A Bidirectional Mendelian Randomization Study of Gut Microbiota and Cerebral Small Vessel Disease.

BACKGROUND: The causal nature of gut microbiota and cerebral small vessel disease (CSVD) is still obscure regardless of evidence supporting their observational correlations. OBJECTIVES: The primary objective of this research is to investigate the potentially pathogenic or protective causal impacts of specific gut microbiota on various neuroimaging subtypes of CSVD. METHODS: We obtained the latest summary-level genome-wide databases for gut microbiota and 9 CSVD traits. The univariable and multivariable Mendelian randomization (MR) studies were conducted to examine the possible causal link between exposure and outcome. Meanwhile, we conducted sensitivity analyses sequentially, containing the heterogeneity, pleiotropy, and leave-one-out analysis. Additionally, to clarify the potential bidirectional causality, the causality from CSVD traits to the identified gut microbiota was implemented through reverse MR analysis. RESULTS: The univariable MR analysis identified 22 genetically predicted bacterial abundances that were correlated with CSVD traits. Although conditioning on macronutrient dietary compositions, 2 suggestive relationships were retained using the multivariable MR analysis. Specifically, the class Negativicutes and order Selenomonadales exhibited a negative causal association with strictly lobar cerebral microbleeds, one neuroimaging trait of CSVD. There is insufficient evidence indicating the presence of heterogeneity and horizontal pleiotropy. Furthermore, the identified causal relationship was not driven by any single nucleotide polymorphism. The results of the reverse MR analysis did not reveal any statistically significant causality from CSVD traits to the identified gut microbiota. CONCLUSIONS: Our study indicated several suggestive causal effects from gut microbiota to different neuroimaging subtypes of CSVD. These findings provided a latent understanding of the pathogenesis of CSVD from the perspective of the gut-brain axis.

Process approach as a cognitive biomarker related to gray matter volume in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Process approach is valuable for memory assessment in Alzheimer's disease (AD) and mild cognitive impairment (MCI), yet its underlying mechanisms remain elusive. This study aims to synergize the process approach with brain structure analysis to explore both the discriminative capacity and potential mechanisms underlying the process approach. METHODS: 37 subjects of MCI, 35 subjects of AD and 38 subjects of healthy control (HC) were included. The process approach in Auditory Verbal Learning Test (AVLT), including discriminability (A'), response bias (B"D), semantic clustering (LBCsem) and serial clustering (LBCser) was performed. The gray matter volume (GMV) was analyzed by voxel-based morphometry. Receiver operating characteristic (ROC) analysis and partial correlations were conducted to explore the value of the process approach and investigate the relationship between the process approach, traditional indices of AVLT and GMV. RESULTS: ROC analysis showed the value of A', B"D and LBCser in differentiating MCI and AD. Combining AVLT-Immediately Recall (AVLT-IR) and LBCser showed a higher value in diagnosing MCI. Partial correlations revealed that in the MCI group, A' and B"D were mainly positively associated with GMV of the hippocampus and temporal lobe. CONCLUSION: This study indicated that the process approach is a promising cognitive biomarker to detect MCI and AD.

Altered dynamic functional network connectivity and topological organization variance in patients with white matter hyperintensities.

White matter hyperintensities (WMHs) of presumed vascular origin are important imaging biomarkers of cerebral small vessel disease (CSVD). Previous studies have verified abnormal functional brain networks in CSVD. However, most of these studies rely on static functional connectivity, and only a few focus on the varying severity of the WMHs. Hence, our study primarily explored the disrupted dynamic functional network connectivity (dFNC) and topological organization variance in patients with WMHs. This study included 38 patients with moderate WMHs, 47 with severe WMHs, and 68 healthy controls (HCs). Ten independent components were chosen using independent component analysis based on resting-state functional magnetic resonance imaging. The dFNC of each participant was estimated using sliding windows and k-means clustering. We identified three reproducible dFNC states. Among them, patients with WMHs had a significantly higher occurrence in the sparsely connected State 1, but a lower occurrence and shorter duration in the positive and stronger connected State 3. Regarding topological organization variance, patients with WMHs showed higher variance in local efficiency but not global efficiency compared to HCs. Among the WMH subgroups, patients with severe WMHs showed similar but more obvious alterations than those with moderate WMHs. These altered network characteristics indicated an imbalance between the functional segregation and integration of brain networks, which was correlated with global cognition, memory, executive functions, and visuospatial abilities. Our study confirmed aberrant dFNC state metrics and topological organization variance in patients with moderate-to-severe WMHs; thus, it might provide a new pathway for exploring the pathogenesis of cognitive impairment.

Efficient target capture and transport by fuel-free micromotors in a multichannel microchip.

Efficient capture and transport of biological targets by functionalized micromotors in microfluidic chips have emerged as to be promising for bioanalysis and detection of targets. However, the crucial step-target capture-is still inefficient due to the low utilization of active spots on the functionalized motor surfaces. Herein, we designed a multichannel microchip for integrating confined space with the oscillatory movement of micromotors to increase the capture efficiency. Acoustically driven, magnetically guided Au/Ni/Au micromotors were employed as the target carriers, while E. coli bacteria were chosen as the targets. Under optimized conditions, a capture efficiency of 96% and an average loading number of 3-4 (targets per single motor) could be achieved. The possibility of simple separation of targets from micromotors has also been demonstrated. This microfluidic system could facilitate the integration of multiple steps for bioanalysis and detection of targets.

Visible-Light-Promoted α-C(sp3)-H Amination of Ethers with Azoles and Amides.

A visible-light-induced highly efficient C(sp3)-H amination of ethers with amides and azoles has been presented under mild conditions via a nitrogen- and carbon-centered radical coupling process. This protocol successfully utilizes 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and tert-butyl nitrite (TBN) as cocatalysts to deliver the aminated products of ethers under aerobic conditions. Notably, the developed reaction features the corresponding products in good yields (up to 93%) with a wide substrate scope. The mechanistic study indicates that C-N bond formation proceeds via a direct radical cross-coupling process. Preliminary biological activity analysis indicates that the resulting products have good and selective inhibitory activity on osteosarcoma (OS) cell lines and are promising for use as hits for drug discovery.

The association between alpha diversity of gut microbiota, neuroimaging markers and cognitive function in cerebral small vessel disease.

There is increasing recognition of gut microbial dysbiosis in cerebral small vessel disease (CSVD). The altered diversity in a single ecosystem - alpha diversity index of gut microbiota has attracted wide attention. Our study aims to determine whether the alpha diversity index differs among healthy control (HC), CSVD with and without cognitive impairment. Moreover, we investigate the correlation between the alpha diversity index, neuroimaging markers, and cognitive function. We recruited 40 HC, 43 CSVD patients without cognitive impairment (CSVD-NCI), and 35 CSVD patients with mild cognitive impairment (CSVD-MCI). Clinical and neuropsychological assessments, MRI scanning, and gut microbiota analysis were performed on all participants. The alpha diversity indexes Chao1 and Shannon were calculated to evaluate community richness and diversity in a sample, respectively. Individual neuroimaging markers of CSVD and the CSVD burden score were also evaluated. A significantly lower level of Chao 1 rather than the Shannon index was observed in the CSVD subgroups than in the HC group. The level of the Chao 1 index was negatively correlated with both CMB counts, a neuroimaging characteristic of CSVD, and CSVD burden score in patients with CSVD. Additionally, the Chao 1 index has been associated with general cognitive function, information processing speed, and language function in patients with CSVD. Remarkably, the increased CSVD burden score mediated the effects of decreased levels of Chao 1 on information processing speed and language function. Hence, the alterations in species richness may be associated with CSVD-related cognitive impairment and mediated by CSVD neuroimaging markers.

Synergistic effect of folate and MTHFR C677T on hippocampal subfields and perfusion in Alzheimer's disease.

BACKGROUND: Low folate intake and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have been suggested to increase the risk of Alzheimer's disease (AD). However, the synergistic effects and their impact on brain structure and perfusion remain unclear. METHODS: This study explored the effects of dietary and genetic deficiencies in folate metabolism on the volume of the hippocampal subregions, cerebral perfusion, and cognitive decline in 71 cognitively unimpaired (CU) individuals and 102 patients with mild cognitive impairment (MCI) due to AD or AD. All participants underwent magnetic resonance imaging, laboratory examinations, and neuropsychological assessments. The hippocampal subfields were segmented using Freesurfer, and arterial spin labeling was used to measure the cerebral blood flow. RESULTS: We found a significant group-by-MTHFR interaction effect on folate. Patients with AD and the 677 T allele showed hypoperfusion in the left precuneus compared to patients without this mutation, which mediated the relationship between low folate level and cognitive decline in patients carrying the 677 T allele. Moreover, a synergistic effect was observed for the combination of decreased folate concentrations and the presence of the MTHFR 677 T allele on the atrophy of specific hippocampal subregions in patients with AD. CONCLUSIONS: In addition to offering insights into the neuronal mechanism underlying gene-dependent folate-induced cognitive impairment in AD, these findings may have clinical significance for the allocation of auxiliary folate supplementation therapy in patients with AD with low folate levels and carrying the MTHFR 677 T allele and may eventually promote the selection of early individualized AD drug therapy.

Disrupted dynamic network attribution associated with gait disorder in cerebral small vessel disease.

BACKGROUND AND AIMS: Previous research has focused on static functional connectivity in gait disorders caused by cerebral small vessel disease (CSVD), neglecting dynamic functional connections and network attribution. This study aims to investigate alterations in dynamic functional network connectivity (dFNC) and topological organization variance in CSVD-related gait disorders. METHODS: A total of 85 patients with CSVD, including 41 CSVD patients with gait disorders (CSVD-GD), 44 CSVD patients with non-gait disorders (CSVD-NGD), and 32 health controls (HC) were enrolled in this study. Five networks composed of 10 independent components were selected using independent component analysis. Sliding time window and k-means clustering methods were used for dFNC analysis. The relationship between alterations in the dFNC properties and gait metrics was further assessed. RESULTS: Three reproducible dFNC states were determined (State 1: sparsely connected, State 2: intermediate pattern, State 3: strongly connected). CSVD-GD showed significantly higher fractional windows (FW) and mean dwell time (MDT) in State 1 compared to CSVD-NGD. Higher local efficiency variance was observed in the CSVD-GD group compared to HC, but no differences were found in the global efficiency comparison. Both the FW and MDT in State 1 were negatively correlated with gait speed and step length, and the relationship between MDT of State 1 and gait speed was mediated by overall cognition, information processing speed and executive function. CONCLUSIONS: Our study uncovered abnormal dFNC indicators and variations in topological organization in CSVD-GD, offering potential early prediction indicators and freshening insights into the underlying pathogenesis of gait disturbances in CSVD.

Boosting Phosphoric Acid Retention in Polymer Electrolyte Membranes by Zwitterions: Insights from DFT Calculations and MD Simulations.

Effective retention of phosphoric acid (PA) is crucial for the efficient operation of fuel cells based on PA-doped polymeric membranes, which is highly challenging due to the moisture-induced loss of PA. Therefore, a comprehensive understanding of the interplay among PA, functional groups, and water is essential for designing membrane materials. Using density functional theory (DFT) calculations and molecular dynamics (MD) simulations, we unveil the remarkable capability of zwitterions to effectively sequester PA, thereby unlocking the potential for fuel cell optimization. Our DFT calculations show that zwitterions, termed "charged proton-accepting bases", exhibit stronger interactions with PA compared to the traditional neutral proton-accepting bases. Furthermore, the presence of water amplifies such a discrepancy, with the zwitterion-PA interactions playing a dominant role in the zwitterion-PA-water cluster due to the strongest affinity of zwitterions to PA. Conversely, the ability of neutral bases to retain PA is significantly attenuated by moisture as the interactions between water and PA surpass those between neutral bases and PA. The strong zwitterion-PA associations arise primarily from the formation of multiple hydrogen bonds. Furthermore, MD simulations reveal the uniform distribution of zwitterions in aqueous environments and their pronounced affinities for both PA and water. In contrast, neutral bases tend to aggregate, interacting limitedly with PA. These findings underscore the effectiveness of zwitterions in boosting PA retention in fuel cells.

Regioselectively Electrochemical Synthesis of N2-Selective C-H Amination of Ethers with N-Tosyl 1,2,3-Triazole via Triazole Radical Cation.

A regioselective electrochemical C-H amination method to synthesize N2-substituted 1,2,3-triazole using easily accessible ethers has been developed. Various substituents, including heterocycles, have a good tolerance, and 24 examples were obtained in moderate to good yields. Control experiments and DFT calculation investigations demonstrate that the electrochemical synthesis undergoes a N-tosyl 1,2,3-triazole radical cation process promoted by the single-electron transfer of the lone pair electrons of the aromatic N-heterocycle, and the desulfonation is responsible for the high N2-regioselectivity.

Metabolic syndrome-related cognitive impairment with white matter hyperintensities and functional network analysis.

OBJECTIVE: This study aimed to explore the relationship between white matter hyperintensities (WMHs) and cognitive impairment related to metabolic syndrome (MetS) and the underlying neural network mechanisms. METHODS: This cross-sectional study included 50 participants with MetS and WMHs (MetS-WMHs), 45 with MetS without WMHs, and 50 control participants. All participants underwent resting-state functional magnetic resonance imaging and a detailed cognitive evaluation. A graph theory analysis based on resting-state functional magnetic resonance imaging was conducted to calculate functional network properties. A mediation analysis was conducted to determine the relationship between WMHs and MetS-related cognitive impairment. RESULTS: Compared with the control group, the participants in the MetS-WMHs group displayed lower global efficiency, local efficiency, and nodal efficiency, mainly located in the regions of the salience network. Furthermore, a significant correlation was observed between functional network efficiency and cognitive performance. Mediation analysis indicated that WMHs served as a mediating variable between MetS and cognitive decline, affecting attention/executive function, language, and global cognitive function. CONCLUSIONS: WMHs mediated the association between MetS and cognitive function, with a decline in the efficiency of functional brain networks being a probable neural mechanism.

YKL-40 as a novel biomarker related to white matter damage and cognitive impairment in patients with cerebral small vessel disease.

YKL-40 is a novel neuroinflammatory marker associated with white matter damage and cognitive dysfunction. 110 CSVD patients, including 54 with mild cognitive impairment (CSVD-MCI), 56 with no cognitive impairment (CSVD-NCI), and 40 healthy controls (HCs) underwent multimodal magnetic resonance examination, serum YKL-40 level detection and cognitive function assessment to investigate the association between YKL-40 and white matter damage and cognitive impairment in cerebral small vessel disease (CSVD) patients. White matter hyperintensities volume was calculated using the Wisconsin White Matter Hyperintensity Segmentation Toolbox (W2MHS) for white matter macrostructural damage evaluation. For white matter microstructural damage evaluation, fractional anisotropy (FA) and mean diffusivity (MD) indices of the region of interest were analyzed based on diffusion tensor imaging (DTI) images using the Tract-Based Spatial Statistics (TBSS) pipeline. The serum YKL-40 level of CSVD was significantly higher than those of HCs, and the CSVD-MCI was higher than in HCs and CSVD-NCI. Furthermore, serum YKL-40 provided high diagnostic accuracy for CSVD and CSVD-MCI. The macroscopic and microstructure of white matter in CSVD-NCI and CSVD-MCI patients indicated different degrees of damage. Disruption of white matter macroscopic and microstructure was significantly associated with YKL-40 levels and cognition deficits. Moreover, the white matter damage mediated the associations between the increased serum YKL-40 levels and cognitive impairment. Our findings demonstrated that YKL-40 might be a potential biomarker of white matter damage in CSVD, whereas white matter damage was associated with cognitive impairment. Serum YKL-40 measurement provides complementary information regarding the neural mechanism of CSVD and its associated cognitive impairment.

Altered serum amyloid beta and cerebral perfusion and their associations with cognitive function in patients with subcortical ischemic vascular disease.

Subcortical ischemic vascular disease (SIVD) is one of the important causes of cognitive dysfunction, altered amyloid-beta (Aß) and cerebral perfusion may be involved in the pathophysiological mechanism of SIVD and are closely related to cognitive function. We aimed to investigate altered serum Aß and cerebral perfusion in patients with SIVD and their correlation with cognitive function. Seventy-four healthy controls (HCs) and 74 SIVD patients, including 38 SIVD patients with no cognitive impairment (SIVD-NCI) and 36 SIVD patients with mild cognitive impairment (SIVD-MCI) underwent the measurement of serum Aß40 and Aß42 levels, pseudo-continuous arterial spin labeling MRI scanning, and cognitive evaluation. Compared to the healthy controls (HCs), the level of serum Aß40 and Aß40/42 ratio increased and Aß42 decreased in SIVD patients. The serum Aß40 level and Aß40/42 ratio in patients with SIVD-MCI were significantly higher than those in the HCs and SIVD-NCI, and the level of Aß42 in the SIVD-MCI was lower than the HCs. In addition, the serum Aß40/42 ratio provided high diagnostic accuracy for SIVD and SIVD-MCI, it was further identified as an independent risk factor for cognitive impairment. Patients with SIVD-NCI and SIVD-MCI exhibited both increased and decreased cerebral blood flow (CBF) in regional. The Aß40/42 ratio was associated with global CBF, while altered global and regional CBF was associated with cognitive deficits. In addition, white matter hyperintensities volume (WMHV) correlated with Aß40/42 ratio, CBF, and cognition. The relationship between Aß40/42 ratio and cognition was partially mediated by altered CBF. Based on these results, we conclude that the serum Aß40/42 ratio may be a potential biomarker that can complement current methods for the prediction and diagnosis of cognitive impairment in SIVD patients. In addition, serum Aß may play a role in cognitive function by regulating CBF, which provides new insights into the intervention, treatment, and prevention of cognitive impairment in SIVD.