% CI: 1.47, 35.50, Z = 2.13, p = 0.03). However, there were no significant differences in FVC% value and FSS scores at 0-5 months and 6-12 months between the two groups.

CONCLUSION: Rehabilitation therapy is helpful in improving the short-, medium-, and long-term global function score of patients with ALS, with positive effects on respiratory function.}, } @article {pmid38765264, year = {2024}, author = {Colognesi, M and Shkodra, A and Gabbia, D and Kawamata, H and Manfredi, PL and Manfredi, G and De Martin, S}, title = {Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1384829}, pmid = {38765264}, issn = {1664-2295}, abstract = {INTRODUCTION: The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression.

METHODS: Here, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity.

RESULTS: We found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p < 0.01 vs. control untreated mice) and an extension of lifespan (p < 0.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (p < 0.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles.

CONCLUSION: In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.}, } @article {pmid38765173, year = {2024}, author = {Souayah, N and Chen, H and Chong, ZZ and Patel, T and Pahwa, A and Menkes, DL and Cunningham, T}, title = {Novel strategy: Identifying new markers for demyelination in diabetic distal symmetrical polyneuropathy.}, journal = {Heliyon}, volume = {10}, number = {9}, pages = {e30419}, pmid = {38765173}, issn = {2405-8440}, abstract = {OBJECTIVE: To develop a novel strategy for identifying acquired demyelination in diabetic distal symmetrical polyneuropathy (DSP).

BACKGROUND: Motor nerve conduction velocity (CV) slowing in diabetic DSP exceeds expectations for pure axonal loss thus implicating superimposed acquired demyelination.

METHODS: After establishing demyelination confidence intervals by regression analysis of nerve conduction data from chronic inflammatory demyelinating polyneuropathy (CIDP), we prospectively studied CV slowing in 90 diabetic DSP patients with and without at least one motor nerve exhibiting CV slowing (groups A and B) into the demyelination range by American Academy of Neurology (AAN) criteria respectively and 95 amyotrophic lateral sclerosis (ALS) patients. Simultaneously, secretory phospholipase A2 (sPLA2) activity was assessed in both diabetic groups and 46 healthy controls.

RESULTS: No ALS patient exhibited CV slowing in more than two motor nerves based on AAN criteria or the confidence intervals. Group A demonstrated a significantly higher percentage of patients as compared to group B fulfilling the above criteria, with an additional criterion of at least one motor nerve exhibiting CV slowing in the demyelinating range and a corresponding F response in the demyelinating range by AAN criteria (70.3 % vs. 1.9 %; p < 0.0001). Urine sPLA2 activity was increased significantly in diabetic groups as compared to healthy controls (942.9 ± 978.0 vs. 591.6 ± 390.2 pmol/min/ml, p < 0.05), and in group A compared to Group B (1328.3 ± 1274.2 vs. 673.8 ± 576.9 pmol/min/ml, p < 0.01). More patients with elevated sPLA2 activity and more than 2 motor nerves with CV slowing in the AAN or the confidence intervals were identified in group A as compared to group B (35.1 % vs. 5.7 %, p < 0.001). Furthermore, 13.5 % of patients in diabetic DSP Group A, and no patients in diabetic DSP Group B, fulfilled an additional criterion of more than one motor nerve with CV slowing into the demyelinating range with its corresponding F response into the demyelinating range by AAN criteria.

CONCLUSION: A combination of regression analysis of electrodiagnostic data and a urine biological marker of systemic inflammation identifies a subgroup of diabetic DSP with superimposed acquired demyelination that may respond favorably to immunomodulatory therapy.}, } @article {pmid38763702, year = {2024}, author = {Dorrity, TJ and Shin, H and Gertie, JA and Chung, H}, title = {The Sixth Sense: Self-nucleic acid sensing in the brain.}, journal = {Advances in immunology}, volume = {161}, number = {}, pages = {53-83}, pmid = {38763702}, issn = {1557-8445}, support = {R01 AR050026/AR/NIAMS NIH HHS/United States ; R01 NS127802/NS/NINDS NIH HHS/United States ; T32 AR076953/AR/NIAMS NIH HHS/United States ; T32 GM145440/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Brain/metabolism/immunology ; Animals ; *Receptors, Pattern Recognition/metabolism ; *Immunity, Innate ; *Nucleic Acids/immunology/metabolism ; Homeostasis ; Signal Transduction ; }, abstract = {Our innate immune system uses pattern recognition receptors (PRRs) as a first line of defense to detect microbial ligands and initiate an immune response. Viral nucleic acids are key ligands for the activation of many PRRs and the induction of downstream inflammatory and antiviral effects. Initially it was thought that endogenous (self) nucleic acids rarely activated these PRRs, however emerging evidence indicates that endogenous nucleic acids are able to activate host PRRs in homeostasis and disease. In fact, many regulatory mechanisms are in place to finely control and regulate sensing of self-nucleic acids by PRRs. Sensing of self-nucleic acids is particularly important in the brain, as perturbations to nucleic acid sensing commonly leads to neuropathology. This review will highlight the role of nucleic acid sensors in the brain, both in disease and homeostasis. We also indicate the source of endogenous stimulatory nucleic acids where known and summarize future directions for the study of this growing field.}, } @article {pmid38762759, year = {2024}, author = {Wang, Z and Xiong, S and Wu, Z and Wang, X and Gong, Y and Zhu, WG and Xu, X}, title = {VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.}, journal = {Autophagy}, volume = {20}, number = {9}, pages = {2041-2054}, pmid = {38762759}, issn = {1554-8635}, mesh = {*Autophagy/physiology/genetics ; Humans ; *Valosin Containing Protein/metabolism/genetics ; *Beclin-1/metabolism ; *Ubiquitination ; Ataxin-3/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism ; HeLa Cells ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Stability ; HEK293 Cells ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. Abbreviation: ATG14:autophagy related 14; Baf A1:bafilomycin A1;CMT2Y: Charcot-Marie-Toothdisease, axonal, 2Y; CYB5R3: cytochromeb5 reductase 3; DDRGK1: DDRGK domain containing 1; DMEM:Dulbecco'smodified Eagle's medium;ER:endoplasmic reticulum; FBS:fetalbovine serum;FTDALS6:frontotemporaldementia and/or amyotrophic lateral sclerosis 6; IBMPFD1:inclusion bodymyopathy with early-onset Paget disease with or withoutfrontotemporal dementia 1; LC-MS/MS:liquid chromatography tandem mass spectrometry; MAP1LC3B/LC3B:microtubule associated protein 1 light chain 3 beta; MS: massspectrometry; NPLOC4: NPL4 homolog, ubiquitin recognition factor;PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3;PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K:phosphatidylinositol 3-kinase; RPL26: ribosomal protein L26; RPN1:ribophorin I; SQSTM1/p62: sequestosome 1; UBA5: ubiquitin likemodifier activating enzyme 5; UFC1: ubiquitin-fold modifierconjugating enzyme 1; UFD1: ubiquitin recognition factor in ERassociated degradation 1; UFL1: UFM1 specific ligase 1; UFM1:ubiquitin fold modifier 1; UFSP2: UFM1 specific peptidase 2; UVRAG:UV radiation resistance associated; VCP/p97: valosin containingprotein; WT: wild-type.}, } @article {pmid38762656, year = {2024}, author = {Li, Z and Kang, H}, title = {Efficacy of non-pharmacological interventions for individuals with amyotrophic lateral sclerosis: systematic review and network meta-analysis of randomized control trials.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {11365}, pmid = {38762656}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/physiopathology ; Humans ; *Randomized Controlled Trials as Topic ; *Quality of Life ; *Network Meta-Analysis ; Exercise Therapy/methods ; Treatment Outcome ; Muscle Strength ; }, abstract = {This network meta-analysis (NMA) aimed to compare the efficacy of five non-pharmacological interventions, including exercise intervention (EI), nutritional intervention (NI), respiratory intervention (RI), psychological intervention (PSI), and integrated physical intervention (IPI), on functional status, quality of life, muscle strength, pulmonary function, and safety in patients with amyotrophic lateral sclerosis (ALS). We searched nine databases, PubMed, Cochrane, Embase, Scopus, Web of Science, CNKI, CBM, WFPD, and CSTJ, for randomized controlled trials of ALS patients. The primary outcome was the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were the McGill Quality of Life Questionnaire (McGill-QoL), Medical Research Council (MRC)-sum score, Forced Vital Capacity (FVC), and Fatigue Severity Scale (FSS) score. This NMA was conducted using random-effect models to calculate the standard mean difference (SMD) and 95% confidence interval (CI). All types of supplemental interventions had some benefit for patients with ALS. EI had a beneficial effect on the ALSFRS-R score (SMD: 1.01; 95% CI 0.50-1.51), FVC (SMD: 0.78; 95% CI 0.02-1.55), McGill-QoL (SMD: 0.71 95% CI 0.33-1.08), and MRC (SMD: 1.11; 95% CI 0.08-2.14). RI had a beneficial effect on the ALSFRS-R score (SMD: 0.83 95% CI 0.12-1.55). IPI had a beneficial effect on the ALSFRS-R score (SMD: 0.65 95% CI 0.06-1.24). NI had a beneficial effect on the McGill-QoL (SMD: 0.63 95% CI 0.02-1.23). The current study findings support a multimodal intervention strategy with an emphasis on EI for slowing disease progression in patients with ALS.}, } @article {pmid38762243, year = {2024}, author = {Ponzini, E}, title = {Tear biomarkers.}, journal = {Advances in clinical chemistry}, volume = {120}, number = {}, pages = {69-115}, doi = {10.1016/bs.acc.2024.03.002}, pmid = {38762243}, issn = {2162-9471}, mesh = {Humans ; *Tears/metabolism/chemistry ; *Biomarkers/analysis/metabolism ; Eye Diseases/diagnosis/metabolism ; }, abstract = {An extensive exploration of lacrimal fluid molecular biomarkers in understanding and diagnosing a spectrum of ocular and systemic diseases is presented. The chapter provides an overview of lacrimal fluid composition, elucidating the roles of proteins, lipids, metabolites, and nucleic acids within the tear film. Pooled versus single-tear analysis is discussed to underline the benefits and challenges associated with both approaches, offering insights into optimal strategies for tear sample analysis. Subsequently, an in-depth analysis of tear collection methods is presented, with a focus on Schirmer's test strips and microcapillary tubes methods. Alternative tear collection techniques are also explored, shedding light on their applicability and advantages. Variability factors, including age, sex, and diurnal fluctuations, are examined in the context of their impact on tear biomarker analysis. The main body of the chapter is dedicated to discussing specific biomarkers associated with ocular discomfort and a wide array of ocular diseases. From dry eye disease and thyroid-associated ophthalmopathy to keratoconus, age-related macular degeneration, diabetic retinopathy, and glaucoma, the intricate relationship between molecular biomarkers and these conditions is thoroughly dissected. Expanding beyond ocular pathologies, the chapter explores the applicability of tear biomarkers in diagnosing systemic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and cancer. This broader perspective underscores the potential of lacrimal fluid analysis in offering non-invasive diagnostic tools for conditions with far-reaching implications.}, } @article {pmid38761668, year = {2024}, author = {Silani, V}, title = {Continuity of treatment in ALS: Benefits and challenges of maintaining riluzole over the course of the disease.}, journal = {Journal of the neurological sciences}, volume = {461}, number = {}, pages = {123038}, doi = {10.1016/j.jns.2024.123038}, pmid = {38761668}, issn = {1878-5883}, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Neuroprotective Agents/therapeutic use ; Male ; Female ; Middle Aged ; }, } @article {pmid38760965, year = {2024}, author = {Lee, SY and Yoo, SH and Cho, B and Kim, KH and Jang, MS and Shin, J and Hwang, I and Choi, SJ and Sung, JJ and Kim, MS}, title = {Burden and preparedness of care partners of people living with amyotrophic lateral sclerosis at home in Korea: A care partner survey.}, journal = {Muscle & nerve}, volume = {70}, number = {3}, pages = {306-315}, doi = {10.1002/mus.28115}, pmid = {38760965}, issn = {1097-4598}, support = {HC21C0115//Patient-Centered Clinical Research Coordinating Center(PACEN) funded by the Ministry of Health and Welfare, Republic of Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology/nursing ; Male ; Republic of Korea/epidemiology ; Female ; *Caregivers/psychology ; Middle Aged ; Aged ; Adult ; Surveys and Questionnaires ; Depression/psychology/therapy/epidemiology ; Home Care Services ; Cost of Illness ; Tracheostomy ; Spouses/psychology ; Caregiver Burden/psychology ; }, abstract = {INTRODUCTION/AIMS: The care burden of people living with amyotrophic lateral sclerosis (pALS) increases with disease progression. This study aimed to investigate the home care status and preparedness of care partners of pALS (cALS) in Korea.

METHODS: An online survey was conducted with family care partners of patients diagnosed with ALS for over 1 year in 2022. The data collected included care time, depression evaluated using the patient health questionnaire-9 (PHQ-9), preparedness for caregiving scale (PCS), and caregiver competence scale (CCS). Results were compared based on whether the pALS underwent a tracheostomy or not.

RESULTS: Ninety-eight cALS of 98 pALS participated in the study, of whom 59 pALS had undergone tracheostomy. Among the cALS, 60.2% were spouses, and 34.7% were children. The cALS took care of the patients for 13 (8-20) hours/day (median, interquartile range [IQR]) on weekdays and 15 (10-24) h/day on weekends. Among the cALS, 91.8% were depressed, and 28.6% had severe depression. The median (IQR) PCS and CCS scores were low (11/32 (8-15) and 8/20 (8-11), respectively), and both were lower in those caring for patients without than with tracheostomy (p < .001 and p < .02, respectively). Most cALS (77.6%) wished to continue caring for their pALS at home.

DISCUSSION: Family care partners of pALS spend more than half of each day caring for patients and are often depressed. Most cALS preferred providing care at home, but felt ill-prepared. Designing home-based medical care is necessary for pALS to thrive at home.}, } @article {pmid38760935, year = {2024}, author = {Fiadeiro, MB and Diogo, JC and Silva, AA and Kim, YS and Cristóvão, AC}, title = {NADPH Oxidases in Neurodegenerative Disorders: Mechanisms and Therapeutic Opportunities.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {7-9}, pages = {522-541}, doi = {10.1089/ars.2023.0002}, pmid = {38760935}, issn = {1557-7716}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *NADPH Oxidases/metabolism/antagonists & inhibitors ; *Reactive Oxygen Species/metabolism ; Animals ; Oxidative Stress ; }, abstract = {Significance: The nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme family, located in the central nervous system, is recognized as a source of reactive oxygen species (ROS) in the brain. Despite its importance in cellular processes, excessive ROS generation leads to cell death and is involved in the pathogenesis of neurodegenerative disorders. Recent advances: NOX enzymes contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke, highlighting their potential as targets for future therapeutic development. This review will discuss NOX's contribution and therapeutic targeting potential in neurodegenerative diseases, focusing on PD, AD, ALS, and stroke. Critical issues: Homeostatic and physiological levels of ROS are crucial for regulating several processes, such as development, memory, neuronal signaling, and vascular homeostasis. However, NOX-mediated excessive ROS generation is deeply involved in the damage of DNA, proteins, and lipids, leading to cell death in the pathogenesis of a wide range of diseases, namely neurodegenerative diseases. Future directions: It is essential to understand the role of NOX homologs in neurodegenerative disorders and the pathological mechanisms undergoing neurodegeneration mediated by increased levels of ROS. This further knowledge will allow the development of new specific NOX inhibitors and their application for neurodegenerative disease therapeutics. Antioxid. Redox Signal. 41, 522-541.}, } @article {pmid38760174, year = {2024}, author = {Pal, A and Grossmann, D and Glaß, H and Zimyanin, V and Günther, R and Catinozzi, M and Boeckers, TM and Sterneckert, J and Storkebaum, E and Petri, S and Wegner, F and Grill, SW and Pan-Montojo, F and Hermann, A}, title = {Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.}, journal = {Life science alliance}, volume = {7}, number = {8}, pages = {}, pmid = {38760174}, issn = {2575-1077}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; *Glycolates/metabolism/pharmacology ; *Mitochondria/metabolism ; *Protein Deglycase DJ-1/metabolism/genetics ; *Lactic Acid/metabolism ; *Superoxide Dismutase-1/metabolism/genetics ; Membrane Potential, Mitochondrial ; Motor Neurons/metabolism ; Lysosomes/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.}, } @article {pmid38759931, year = {2024}, author = {Guo, X and Zhang, Z and Gu, J and Ke, P and Liu, J and Meng, Y and Zheng, W and Que, W and Fan, R and Luo, J and Xiao, F}, title = {FUDNC1-dependent mitophagy ameliorate motor neuron death in an amyotrophic lateral sclerosis mouse model.}, journal = {Neurobiology of disease}, volume = {197}, number = {}, pages = {106534}, doi = {10.1016/j.nbd.2024.106534}, pmid = {38759931}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Mitophagy/physiology ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Mice ; *Disease Models, Animal ; *Mitochondrial Proteins/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Humans ; Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1[G93A] or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1[G93A] mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1[G93A] mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1[G93A] mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.}, } @article {pmid38759788, year = {2024}, author = {Kumar, RP and Sivan, V and Bachir, H and Sarwar, SA and Ruzicka, F and O'Malley, GR and Lobo, P and Morales, IC and Cassimatis, ND and Hundal, JS and Patel, NV}, title = {Can Artificial Intelligence Mitigate Missed Diagnoses by Generating Differential Diagnoses for Neurosurgeons?.}, journal = {World neurosurgery}, volume = {187}, number = {}, pages = {e1083-e1088}, doi = {10.1016/j.wneu.2024.05.052}, pmid = {38759788}, issn = {1878-8769}, mesh = {Humans ; Diagnosis, Differential ; *Artificial Intelligence ; *Neurosurgeons ; *Missed Diagnosis ; Neurosurgery ; Diagnostic Errors ; }, abstract = {BACKGROUND/OBJECTIVE: Neurosurgery emphasizes the criticality of accurate differential diagnoses, with diagnostic delays posing significant health and economic challenges. As large language models (LLMs) emerge as transformative tools in healthcare, this study seeks to elucidate their role in assisting neurosurgeons with the differential diagnosis process, especially during preliminary consultations.

METHODS: This study employed 3 chat-based LLMs, ChatGPT (versions 3.5 and 4.0), Perplexity AI, and Bard AI, to evaluate their diagnostic accuracy. Each LLM was prompted using clinical vignettes, and their responses were recorded to generate differential diagnoses for 20 common and uncommon neurosurgical disorders. Disease-specific prompts were crafted using Dynamed, a clinical reference tool. The accuracy of the LLMs was determined based on their ability to identify the target disease within their top differential diagnoses correctly.

RESULTS: For the initial differential, ChatGPT 3.5 achieved an accuracy of 52.63%, while ChatGPT 4.0 performed slightly better at 53.68%. Perplexity AI and Bard AI demonstrated 40.00% and 29.47% accuracy, respectively. As the number of considered differentials increased from 2 to 5, ChatGPT 3.5 reached its peak accuracy of 77.89% for the top 5 differentials. Bard AI and Perplexity AI had varied performances, with Bard AI improving in the top 5 differentials at 62.11%. On a disease-specific note, the LLMs excelled in diagnosing conditions like epilepsy and cervical spine stenosis but faced challenges with more complex diseases such as Moyamoya disease and amyotrophic lateral sclerosis.

CONCLUSIONS: LLMs showcase the potential to enhance diagnostic accuracy and decrease the incidence of missed diagnoses in neurosurgery.}, } @article {pmid38759454, year = {2024}, author = {Wei, Y and Zhong, S and Yang, H and Wang, X and Lv, B and Bian, Y and Pei, Y and Xu, C and Zhao, Q and Wu, Y and Luo, D and Wang, F and Sun, H and Chen, Y}, title = {Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.}, journal = {European journal of medicinal chemistry}, volume = {272}, number = {}, pages = {116496}, doi = {10.1016/j.ejmech.2024.116496}, pmid = {38759454}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.}, } @article {pmid38759021, year = {2024}, author = {Pupillo, E and Al-Chalabi, A and Sassi, S and Arippol, E and Tinti, L and Vitelli, E and Copetti, M and Leone, MA and Bianchi, E}, title = {Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Journal of neuromuscular diseases}, volume = {11}, number = {4}, pages = {749-765}, pmid = {38759021}, issn = {2214-3602}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Clinical Trials as Topic/standards ; *Research Design ; }, abstract = {BACKGROUND: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found.

OBJECTIVE: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022.

METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses.

RESULTS: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%.

CONCLUSION: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.}, } @article {pmid38758376, year = {2024}, author = {Li, X and Song, C and Wang, Y and Wang, J and Tang, Q and Wu, Z and Zhou, Y and Sun, J and Jia, Y and Lin, Z and Li, S}, title = {Accuracy of 14 intraocular lens power calculation formulas in extremely long eyes.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {262}, number = {11}, pages = {3619-3628}, pmid = {38758376}, issn = {1435-702X}, support = {2020SKC2002//Project Supported by Science and Technology Innovation Program of Socialization Investment of Hunan Province/ ; }, mesh = {Humans ; Retrospective Studies ; *Lenses, Intraocular ; *Refraction, Ocular/physiology ; *Axial Length, Eye ; Female ; Male ; Aged ; *Biometry/methods ; *Optics and Photonics ; Middle Aged ; Reproducibility of Results ; Visual Acuity ; Aged, 80 and over ; Adult ; Lens Implantation, Intraocular ; }, abstract = {PURPOSE: To compare the accuracy of 14 formulas in calculating intraocular lens (IOL) power in extremely long eyes with axial length (AL) over 30.0 mm.

METHODS: In this retrospective study, 211 eyes (211 patients) with ALs > 30.0 mm were successfully treated with cataract surgery without complications. Ocular biometric parameters were obtained from IOLMaster 700. Fourteen formulas were evaluated using the optimized A constants: Barrett Universal II (BUII), Kane, Emmetropia Verifying Optical (EVO) 2.0, PEARL-DGS, T2, SRK/T, Holladay 1, Holladay 2, Haigis and Wang-Koch AL adjusted formulas (SRK/Tmodified-W/K, Holladay 1modified-W/K, Holladay 1NP-modified-W/K, Holladay 2modified-W/K, Holladay 2NP-modified-W/K). The mean prediction error (PE) and standard deviation (SD), mean absolute errors (MAE), median absolute errors (MedAE), and the percentage of prediction errors (PEs) within ± 0.25 D, ± 0.50 D, ± 1.00 D were analyzed.

RESULTS: The Kane formula had the smallest MAE (0.43 D) and MedAE (0.34 D). The highest percentage of PE within ± 0.25 D was for EVO 2.0 (37.91%) and the Holladay 1NP-modified-W/K formulas (37.91%). The Kane formula had the highest percentage of PEs in the range of ± 0.50, ± 0.75, ± 1.00, and ± 2.00 D. There was no significant difference in PEs within ± 0.25, ± 0.50 ± 0.75 and ± 1.00 D between BUII, Kane, EVO 2.0 and Wang-Koch AL adjusted formulas (P > .05) by using Cochran's Q test. The Holladay 2modified-W/K formula has the lowest percentage of hyperopic outcomes (29.38%).

CONCLUSIONS: The BUII, Kane, EVO 2.0 and Wang-Koch AL adjusted formulas have comparable accuracy for IOL power calculation in eyes with ALs > 30.0 mm.}, } @article {pmid38758353, year = {2024}, author = {Mavroudis, I and Alexiou, P and Petridis, F and Ciobica, A and Balmus, IM and Gireadă, B and Gurzu, IL and Novac, O and Novac, B}, title = {Patients' and caregivers' attitudes towards patient assisted suicide or euthanasia in amyotrophic lateral sclerosis-a meta-analysis.}, journal = {Acta neurologica Belgica}, volume = {124}, number = {5}, pages = {1489-1498}, pmid = {38758353}, issn = {2240-2993}, mesh = {*Amyotrophic Lateral Sclerosis/psychology ; Humans ; *Suicide, Assisted/psychology ; *Caregivers/psychology ; *Euthanasia/psychology ; Attitude to Death ; }, abstract = {Assisted suicide and euthanasia are long debated topics in amyotrophic lateral sclerosis (ALS) patients care. We conducted a meta-analysis to evaluate the attitudes of ALS patients and their caregivers toward physician-assisted suicide (PAS) and euthanasia. Also, we were interested to identify the factors associated with the positive or negative attitude of patients and caregivers towards PAS/euthanasia. A thorough search of the online databases (PubMed, Cochrane Library, and Web of Science) was conducted and eligibility criteria according to the PRISMA guidelines were used to include the studies in the current meta-analysis. The assessment of the quality of the selected studies was carried out using a pre-specified set of criteria by Cochrane. The studies that were selected for this meta-analysis suggested that the expression of the wish to die is more likely correlated with depression, anxiety, hopelessness, and lack of optimism. The overall prevalence of considering PAS/euthanasia significantly varies in a dependent manner over the cultural, legal, and societal factors. In this context, we found that the opinion on this topic can be deeply personal and may vary widely among individuals and communities. Lower quality of life and lower religiosity were associated with a positive attitude toward PAS/euthanasia. On the other hand, patients who are more religious are less likely to choose PAS/euthanasia. Gender does not appear to play a significant role in determining attitudes towards PAS/euthanasia in ALS patients. Other factors, such as education and psychological state, could also be important. In conclusion, end-of-life decisions in ALS patients are complex and require careful consideration of individual values, beliefs, and preferences. Understanding the factors that influence a patient's attitude towards PAS/euthanasia can help healthcare providers to offer appropriate care and support for these patients and their families.}, } @article {pmid38758288, year = {2024}, author = {Qi, C and Kobayashi, R and Kawakatsu, S and Kametani, F and Scheres, SHW and Goedert, M and Hasegawa, M}, title = {Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G.}, journal = {Acta neuropathologica}, volume = {147}, number = {1}, pages = {86}, pmid = {38758288}, issn = {1432-0533}, support = {JSPS KAKENHI//Japanese society for the promotion of science/ ; MC_UP_A025_1013/MRC_/Medical Research Council/United Kingdom ; JPMH20GB1002//Ministry of Health, Labour and Welfare/ ; JPMH23GB1003//Ministry of Health, Labour and Welfare/ ; MC_UP_A025-1013/MRC_/Medical Research Council/United Kingdom ; JP20K07922//Japanese society for the promotion of science/ ; MC_U105184291/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Tauopathies/genetics/pathology ; *Chronic Traumatic Encephalopathy/pathology/genetics ; *tau Proteins/genetics/metabolism ; *Valosin Containing Protein/genetics ; *Mutation ; Vacuoles/pathology/ultrastructure ; Male ; Adenosine Triphosphatases/genetics ; Cell Cycle Proteins/genetics ; Middle Aged ; Frontotemporal Dementia/genetics/pathology ; Brain/pathology ; Female ; }, abstract = {Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.}, } @article {pmid38758193, year = {2024}, author = {Oliveira Santos, M and de Carvalho, M}, title = {Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {6}, pages = {549-553}, doi = {10.1080/14737175.2024.2355983}, pmid = {38758193}, issn = {1744-8360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients.

AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed.

EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.}, } @article {pmid38758158, year = {2024}, author = {Zou, X and Shi, Y and Zhang, T and Huang, A and Cui, H and Wang, T}, title = {Electroacupuncture Combined with Chinese Herbal Medicine, Qidong Huoluo Granule, for Amyotrophic Lateral Sclerosis: An 8-Month Case Report.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {38758158}, issn = {1078-6791}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder characterized by progressive muscle weakness and eventual paralysis, for which there is currently no curative treatment. Mainstream medical interventions primarily focus on providing supportive care. However, acupuncture offers promising avenues for alleviating symptoms and enhancing quality of life. Specific acupuncture points are targeted to address bulbar paralysis as well as paralysis affecting the upper and lower extremities.

OBJECTIVE: To investigate the efficacy of electroacupuncture combined with Chinese herbal medicine in delaying disease progression and alleviating symptoms of bulbar paralysis in patients with ALS.

CASE PRESENTATION: A 51-year-old male presented with a 4-year and 8-month history of weakness in his left arm and both legs, accompanied by muscle cramps and diminished coordination, which had rapidly worsened over the past year. ALS was diagnosed, and the patient was initiated on oral Riluzole (50 mg) and Qidong Huoluo granule, a Chinese herbal compound, administered twice daily. Concurrently, he underwent acupuncture treatment sessions twice weekly for over 8 months.

RESULTS: Following acupuncture therapy, the patient experienced gradual stabilization of symptoms, notably improvement in swallowing function. The combination of electroacupuncture and Qidong Huoluo granule resulted in sustained clinical enhancements post-treatment, including improvements in speech, coughing, articulation, and breathing.

CONCLUSION: Electroacupuncture therapy demonstrates the potential to slow disease progression and ameliorate symptoms of bulbar paralysis in ALS patients. However, further robust clinical research is imperative to explain the precise therapeutic role of electroacupuncture in managing this debilitating condition. Continued investigation into the efficacy and safety profile of electroacupuncture holds promise for advancing treatment modalities for ALS.}, } @article {pmid38757649, year = {2024}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Reply to Glycemic Index/Load Effect on ALS Progression: Potential Interaction with Riluzole.}, journal = {Annals of neurology}, volume = {96}, number = {1}, pages = {208-209}, doi = {10.1002/ana.26971}, pmid = {38757649}, issn = {1531-8249}, support = {K23NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Riluzole/therapeutic use/pharmacology ; *Disease Progression ; *Glycemic Index/drug effects ; Neuroprotective Agents/therapeutic use/pharmacology ; Blood Glucose/drug effects/metabolism ; }, } @article {pmid38756356, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Colorectal anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Frontiers in surgery}, volume = {11}, number = {}, pages = {1371567}, pmid = {38756356}, issn = {2296-875X}, abstract = {BACKGROUND: Anastomotic leaks (ALs) are a significant and feared postoperative complication, with incidence of up to 30% despite advances in surgical techniques. With implications such as additional interventions, prolonged hospital stays, and hospital readmission, ALs have important impacts at the level of individual patients and healthcare providers, as well as healthcare systems as a whole. Challenges in developing unified definitions and grading systems for leaks have proved problematic, despite acknowledgement that colorectal AL is a critical issue in intestinal surgery with serious consequences. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs, and consequences of this postoperative complication.

METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following keywords: anastomosis, anastomotic leak, colorectal, surgery, grading system, complications, risk factors, and consequences. Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.

RESULTS: A universally accepted definition and grading system for ALs continues to be lacking, leading to variability in reported incidence in the literature. Additional factors add to variability in estimates, including differences in the anastomotic site and institutional/individual differences in operative technique. Various groups have worked to publish guidelines for defining and grading AL, with the International Study Group of Rectal Cancer (ISGRC/ISREC) definition the current most recommended universal definition for colorectal AL. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.

CONCLUSIONS: Colorectal AL remains a significant challenge in intestinal surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, } @article {pmid38755145, year = {2024}, author = {Garcia-Montojo, M and Fathi, S and Rastegar, C and Simula, ER and Doucet-O'Hare, T and Cheng, YHH and Abrams, RPM and Pasternack, N and Malik, N and Bachani, M and Disanza, B and Maric, D and Lee, MH and Wang, H and Santamaria, U and Li, W and Sampson, K and Lorenzo, JR and Sanchez, IE and Mezghrani, A and Li, Y and Sechi, LA and Pineda, S and Heiman, M and Kellis, M and Steiner, J and Nath, A}, title = {TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {4163}, pmid = {38755145}, issn = {2041-1723}, support = {I01 BX002466/BX/BLRD VA/United States ; NS003130//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Asparaginase/genetics/metabolism ; Autoantigens/genetics/metabolism ; Brain/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Motor Cortex/metabolism/pathology ; *Neurons/metabolism/pathology ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; Endogenous Retroviruses/genetics/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.}, } @article {pmid38753998, year = {2025}, author = {Yin, Z and Yang, Z and Liu, Y and Zhao, L and Liang, F}, title = {Oxidative stress and neurodegenerative diseases: a bidirectional Mendelian randomization study.}, journal = {Nutritional neuroscience}, volume = {28}, number = {1}, pages = {107-115}, doi = {10.1080/1028415X.2024.2352195}, pmid = {38753998}, issn = {1476-8305}, mesh = {*Mendelian Randomization Analysis ; Humans ; *Oxidative Stress ; *Neurodegenerative Diseases/genetics ; *Genome-Wide Association Study ; Alzheimer Disease/genetics ; Uric Acid/blood ; Zinc/blood ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; alpha-Tocopherol/blood ; Biomarkers/blood ; }, abstract = {INTRODUCTION: Oxidative stress (OS) has been linked to neurodegenerative diseases in numerous epidemiological studies; however, whether it is a pathogenesis or a downstream factor remains controversial.

METHODS: A two-sample bidirectional Mendelian randomization (MR) analysis was implemented to examine evidence of causality of 15 OS injury markers with 3 major neurodegenerative diseases using available genome-wide association studies statistics. As a main approach, inverse-variance weighted (IVW) analysis was performed. The weighted-median (WM) analysis was used to validate the relationship. In order to investigate the existence of horizontal pleiotropy and correct the IVW estimate, the Radial MR approach was applied. To gauge the consistency and robustness of the findings, several sensitivity and pleiotropy analyses were used. For this analysis, p < 0.05 indicates a nominally causal association; according to the Bonferroni correction test, p < 0.0011 indicates a statistically significant causal association.

RESULTS: Via IVW and WM, in directional MR, it was genetically predicted that zinc was nominally causally correlated with the risk of Parkinson's disease but not after Bonferroni correction test; alpha-tocopherol was nominally causally correlated with the risk of Amyotrophic lateral sclerosis (ALS) but not after Bonferroni correction test; furthermore, in reverse MR, it was genetically predicted that Alzheimer's disease was causally correlated with uric acid but not after Bonferroni correction test. These above findings were stable across sensitivity and pleiotropy analyses.

CONCLUSIONS: Based on the current study, there is no authentic genetic causal association between OS biomarkers and neurodegenerative diseases. The complex relationship is required to be confirmed in future experimental research.}, } @article {pmid38753768, year = {2024}, author = {Prasad, K and Hassan, MI and Raghuvanshi, S and Kumar, V}, title = {Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features.}, journal = {PloS one}, volume = {19}, number = {5}, pages = {e0301267}, pmid = {38753768}, issn = {1932-6203}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; C9orf72 Protein/genetics/metabolism ; *Cerebellum/metabolism/pathology ; *Frontal Lobe/metabolism/pathology ; Frontotemporal Dementia/genetics/pathology/metabolism ; MicroRNAs/genetics/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative diseases for which at present no cure is available. Despite the extensive research the progress from diagnosis to prognosis in ALS and frontotemporal dementia (FTD) has been slow which represents suboptimal understanding of disease pathophysiological processes. In recent studies, several genes have been associated with the ALS and FTD diseases such as SOD1, TDP43, and TBK1, whereas the hexanucleotide GGGGCC repeat expansion (HRE) in C9orf72 gene is a most frequent cause of ALS and FTD, that has changed the understanding of these diseases.

METHODS: The goal of this study was to identify and spatially determine differential gene expression signature differences between cerebellum and frontal cortex in C9orf72-associated ALS (C9-ALS), to study the network properties of these differentially expressed genes, and to identify miRNAs targeting the common differentially expressed genes in both the tissues. This study thus highlights underlying differential cell susceptibilities to the disease mechanisms in C9-ALS and suggesting therapeutic target selection in C9-ALS.

RESULTS: In this manuscript, we have identified that the genes involved in neuron development, protein localization and transcription are mostly enriched in cerebellum of C9-ALS patients, while the UPR-related genes are enriched in the frontal cortex. Of note, UPR pathway genes were mostly dysregulated both in the C9-ALS cerebellum and frontal cortex. Overall, the data presented here show that defects in normal RNA processing and the UPR pathway are the pathological hallmarks of C9-ALS. Interestingly, the cerebellum showed more strong transcriptome changes than the frontal cortex.

CONCLUSION: Interestingly, the cerebellum region showed more significant transcriptomic changes as compared to the frontal cortex region suggesting its active participation in the disease process. This nuanced understanding may offer valuable insights for the development of targeted therapeutic strategies aimed at mitigating disease progression in C9-ALS.}, } @article {pmid38751620, year = {2024}, author = {Shojaei, M and Zhou, Q and Palumbo, G and Schaefer, R and Kaskinoro, J and Vehmaan-Kreula, P and Bartenstein, P and Brendel, M and Edbauer, D and Lindner, S}, title = {Development and Preclinical Evaluation of a Copper-64-Labeled Antibody Targeting Glycine-Alanine Dipeptides for PET Imaging of C9orf72-Associated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.}, journal = {ACS pharmacology & translational science}, volume = {7}, number = {5}, pages = {1404-1414}, pmid = {38751620}, issn = {2575-9108}, abstract = {Aggregating poly(glycine-alanine) (poly-GA) is derived from the unconventional translation of the pathogenic intronic hexanucleotide repeat expansion in the C9orf72 gene, which is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly-GA accumulates predominantly in neuronal cytoplasmic inclusions unique to C9orf72 ALS/FTD patients. Poly-GA is, therefore, a promising target for PET/CT imaging of FTD/ALS to monitor disease progression and therapeutic interventions. A novel [64]Cu-labeled anti-GA antibody (mAb1A12) targeting the poly-GA protein was developed and evaluated in a transgenic mouse model. It was obtained with high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity, and showed high stability in vitro and ex vivo and specifically bound to poly-GA. The affinity of NODAGA-mAb1A12 for poly-GA was not affected by this modification. [[64]Cu]Cu-NODAGA-mAb1A12 was injected into transgenic mice expressing GFP-(GA)175 in excitatory neurons driven by Camk2a-Cre and in control littermates. PET/CT imaging was performed at 2, 20, and 40 h post-injection (p.i.) and revealed a higher accumulation in the cortex in transgenic mice than in wild-type mice, as reflected by higher standardized uptake value ratios (SUVR) using the cerebellum as the reference region. The organs were isolated for biodistribution and ex vivo autoradiography. Autoradiography revealed a higher cortex-to-cerebellum ratio in the transgenic mice than in the controls. Results from autoradiography were validated by immunohistochemistry and poly-GA immunoassays. Moreover, we confirmed antibody uptake in the CNS in a pharmacokinetic study of the perfused tissues. In summary, [[64]Cu]Cu-NODAGA-mAb1A12 demonstrated favorable in vitro characteristics and an increased relative binding in poly-GA transgenic mice compared to wild-type mice in vivo. Our results with this first-in-class radiotracer suggested that targeting poly-GA is a promising approach for PET/CT imaging in FTD/ALS.}, } @article {pmid38751168, year = {2024}, author = {Raffaele, S and Nguyen, N and Milanese, M and Mannella, FC and Boccazzi, M and Frumento, G and Bonanno, G and Abbracchio, MP and Bonifacino, T and Fumagalli, M}, title = {Montelukast improves disease outcome in SOD1[G93A] female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity.}, journal = {British journal of pharmacology}, volume = {181}, number = {18}, pages = {3303-3326}, doi = {10.1111/bph.16408}, pmid = {38751168}, issn = {1476-5381}, support = {GPR17ALS-1//AriSLA ETS - Fondazione Italiana di ricerca per la SLA/ ; 2017NSXP8J//Italian Ministry of University and Research (MUR)/ ; PE0000006//#NEXTGENERATIONEU (NGEU) and the Italian Ministry of University and Research (MUR), NRRP - National Recovery and Resilience Plan/ ; //Foundation Bellandi Bernardoni/ ; }, mesh = {Animals ; Female ; *Cyclopropanes/pharmacology ; *Quinolines/pharmacology ; *Acetates/pharmacology/therapeutic use ; *Oligodendroglia/drug effects/metabolism/pathology ; *Sulfides/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology ; *Mice, Transgenic ; Mice ; Male ; Receptors, Leukotriene/metabolism/genetics ; Receptors, G-Protein-Coupled/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Spinal Cord/drug effects/metabolism/pathology ; Microglia/drug effects/metabolism/pathology ; Nerve Tissue Proteins ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro-regenerative local milieu and re-establish proper oligodendrocyte functions may be beneficial.

EXPERIMENTAL APPROACH: Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein-coupled receptor 17 (GPR17) and of cysteinyl-leukotriene receptor 1 (CysLT1R) receptors on microglia and astrocytes, in the SOD1[G93A] ALS mouse model. We chronically treated SOD1[G93A] mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.

KEY RESULTS: Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1[G93A] mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia/macrophages and astrocytes in the spinal cord of female SOD1[G93A] mice, suggesting enhanced pro-regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex-based difference in the protective activity of MTK.

CONCLUSIONS AND IMPLICATIONS: Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti-asthmatic drug, may be a promising sex-specific strategy for personalized ALS treatment.}, } @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 = {Female ; Humans ; Male ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Astrocytes/pathology/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Mitochondria/pathology/metabolism ; *Mitochondrial Proteins/genetics/metabolism ; *Transcription Factors/genetics/metabolism ; }, 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.}, } @article {pmid38749729, year = {2025}, 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 Sclerosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {64}, number = {1}, pages = {133-136}, doi = {10.2169/internalmedicine.3622-24}, pmid = {38749729}, issn = {1349-7235}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation/therapy/diet therapy/physiopathology ; Aged, 80 and over ; *Exercise Therapy/methods ; *Weight Loss/physiology ; Nutrition Therapy/methods ; Acute Disease ; Deglutition Disorders/etiology/rehabilitation/therapy/physiopathology ; Muscle Strength/physiology ; Body Composition ; Treatment Outcome ; }, abstract = {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. 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. 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.}, } @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}, mesh = {Animals ; *Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism/genetics ; Cholinergic Neurons/metabolism ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; GABAergic Neurons/metabolism ; Locomotion ; Motor Neurons/metabolism ; Movement ; Synaptic Transmission ; *TDP-43 Proteinopathies/genetics/metabolism ; }, 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.}, } @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 = {61}, number = {12}, pages = {10529-10537}, pmid = {38748065}, issn = {1559-1182}, support = {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)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; Risk Factors ; Genetic Predisposition to Disease ; T-Lymphocytes/immunology/metabolism ; Polymorphism, Single Nucleotide/genetics ; Receptors, CCR7/genetics/metabolism ; }, 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 = {25}, number = {5-6}, pages = {563-569}, doi = {10.1080/21678421.2024.2351185}, pmid = {38747354}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy ; *Gastrostomy/methods ; Male ; Female ; Middle Aged ; Aged ; *Respiration, Artificial/statistics & numerical data ; Cohort Studies ; Retrospective Studies ; Enteral Nutrition/methods/statistics & numerical data ; Adult ; Noninvasive Ventilation/methods ; Survival Analysis ; }, 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 {pmid38747109, year = {2024}, author = {Bender, J and Kojeku, T and Preece, E}, title = {Grading lumbar foraminal stenosis - Interrater agreement of radiologists and radiology trainees before and after education of a standardised grading scale.}, journal = {Journal of medical imaging and radiation oncology}, volume = {68}, number = {5}, pages = {511-515}, doi = {10.1111/1754-9485.13669}, pmid = {38747109}, issn = {1754-9485}, mesh = {Humans ; *Spinal Stenosis/diagnostic imaging ; *Lumbar Vertebrae/diagnostic imaging ; *Observer Variation ; *Magnetic Resonance Imaging/methods ; *Radiologists ; Severity of Illness Index ; Radiology/education ; Reproducibility of Results ; Clinical Competence ; Male ; }, abstract = {INTRODUCTION: Lumbar foraminal stenosis is a key contributor to low back pain. Imaging, particularly MRI, is commonly used in the assessment of foraminal stenosis, contributing to treatment planning. The adoption of a standardised grading system to try and improve inter-rater agreement is thought to be of importance. Our study aims to assess the variability of grading lumbar foraminal stenosis amongst reporting doctors, determine whether education about a validated grading scale increases agreement, and determine if these changes persist over time.

METHODS: A single-site study involving MRI reporting registrars/radiologists was performed. Participants were shown select MRI images and asked to grade the degree of stenosis in each on a 4-point scale. Subsequently, they were educated about Lee et al's grading system and asked to re-grade the cases 1 and 6 weeks later. The level of agreement was calculated using Gwet's AC1 coefficient and Krippendorff's Alpha.

RESULTS: The baseline level of agreement was substantial (AC1 = 0.71). This decreased to a moderate level of agreement post-intervention (AC1 = 0.575 at 1-week, P-value 0.033 and AC1 = 0.598 at 6 weeks, P-value 0.012). A grading of severe stenosis was 21% more likely 6 weeks post-education.

CONCLUSION: The baseline agreement at our institution was substantial, thought to be due to the single-centre nature of the study. Moderate agreement was achieved after education regarding the Lee et al.'s scale, in-line with other studies, with changes maintained at 6 weeks, showing retention of the scale parameters. Grading of severe stenosis was more common post intervention.}, } @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 = {60}, number = {1}, pages = {3505-3543}, pmid = {38747014}, issn = {1460-9568}, support = {R01 NS043277/NS/NINDS NIH HHS/United States ; 5T32AG021885/NH/NIH HHS/United States ; R56 NS043277/NS/NINDS NIH HHS/United States ; NS043277/NH/NIH HHS/United States ; T32 GM144300/GM/NIGMS NIH HHS/United States ; T32 AG021885/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Copper/metabolism ; Animals ; Homeostasis/physiology ; Nervous System/metabolism ; }, 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, L and Quinn, CC and Amado, D and Baer, M and Lee, EB and Van Deerlin, VM 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), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69). Only individuals who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [95% CI 1.97-9.14], p<0.001) and an increased hazard (HR= 4.77 [95% CI 2.33-9.79], p<0.001) for developing secondary symptoms in those with a C9orf72 expansion compared to those without. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary symptoms. These data highlight the need for clinician vigilance to detect the onset of secondary motor and cognitive-behavioral symptoms in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.}, } @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 = {25}, number = {5-6}, pages = {506-516}, pmid = {38745522}, issn = {2167-9223}, mesh = {Humans ; *Motor Neuron Disease/psychology/therapy ; Male ; Female ; *Caregivers/psychology ; *Feasibility Studies ; Middle Aged ; Aged ; Behavioral Symptoms/etiology/therapy ; Adult ; }, 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 {pmid3874547