Association of CHAT Gene Polymorphism rs3793790 and rs2177370 with Donepezil Response and the Risk of Alzheimer's Disease Continuum.

Background: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC). Objective: This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC. Material and Methods: According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid ß-protein positive (Aß+) and negative (Aß-) patients were recruited according to the Aß-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aß+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aß+ and 73 Aß- patients using a logistic regression analysis. Results: The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64-28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28-4.95). Conclusion: The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.

Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies.

Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

Development and analysis of two-dimensional point-ahead angle mechanism for space gravitational-wave detection.

To detect low-frequency gravitational waves, it is necessary to eliminate the interference of geo-noise and build a laser interference gravitational-wave detection device in space. Space gravitational-wave detection missions, namely Taiji, LISA, and Tianqin, have been planning to achieve picometer sensitivity on an interferometer arm of several million kilometers to meet the gravitational-wave detection requirements. Because of the orbit evolution and the time delay in interferometer arms, the direction of the transmitted laser beam changes; consequently, a remote telescope cannot receive the laser beam to complete the inter-satellite laser interference. In this study, a two-dimensional point-ahead angle mechanism (2DPAAM) is designed and demonstrated to solve the aforementioned problem. Based on the design concept of aligning the rotation center with the mirror surface center, the 2DPAAM employs a four-link flexible-hinge structure, length expanding and contracting piezoelectric stack actuators, and closed-loop control of capacitive sensors to realize two-dimensional picometer-stable, high-precision rotation. A static model is established to analyze the rotational characteristics, and finite element analysis is performed to study the mechanical properties and to verify the rotational characteristics. The yaw and pitch stiffness errors are ∼0.93% and 5.9%, respectively, when the theoretical results are compared with the simulation results. A series of experiments are conducted on the developed 2DPAAM, and the results show that the rotary ranges of yaw and pitch motions attain ±270 and ±268 µrad, respectively. The rotational accuracies of both yaw and pitch motions attain ∼0.35 µrad, and the optical path difference is less than 10pm/Hz when the frequency is between 1 mHz and 1 Hz, by analogy.

Anthropogenic perturbations on heavy metals transport in sediments in a river-dominated estuary (Modaomen, China) during 2003-2021.

Heavy metal pollutants in sediment greatly impact the estuarine environment and ecosystems, increasingly influenced by anthropogenic perturbations. Here, we examined the surface sediments of the Modaomen estuary in 2003, 2015, and 2021 to understand how human-induced changes influence the fate of heavy metals in the estuary's sediments. The potential ecological risk index (RI) suggests Cd should be the priority pollutant for environmental pollution control due to its high toxicity coefficient. In each sampling period, two main sources were identified through normalized heavy metals and PCA-MLR: natural and mixed anthropogenic sources (agricultural, industrial, and traffic activities), reflecting an increase in heavy metals pollution, later mitigated by successful environmental protection measures. Moreover, anthropogenic activities have not only impacted the sources discharge of heavy metals but have also influenced their spatial and temporal distribution through factors such as land reclamation, leading to sediment coarsening and reduced heavy metal content in specific areas.

Mediation of Regional Cerebral Blood Flow in the Relationship between Specific Gut Microbiota and Cognition in Vascular Cognitive Impairment.

BACKGROUND: Gut microbiota could affect the onset and development of vascular cognitive impairment (VCI) through modulating metabolic and immune pathways. However, the vascular mechanisms involved remain unclear. OBJECTIVE: To investigate the gut microbiota associated with VCI and examine the mediating effects of regional cerebral blood flow (CBF) to explore potential therapeutic targets for VCI. METHODS: This prospective study enrolled patients with VCI (n = 16) and healthy controls (n = 18) from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1 and June 30, 2022. The gut microbiota composition and diversity were determined by 16 S ribosomal RNA gene sequencing. The association between gut microbiota and Montreal Cognitive Assessment (MoCA) scores was determined using Spearman's correlation analysis. Regional CBF was calculated using pseudo-continuous arterial spin labeling. The mediating effects of regional CBF on the relationship between specific gut microbiota and cognition in VCI were investigated using mediation analysis. RESULTS: Compared to healthy controls, patients with VCI had significantly greater abundance of Bifidobacterium, Veillonella, R uminococcus gnavus , Fusobacterium, and Erysipelatoclostridium and smaller abundance of Collinsella. The abundance of Ruminococcus gnavus was negatively associated with MoCA scores in patients with VCI, with the CBF in the left hypothalamus, right hypothalamus, and left amygdala accounting for 63.96%, 48.22%, and 36.51%, respectively, of this association after adjusting for confounders. CONCLUSIONS: Ruminococcus gnavus is associated with cognition in VCI, which is strongly mediated by CBF in the bilateral hypothalamus and left amygdala. These findings highlight the potential regulatory roles of nutrition and metabolism-related areas of the brain in VCI.

Single-Element Dual-Interferometer for Precision Inertial Sensing: Sub-Picometer Structural Stability and Performance as a Reference for Laser Frequency Stabilization.

Future GRACE-like geodesy missions could benefit from adopting accelerometer technology akin to that of the LISA Pathfinder, which employed laser interferometric readout at the sub-picometer level in addition to the conventional capacitive sensing, which is at best at the level of 100 pm. Improving accelerometer performance holds great potential to enhance the scientific output of forthcoming missions, carrying invaluable implications for research in climate, water resource management, and disaster risk reduction. To reach sub-picometer displacement sensing precision in the millihertz range, laser interferometers rely on suppression of laser-frequency noise by several orders of magnitude. Many optical frequency stabilization methods are available with varying levels of complexity, size, and performance. In this paper, we describe the performance of a Mach-Zehnder interferometer based on a compact monolithic optic. The setup consists of a commercial fiber injector, a custom-designed pentaprism used to split and recombine the laser beam, and two photoreceivers placed at the complementary output ports of the interferometer. The structural stability of the prism is transferred to the laser frequency via amplification, integration, and feedback of the balanced-detection signal, achieving a fractional frequency instability better than 6 parts in 1013, corresponding to an interferometer pathlength stability better than 1pm/Hz. The prism was designed to host a second interferometer to interrogate the position of a test mass. This optical scheme has been dubbed "single-element dual-interferometer" or SEDI.

Free Water MR Imaging of White Matter Microstructural Changes is a Sensitive Marker of Amyloid Positivity in Alzheimer's Disease.

BACKGROUND: Extracellular free water (FW) resulting from white matter degeneration limits the sensitivity of diffusion tensor imaging (DTI) in predicting Alzheimer's disease (AD). PURPOSE: To evaluate the sensitivity of FW-DTI in detecting white matter microstructural changes in AD. To validate the effectiveness of FW-DTI indices to predict amyloid-beta (Aß) positivity in mild cognitive impairment (MCI) subtypes. STUDY TYPE: Retrospective. POPULATION: Thirty-eight Aß-negative cognitively healthy (CH) controls (68.74 ± 8.28 years old, 55% female), 15 Aß-negative MCI patients (MCI-n) (68.87 ± 8.83 years old, 60% female), 29 Aß-positive MCI patients (MCI-p) (73.03 ± 7.05 years old, 52% female), and 29 Aß-positive AD patients (72.93 ± 9.11 years old, 55% female). FIELD STRENGTH/SEQUENCE: 3.0T; DTI, T1 -weighted, T2 -weighted, T2 star-weighted angiography, and Aß PET (18 F-florbetaben or 11 C-PIB). ASSESSMENT: FW-corrected and standard diffusion indices were analyzed using trace-based spatial statistics. Area under the curve (AUC) in distinguishing MCI subtypes were compared using support vector machine (SVM). STATISTICAL TESTS: Chi-squared test, one-way analysis of covariance, general linear regression analyses, nonparametric permutation tests, partial Pearson's correlation, receiver operating characteristic curve analysis, and linear SVM. A P value <0.05 was considered statistically significant. RESULTS: Compared with CH/MCI-n/MCI-p, AD showed significant change in tissue compartment indices of FW-DTI. No difference was found in the FW index among pair-wise group comparisons (the minimum FWE-corrected P = 0.114). There was a significant association between FW-DTI indices and memory and visuospatial function. The SVM classifier with tissue radial diffusivity as an input feature had the best classification performance of MCI subtypes (AUC = 0.91), and the classifying accuracy of FW-DTI was all over 89.89%. DATA CONCLUSION: FW-DTI indices prove to be potential biomarkers of AD. The classification of MCI subtypes based on SVM and FW-DTI indices has good accuracy and could help early diagnosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.