Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one downregulation of Galectin-3 ameliorates Aß pathogenesis-induced neuroinflammation in 5 × FAD mice.

Alzheimer's disease (AD) is characterized by ß-amyloid (Aß) aggregation and neuroinflammation, leading to a progressive synaptic loss and cognitive decline. Recent evidence highlights Galectin-3 (Gal-3) as a crucial factor in Aß pathogenesis, yet effective strategies to simultaneously target Gal-3 and Aß are currently insufficient. This study assesses the therapeutic efficacy of D30, an innovative anti-AD compound manifested promising effects on reducing Aß deposition and alleviating neuronal damage in scopolamine-induced AD models. In our study, we administered neurotoxic oligomeric Aß (oAß) to mice and observed increased Gal-3 deposition and microglial activation in the hippocampus, leading to significant cognitive impairments. Similarly, in the 5 × FAD mouse model, known for Aß overproduction, there was a progressive rise in Gal-3 levels and glial cell activation. We then investigated the effects of D30 on 5 × FAD mice, focusing on its modulation of Gal-3 and Aß and impact on neuroinflammatory responses. D30 effectively reduced Aß monomer production by inhibiting the expression of Amyloid Precursor Protein (APP) and presenilin 1 (PS1), as well as decreasing Aß oligomer aggregation. Treatment with D30 not only improved cognitive functions but also reversed dendritic spine loss and increased PSD95 expression in 5 × FAD mice. Notably, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. Mechanistic studies revealed that D30 binds to Gal-3 and disrupts the interaction between Gal-3 and the triggering receptor expressed on myeloid cells 2 (TREM2), as confirmed by fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST). Our findings underscore the interaction between Gal-3 and Aß in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aß is crucial for preventing neuroinflammation and protecting neurons, D30 emerged as a novel compound with promising potential for AD treatment. AIMS: Alzheimer's disease (AD) is characterized by ß-amyloid (Aß) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aß pathogenesis. However, strategies to simultaneously target Gal-3 and Aß are currently insufficient. This study evaluates the therapeutic efficacy of D30, in reducing Gal-3 and Aß pathogenesis. MATERIALS AND METHODS: We applied exogenous oligomeric Aß and used 5 × FAD mice to assess the impact of Aß on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST). KEY FINDINGS: D30 effectively reduced Aß monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aß aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST. SIGNIFICANCE: Our findings underscore the interaction between Gal-3 and Aß in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aß is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.

Efficacy, safety, and response predictors of Astragalus in patients with mild to moderate Alzheimer's disease: A study protocol of an assessor-blind, statistician-blind open-label randomized controlled trial.

Background: This pragmatic clinical trial aims to determine the efficacy and safety of add-on Astragalus membranaceus (AM) for cognition and non-cognition in patients with of mild to moderate Alzheimer's disease complicated with orthostatic hypotension in orthostatic hypotension, elucidate the underlying mechanisms, identify related response predictors, and explore effective drug components. Methods: This is an add-on, assessor-blinded, parallel, pragmatic, randomized controlled trial. At least 66 adults with mild to moderate Alzheimer's disease (AD) and OH aged 50-85 years will be recruited. Participants will be randomized in a 1:1:1 ratio to receive 24 weeks of routine care or add-on low dose AM or add-on high dose AM group. The primary efficacy outcome will be measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Chinese version. Secondary efficacy outcome assessment will include neuropsychological tests, blood pressure, plasma biomarkers, multimodal electroencephalograms, and neuroimaging. Safety outcome measures will include physical examinations, vital signs, electrocardiography, laboratory tests (such as hematologic and blood chemical tests), and adverse event records. Ethics and dissemination: This trial was approved and supervised by Fujian Medical University Union Hospital (2021KJCX040). Independent results, findings will be published in peer-reviewed journals and presented at national and international conferences. Trial registration number: NCT05647473; ClinicalTrials.gov Identifier.

Abnormal brain-heart electrophysiology in mild and severe orthostatic hypotension.

INTRODUCTION: This study investigated the changes in cardiocerebral electrophysiology in patients with mild orthostatic hypotension (MOH) and severe orthostatic hypotension (SOH) and their relationship with the severity of orthostatic hypotension, psychiatric symptoms, and cognitive dysfunction. METHODS: This study included 72 nonorthostatic hypotension (NOH), 17 with MOH, and 11 with SOH. Seated resting-state heart rate variability (HRV) and quantitative electroencephalogram parameters were synchronized and recorded. HRV measures in the time and frequency domains were analyzed, along with the peak frequency and power of the brain waves. RESULTS: Abnormal neuronal activity was found in FP1 in patients with MOH, whereas it was more widespread in FP1, FP2, and O2 in patients with SOH (P < 0.05). Cardiac and cerebral electrophysiological abnormalities were significantly associated with orthostatic hypotension severity, psychiatric symptoms, and cognitive dysfunction. CONCLUSION: Abnormal EEG activity in patients are mainly manifested in the prefrontal and occipital lobes, especially in patients with SOH. These results may help patients to better understand the mechanisms underlying orthostatic hypotension severity and psychiatric and cognitive impairment in orthostatic hypotension.

EMG-YOLO: road crack detection algorithm for edge computing devices.

Introduction: Road cracks significantly shorten the service life of roads. Manual detection methods are inefficient and costly. The YOLOv5 model has made some progress in road crack detection. However, issues arise when deployed on edge computing devices. The main problem is that edge computing devices are directly connected to sensors. This results in the collection of noisy, poor-quality data. This problem adds computational burden to the model, potentially impacting its accuracy. To address these issues, this paper proposes a novel road crack detection algorithm named EMG-YOLO. Methods: First, an Efficient Decoupled Header is introduced in YOLOv5 to optimize the head structure. This approach separates the classification task from the localization task. Each task can then focus on learning its most relevant features. This significantly reduces the model's computational resources and time. It also achieves faster convergence rates. Second, the IOU loss function in the model is upgraded to the MPDIOU loss function. This function works by minimizing the top-left and bottom-right point distances between the predicted bounding box and the actual labeled bounding box. The MPDIOU loss function addresses the complex computation and high computational burden of the current YOLOv5 model. Finally, the GCC3 module replaces the traditional convolution. It performs global context modeling with the input feature map to obtain global context information. This enhances the model's detection capabilities on edge computing devices. Results: Experimental results show that the improved model has better performance in all parameter indicators compared to current mainstream algorithms. The EMG-YOLO model improves the accuracy of the YOLOv5 model by 2.7%. The mAP (0.5) and mAP (0.9) are improved by 2.9% and 0.9%, respectively. The new algorithm also outperforms the YOLOv5 model in complex environments on edge computing devices. Discussion: The EMG-YOLO algorithm proposed in this paper effectively addresses the issues of poor data quality and high computational burden on edge computing devices. This is achieved through optimizing the model head structure, upgrading the loss function, and introducing global context modeling. Experimental results demonstrate significant improvements in both accuracy and efficiency, especially in complex environments. Future research can further optimize this algorithm and explore more lightweight and efficient object detection models for edge computing devices.

Occurrence and Exposure Assessment of Lipophilic Shellfish Toxins in the Zhejiang Province, China.

Although lipophilic shellfish toxins (LSTs) pose a significant threat to the health of seafood consumers, their systematic investigation and risk assessment remain scarce. The goals of this study were as follows: (1) analyze LST levels in commercially available shellfish in Zhejiang province, China, and determine factors influencing LST distribution; (2) assess the acute dietary risk of exposure to LSTs for local consumers during the red tide period; (3) explore potential health risks of LSTs in humans; and (4) study the acute risks of simultaneous dietary exposure to LSTs and paralytic shellfish toxins (PSTs). A total of 546 shellfish samples were collected. LSTs were detected in 89 samples (16.3%) at concentrations below the regulatory limits. Mussels were the main shellfish species contaminated with LSTs. Spatial variations were observed in the yessotoxin group. Acute exposure to LSTs based on multiple scenarios was low. The minimum tolerable exposure durations for LSTs calculated using the mean and the 95th percentile of consumption data were 19.7 and 4.9 years, respectively. Our findings showed that Zhejiang province residents are at a low risk of combined exposure to LSTs and PSTs; however, the risk may be higher for children under 6 years of age in the extreme scenario.

Hypotension with neurovascular changes and cognitive dysfunction: An epidemiological, pathobiological, and treatment review.

ABSTRACT: Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer's disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.

A comprehensive analysis of the oncogenic and prognostic role of TBC1Ds in human hepatocellular carcinoma.

Backgrounds: TBC1D family members (TBC1Ds) are a group of proteins that contain the Tre2-Bub2-Cdc16 (TBC) domain. Recent studies have shown that TBC1Ds are involved in tumor growth, but no analysis has been done of expression patterns and prognostic values of TBC1Ds in hepatocellular carcinoma (HCC). Methods: The expression levels of TBC1Ds were evaluated in HCC using the TIMER, UALCN and Protein Atlas databases. The correlation between the mRNA levels of TBC1Ds and the prognosis of patients with HCC in the GEPIA database was then analyzed. An enrichment analysis then revealed genes that potentially interact with TBC1Ds. The correlation between levels of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC were studied using the TIMER 2.0 database. Finally, a series of in vitro assays verified the role of TBC1Ds in HCC progression. Results: This study revealed the upregulated expression of TBC1Ds in HCC and the strong positive correlation between the mRNA levels of TBC1Ds and poor prognosis of patients with HCC. The functions of TBC1Ds were mainly related to autophagy and the AMPK pathway. There was also a significant correlation between level of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC. The promoting role of TBC1Ds in HCC progression was verified in vitro assays. Conclusion: The results of this analysis indicate that TBC1Ds may serve as new biomarkers for early diagnosis and treatment of HCC.

Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice.

BACKGROUND: Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes. CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.

Brain white matter changes and their associations with non-motor dysfunction in orthostatic hypotension in α-synucleinopathy: A NODDI study.

BACKGROUND: The specific non-motor symptoms associated with α-synucleinopathies, including orthostatic hypotension (OH), cognitive impairment, and emotional abnormalities, have been a subject of ongoing controversy over the mechanisms underlying the development of a vicious cycle among them. The distinct structural alterations in white matter (WM) in patients with α-synucleinopathies experiencing OH, alongside their association with other non-motor symptoms, remain unexplored. This study employs axial diffusivity and density imaging (NODDI) to investigate WM damage specific to α-synucleinopathies with concurrent OH, delivering fresh evidence to supplement our understanding of the pathogenic mechanisms and pathological rationales behind the occurrence of a spectrum of non-motor functional impairments in α-synucleinopathies. METHODS: This study recruited 49 individuals diagnosed with α-synucleinopathies, stratified into an α-OH group (n = 24) and an α-NOH group (without OH, n = 25). Additionally, 17 healthy controls were included for supine and standing blood pressure data collection, as well as neuropsychological assessments. Magnetic resonance imaging (MRI) was utilized for the calculation of NODDI parameters, and tract-based spatial statistics (TBSS) were employed to explore differential clusters. The fibers covered by these clusters were defined as regions of interest (ROI) for the extraction of NODDI parameter values and the analysis of their correlation with neuropsychological scores. RESULTS: The TBSS analysis unveiled specific cerebral regions exhibiting disparities within the α-OH group as compared to both the α-NOH group and the healthy controls. These differences were evident in clusters that indicated a decrease in the acquisition of the neurite density index (NDI), a reduction in the orientation dispersion index (ODI), and an increase in the isotropic volume fraction (FISO) (p < 0.05). The extracted values from these ROIs demonstrated significant correlations with clinically assessed differences in supine and standing blood pressure, overall cognitive scores, and anxiety-depression ratings (p < 0.05). CONCLUSION: Patients with α-synucleinopathies experiencing OH exhibit distinctive patterns of microstructural damage in the WM as revealed by the NODDI model, and there is a correlation with the onset and progression of non-motor functional impairments.

Polyunsaturated fatty acid-derived lipid mediator Resolvin D1 alleviates sepsis-induced disseminated intravascular coagulation via Caspase-1/Gasdermin D pyroptotic pathway.

BACKGROUND & AIMS: Sepsis-induced disseminated intravascular coagulation (DIC) is characterised by abnormal blood clotting resulting from severe infection, contributing to organ dysfunction in sepsis. Resolvin D1 (RvD1) is an endogenous lipid mediator, synthesised from the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) through enzymatic processes involving 15-LOX and 5-LOX. RvD1 is recognised for its protective properties against various inflammatory conditions. This study aims to investigate its potential to modulate coagulation dysfunction in sepsis and to evaluate coagulation disorders in septic patients. METHODS: Sepsis models were established by intraperitoneal injection LPS (20 mg/kg) or cecal ligation and puncture (CLP) followed by injection of RvD1 (10 µg/kg) or saline. The impact of RvD1 on coagulation dysfunction was assessed by clotting time and coagulation indicators such as TAT, D-dimer, PAI-1, and fibrinogen. The activity of the coagulation system in vivo was observed by evaluating dynamic microcirculation, platelets and thrombin in mice using intravital microscopy. The effect of RvD1 on pyroptosis was investigated by measuring NOD-like receptor protein 3 (NLRP3), Caspase-1, Caspase-11, and Gasdermin D (GSDMD) levels via western blot. Caspase-1 knockout mice, GSDMD knockout mice and bone marrow-derived macrophages (BMDMs) were used to elucidate the underlying mechanisms. Lastly, the concentration of RvD1 in plasma from septic patients was quantified to explore its relationship with coagulation and pyroptosis. RESULTS: RvD1 significantly attenuated coagulation dysfunction in septic mice induced by LPS and CLP, and inhibited Caspase-1/GSDMD-dependent pyroptosis in septic mice and bone marrow-derived macrophages. In septic patients, the plasma concentrations of RvD1 was negatively correlated with both coagulation-related indicators and markers of GSDMD activation. CONCLUSION: The results suggest that RvD1 can improve coagulation dysfunction in sepsis by regulating the Caspase-1/GSDMD pyroptotic pathway. Additionally, the concentration of RvD1 in septic patient plasma is related to prognosis and DIC development. RvD1 could be a potential biomarker and a promising therapeutic alternative in sepsis-induced DIC.

Distribution and Probabilistic Risk Assessment of Antibiotics, Illegal Drugs, and Toxic Elements in Gastropods from Southeast China.

We investigated fourteen antibiotics, three illegal drugs, and two toxic elements in commercially available gastropods from southeast China. The data revealed high detection frequencies (DFs) for florfenicol (61.32%), florfenicol amine (47.33%), and thiamphenicol (39.88%), with maximum concentrations of 1110, 2222, and 136 µg/kg wet weight (ww), respectively. The DFs of illegal drugs were 3.54% for leucomalachite green and 0.3% for chloramphenicol. The average levels of Cd and As were 1.17 and 6.12 mg/kg ww, respectively. All chemicals presented diverse DFs in different sampling months. The highest DFs of florfenicol, florfenicol amine, and thiamphenicol were in July. The health risk assessment showed that targeted hazard quotients (THQs) of antibiotics, Cd, and As for children, teens, and adults were all less than one. Notably, the toxic elements (Cd and As) were identified as the primary health risk in gastropods, contributing to over 90% of the total THQs.

Simultaneous Analysis of Nicarbazin, Diclazuril, Toltrazuril, and Its Two Metabolites in Chicken Muscle and Eggs by In-Syringe Dispersive Solid-Phase Filter Clean-Up Followed by Liquid Chromatography-Tandem Mass Spectrometry.

Nicarbazin (NICA) and triazine anticoccidial drugs (diclazuril (DIZ) and toltrazuril (TOZ)) are the primary strategy for preventing and treating coccidiosis. To prevent the development of drug resistance and mitigate the potential chronic toxicity to humans resulting from prolonged exposure, a liquid chromatography-tandem mass spectrometry method with high reliability and sensitivity was developed to determine NICA, DIZ, TOZ, and its two metabolites in chicken muscle and eggs. Upon establishing the extraction conditions involving 10 mL of acetonitrile and 10 min of sonication, in-syringe dispersive solid-phase extraction with silica was performed in combination with n-hexane clean-up. The selection of isotope peaks of precursor ions and low-mass range scanning allowed the two transitions for the quantification of all compounds. The limits of detection for DIZ and NICA were both 0.1 µg/kg, and for TOZ and metabolites, they were 0.3 µg/kg; the limits of quantitation were 0.3 and 1 µg/kg, respectively. The linear range was 0.25-50 ng/mL with a correlation coefficient r > 0.999. The average recoveries at three spiking levels in muscle and eggs were 90.1-105.2% and 94.0-103.7% with the relative standard deviations of 3.0-8.1% and 3.1-14.4%, respectively. The precision, accuracy, and stability were evaluated by three quality control samples.

Antibiotic residues in commercial freshwater fish from southeast China: distribution and human health risk assessment.

We investigated 14 antibiotic residues in 8 marketed freshwater fish species from southeast China and estimated the associated health risks to local consumers. The antibiotic residues were determined by UPLC-MS/MS. Our findings revealed widespread distribution of quinolones (QNs), tetracyclines (TCs), and chloramphenicols (CAPs) in the freshwater fish. Notably, the average concentrations of enrofloxacin and ciprofloxacin reached levels as high as 62.5 µg/kg wet weight (ww) and 11.7 µg/kg ww, respectively, and detection frequencies were 68.7% for enrofloxacin and 31.6% for ciprofloxacin. Additionally, we detected chloramphenicol, a prohibited antibiotic, in samples with a detection frequency of 0.76%. Among the fish species, the mean concentration of total antibiotic residues was highest in bluntnose black bream (263.3 µg/kg), followed by English perch (52.4 µg/kg), crucian carp (46.3 µg/kg), black carp (28.6 µg/kg), yellowcheek carp (21.0 µg/kg), grass carp (15.3 µg/kg), bighead carp (3.78 µg/kg), and mandarin fish (3.69 µg/kg). We estimated the daily intake values of these antibiotic residues which were lower than the acceptable daily intake values and hazard indexes were much less than 1. It indicates that there is very low direct health risk to consumers. Despite that, investigation on the chronic impact, such as antibiotic-resistant bacteria, gut microbiota disruption, and allergic reactions, is urgently needed.

Prognostic value of the systemic immune-inflammation index in patients with acute respiratory distress syndrome: A retrospective study.

Background: Inflammation is critical in the etiology and progression of acute respiratory distress syndrome (ARDS). This study aims to rigorously assess the predictive capacity of systemic immune-inflammation index (SII) in determining the outcomes of patients with ARDS. Methods: Patient data were extracted from version 2.2 of the Medical Information Mart for Intensive Care IV (MIMIC-IV). The Receiver Operating Characteristic (ROC) curve was deployed to determine the optimal cutoff value for the SII, facilitating the stratification of participants into distinct cohorts based on SII levels. The relationship between SII and survival outcomes was rigorously evaluated using Cox proportional hazards models. The association between SII and patient survival was rigorously examined using Cox proportional-hazard models. The impact of varying SII levels on mortality was quantitatively assessed through these models, with the results articulated as hazard ratios (HRs) and 95% confidence intervals (CIs). Three distinct models were formulated for this analysis: Model 1 employed univariate Cox regression to relate SII with mortality; Model 2 introduced adjustments for age and sex; and Model 3 extended these adjustments to include age, sex, race, SAPS II, APSIII, Hemoglobin, Albumin, Pneumonia, SpO2, and SBP. Results: Post-application of the inclusion criteria, a cohort of 976 eligible patients was delineated for detailed examination. Univariate analysis focusing on 30-day mortality within the SII ≥1694, the hazard ratio (HR) was 1.42 (95% confidence interval (CI): 1.11, 1.81). However, after adjusting for confounding factors such as age, sex, race, Simplified Acute Physiology Score II (SAPS II), Acute Physiology Score (APS) III, Hemoglobin, Albumin, Pneumonia, SpO2, and Systolic Blood Pressure (SBP), an SII value of ≥1694 was identified as an independent and significant risk factor for mortality in patients with ARDS, with an HR of 1.38 (95% CI: 1.08-1.77, P = 0.0016). This trend was consistent for 90-day and one-year mortality rates. Conclusions: SII surfaced as an autonomous determinant of mortality in ARDS patients, affirming its status as an accessible and dependable prognostic indicator for individuals newly diagnosed with this critical condition. Additional research is imperative to further elucidate the prognostic implications of SII in the therapeutic management of patients with ARDS.

Aberrant microstructural integrity of white matter in mild and severe orthostatic hypotension: A NODDI study.

OBJECTIVE: Scarce evidence is available to elucidate the association between the abnormal microstructure of white matter (WM) and cognitive performance in patients with orthostatic hypotension (OH). This study investigated the microstructural integrity of WM in patients with mild OH (MOH) and severe OH (SOH) and evaluated the association of abnormal WM microstructure with the broad cognitive domains and cognition-related plasma biomarkers. METHODS: Our study included 72 non-OH (NOH), 17 MOH, and 11 SOH participants. Across the groups, the WM integrity was analyzed by neurite orientation dispersion and density imaging (NODDI), and differences in WM microstructure were evaluated by nonparametric tests and post hoc models. The correlations between WM microstructure and broad cognitive domains and cognition-related plasma biomarkers were assessed by Spearman's correlation analysis. RESULTS: The abnormal WM microstructure was localized to the WM fiber bundles in MOH patients but distributed widely in SOH cohorts (p < 0.05). Further analysis showed that the neurite density index of the left cingulate gyrus was negatively associated with amyloid ß-40, glial fibrillary acidic protein, neurofilament light chain, phospho-tau181 (p < 0.05) but positively with global cognitive function (MOCA, MMSE, AER-III), memory, attention, language, language fluency, visuospatial function and amyloid ß-40 / amyloid ß-42 (p < 0.05). Additionally, other abnormal WM microstructures of OH were associated with broad cognitive domains and cognition-related plasma biomarkers to varying degrees. CONCLUSION: The findings evidence that abnormal WM microstructures may present themselves as early as in the MOH phase and that these structural abnormalities are associated with cognitive functions and cognition-related plasma biomarkers.

Synchronous monitoring of brain-heart electrophysiology using heart rate variability coupled with rapid quantitative electroencephalography in orthostatic hypotension patients with α-synucleinopathies: Rapid prediction of orthostatic hypotension and preliminary exploration of brain stimulation therapy.

BACKGROUND: In α-synucleinopathies, the dysfunction of the autonomic nervous system which typically manifests as orthostatic hypotension (OH) often leads to severe consequences and poses therapeutic challenges. This study aims to discover the brain-cardiac electrophysiological changes in OH patients with α-synucleinopathies using the rapid quantitative electroencephalography (qEEG) coupled with heart rate variability (HRV) technique to identify rapid, noninvasive biomarkers for early warning and diagnosis, as well as shed new light on complementary treatment approaches such as brain stimulation targets. METHODS: In this study, 26 subjects of α-synucleinopathies with OH (α-OH group), 21 subjects of α-synucleinopathies without OH (α-NOH group), and 34 healthy controls (control group) were included from September 2021 to August 2023 (NCT05527067). The heart rate-blood pressure variations in supine and standing positions were monitored, and synchronization parameters of seated resting-state HRV coupled with qEEG were collected. Time-domain and frequency-domain of HRV measures as well as peak frequency and power of the brainwaves were extracted. Differences between these three groups were compared, and correlations between brain-heart parameters were analyzed. RESULTS: The research results showed that the time-domain parameters such as MxDMn, pNN50, RMSSD, and SDSD of seated resting-state HRV exhibited a significant decrease only in the α-OH group compared to the healthy control group (p < 0.05), while there was no significant difference between the α-NOH group and the healthy control group. Several time-domain and frequency-domain parameters of seated resting-state HRV were found to be correlated with the blood pressure changes within the first 5 min of transitioning from supine to standing position (p < 0.05). Differences were observed in the power of beta1 waves (F4 and Fp2) and beta2 waves (Fp2 and F4) in the seated resting-state qEEG between the α-OH and α-NOH groups (p < 0.05). The peak frequency of theta waves in the Cz region also showed a difference (p < 0.05). The power of beta2 waves in the Fp2 and F4 brain regions correlated with frequency-domain parameters of HRV (p < 0.05). Additionally, abnormal electrical activity in the alpha, theta, and beta1 waves was associated with changes in heart rate and blood pressure within the first 5 min of transitioning from supine to standing position (p < 0.05). CONCLUSION: Rapid resting-state HRV with certain time-domain parameters below normal levels may serve as a predictive indicator for the occurrence of orthostatic hypotension (OH) in patients with α-synucleinopathies. Additionally, the deterioration of HRV parameters correlates with synchronous abnormal qEEG patterns, which can provide insights into the brain stimulation target areas for OH in α-synucleinopathy patients.

Undrained shear behavior of silty sand with a constant state parameter considering initial stress anisotropy effect.

Field observations in sedimentation and erosion-prone areas indicate that most natural sand deposits may contain a certain amount of non-plastic fines and are often under anisotropic stress conditions. A series of triaxial compression tests were performed on clean and silty sand with fines content fc ranging from 0 to 20% at an initial mean effective stress of p0' = 100 kPa and varying consolidation conditions to understand the impact of initial stress anisotropy on undrained shear behavior. The results indicate that the state parameter ψ is a superior predictor for characterizing the responses of sand-fines mixtures compared to the global void ratio and relative density. A comparison of the behavior of clean and silty sand with a constant ψ (= - 0.03) confirms that the sample with 10% fc exhibits the strongest dilation and greatest shear resistance, irrespective of the consolidation conditions. It is also demonstrated that the initial stress anisotropy with a comparably higher static stress ratio ηs typically diminishes the shear strength of mixtures. However, the influence of initial stress anisotropy on soil stiffness is not unilateral. The sample consolidated to a negative ηs is stiffer than that under isotropic consolidation, while the presence of a positive ηs leads to a decrease in the secant Young's modulus.

Identification of common core ion channel genes in epilepsy and Alzheimer's disease.

BACKGROUND: Although available literature indicates that the incidence of dementia in the epilepsy population and the risk of seizures in the Alzheimer's disease (AD) population are high, the specific genetic risk factors and the interaction mechanism are unclear, rendering rational genetic interpretation rather challenging. AIMS: Our work aims to identify the common core ion channel genes in epilepsy and AD. METHODS: In this study, we first integrated gene expression omnibus datasets (GSE48350 and GSE6834) on AD and epilepsy to identify differentially expressed genes (DEGs), performing Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs. The related protein-protein interaction (PPI) network was constructed for DEGs, and the hub gene was evaluated. RESULTS: A total of 2800 and 35 genes were identified in GSE48350 and GSE6834, and 12 DEGs were significantly differentially expressed between the datasets. KEGG pathway analysis showed that DEGs were primarily enriched in glutamatergic synapse and dopaminergic synapse pathways. SCN2A, GRIA1, and KCNJ9 were the hub genes with high connectivity. CONCLUSIONS: The findings suggest that the three genes, SCN2A, GRIA1, and KCNJ9, may serve as potential targets for treating AD comorbid with epilepsy.

Efficacy analysis of three brain stimulation techniques for Alzheimer's disease: a meta-analysis of repeated transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation.

INTRODUCTION: This systematic review and meta-analysis study investigates the efficacy of repeated transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS) using neuropsychological assessments as a potential treatment option for Alzheimer's disease (AD). METHODS: PubMed, Embase, and the Cochrane Library were searched for studies on rTMS, tDCS, and DBS for the treatment of patients with AD between April 1970 and October 2022. The mini-Mental State Examination (MMSE) and AD Assessment Scale - Cognitive Subscale (ADAS-Cog) were adopted as the efficacy index. RESULTS: The analysis yielded 17 eligible studies. rTMS greatly improved the cognition of patients with AD (immediate post-treatment WMD of MMSE score: 2.06, p < 0.00001; short-term follow-up WMD of MMSE score: 2.12, p = 0.006; WMD of ADAS-Cog score in single-arm studies: -4.97, p = 0.001). DBS did not reverse the progression of cognitive decline (WMD of ADAS-Cog score in single-arm studies: 7.40, p < 0.00001). Furthermore, tDCS demonstrated no significant efficacy in improving cognition in random clinical trials or single-arm studies. CONCLUSION: rTMS is a promising non-medicinal alternative for cognitive improvement inpatients with AD.