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.

Continuous and Controllable Preparation of Sodium Alginate Hydrogel Tubes Guided by the Soft Cap Inspired by the Apical Growth of the Plant.

Hydrogel tubes made of sodium alginate (SA) have potential applications in drug delivery, soft robots, biomimetic blood vessels, tissue stents, and other fields. However, the continuous preparation of hollow SA hydrogel tubes with good stability and size control remains a huge challenge for chemists, material scientists, and medical practitioners. Inspired by the plant apical growth strategy, a new method named soft cap-guided growth was proposed to produce SA hydrogel tubes. Due to the introduction of inert low gravity substances, such as air and heptane, into the extrusion needle in front of calcium chloride solution to form a soft cap, the SA hydrogel tubes with controllable sizes were fabricated rapidly and continuously without using a template through a negative gravitropism mechanism. The SA hydrogel tubes had good tensile strength, high burst pressure, and good cell compatibility. In addition, hydrogel tubes with complex patterns were conveniently created by controlling the motion path of a soft cap, such as a rotating SA bath or magnetic force. Our research provided a simple innovative technique to steer the growth of hydrogel tubes, which made it possible to mass produce hydrogel tubes with controllable sizes and programmable patterns.

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 CE 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.

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.

The potential of EZH2 expression to facilitate treatment choice in stage II colorectal adenocarcinoma.

BACKGROUND: The current selection criteria of patients with stage II colorectal carcinoma (CRC) suitable for adjuvant therapy are not satisfactory. Enhancer of zeste homolog 2 (EZH2) has been demonstrated to be over-expressed in CRC. However, data regarding the role of EZH2 in CRC survival remains controversial, and little is known about it in stage II CRC. Thus, we conducted this study to investigate the clinical significance of EZH2 expression in stage II CRC. METHODS: Cases with stage II CRC resected between 2015 and 2018 were retrospectively reviewed. EZH2 expression was analyzed by immunohistochemistry using tissue microarrays. The relationship between EZH2 expression and clinicopathological variables was analyzed. Survival curves were estimated by the Kaplan-Meier approach. RESULTS: We found high EZH2 expression in 134 of 221 analyzable stage II tumors (60.63%). No significant associations were observed between EZH2 expression and common clinicopathological factors. Survival analyses showed that cases receiving surgery alone had inferior overall survival (OS) than those receiving surgery and chemotherapy (P=0.0075) in stage II CRC with high EZH2 expression, however, metastasis-free survival (MFS) was similar between these two subgroups. Treatment choice had no impact on the survival of stage II CRC with low EZH2 expression. CONCLUSION: The OS of stage II CRC with high EZH2 expression improved more strikingly with surgery and adjuvant chemotherapy than with surgery alone, which suggests the potential of EZH2 expression as a biomarker to help identify a subgroup of early-stage CRC benefiting from surgery and adjuvant chemotherapy. More large-scale studies are warranted to corroborate this finding and to further evaluate the predictive nature of EZH2.

Thermochromic Hydrogels with Adjustable Transition Behavior for Smart Windows.

With the fast economic development and accelerating urbanization, more and more skyscrapers made entirely of concrete and glass are being constructed. To keep a comfortable indoor environment, massive energy for air conditioning or heating appliances is consumed. A huge amount of heat (>30%) is gained or released through glass windows. Using smart windows with the capability to modulate light is an effective way to reduce building energy consumption. Thermochromic hydrogel is one of the potential smart window materials due to its excellent thermal response, high radiation-blocking efficiency, cost-effectiveness, biocompatibility, and good uniformity. In this work, polyhydroxypropyl acrylate (PHPA) hydrogels with controllable lower critical solution temperature (LCST) were prepared by photopolymerization. The transition temperature and transition rate under "static transition" conditions were investigated. Unlike "static" conditions in which the transition temperature was not affected by the initial and final temperature and heating/cooling ramp, the transition temperature varied with the rate of temperature change under dynamic conditions. The "dynamic" transition temperature of the PHPA hydrogel gradually increased with the increase of the heating rate. It was the result of the movement of the molecular chains lagging behind the temperature change when the temperature change was too fast. The results of the solar irradiation experiment by filling PHPA hydrogels into double glazing windows showed that the indoor temperature was about 15 °C lower than that of ordinary glass windows, indicating that it can significantly reduce the energy consumption of air conditioning. In addition, a wide range of adjustable transition temperatures and fast optical response make PHPA hydrogels potentially applicable to smart windows.

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.

The Hippocampal Subfield Volume Reduction and Plasma Biomarker Changes in Mild Cognitive Impairment and Alzheimer's Disease.

Background: The hippocampus consists of histologically and functionally distinct subfields, which shows differential vulnerabilities to Alzheimer's disease (AD)-associated pathological changes. Objective: To investigate the atrophy patterns of the main hippocampal subfields in patients with mild cognitive impairment (MCI) and AD and the relationships among the hippocampal subfield volumes, plasma biomarkers and cognitive performance. Methods: This cross-sectional study included 119 patients stratified into three categories: normal cognition (CN; N = 40), MCI (N = 39), and AD (N = 40). AD-related plasma biomarkers were measured, including amyloid-ß (Aß)42, Aß40, Aß42/Aß40 ratio, p-tau181, and p-tau217, and the hippocampal subfield volumes were calculated using automated segmentation and volumetric procedures implemented in FreeSurfer. Results: The subiculum body, cornu ammonis (CA) 1-head, CA1-body, CA4-body, molecular_layer_HP-head, molecular_layer_HP-body, and GC-ML-DG-body volumes were smaller in the MCI group than in the CN group. The subiculum body and CA1-body volumes accurately distinguished MCI from CN (area under the curve [AUC] = 0.647-0.657). The subiculum-body, GC-ML-DG-body, CA4-body, and molecular_layer_HP-body volumes accurately distinguished AD from MCI (AUC = 0.822-0.833) and AD from CN (AUC = 0.903-0.905). The p-tau 217 level served as the best plasma indicator of AD and correlated with broader hippocampal subfield volumes. Moreover, mediation analysis demonstrated that the subiculum-body volume mediated the associations between the p-tau217 and p-tau181 levels, and the Montreal Cognitive Assessment and Auditory Verbal Learning Test recognition scores. Conclusions: Hippocampal subfields with distinctive atrophy patterns may mediate the effects of tau pathology on cognitive function. The subiculum-body may be the most clinically meaningful hippocampal subfield, which could be an effective target region for assessing disease progression.

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.

Photocuring 3D Printing of Hydrogels: Techniques, Materials, and Applications in Tissue Engineering and Flexible Devices.

Photocuring 3D printing of hydrogels, with sophisticated, delicate structures and biocompatibility, attracts significant attention by researchers and possesses promising application in the fields of tissue engineering and flexible devices. After years of development, photocuring 3D printing technologies and hydrogel inks make great progress. Herein, the techniques of photocuring 3D printing of hydrogels, including direct ink writing (DIW), stereolithography (SLA), digital light processing (DLP), continuous liquid interface production (CLIP), volumetric additive manufacturing (VAM), and two photon polymerization (TPP) are reviewed. Further, the raw materials for hydrogel inks (photocurable polymers, monomers, photoinitiators, and additives) and applications in tissue engineering and flexible devices are also reviewed. At last, the current challenges and future perspectives of photocuring 3D printing of hydrogels are discussed.

[Changes in Plasma Amyloid-ß Level and Their Relationship With White Matter Microstructure in Patients With Mild Cognitive Impairment].

Objective To investigate the changes in plasma amyloid-ß (Aß) level and their relationship with white matter microstructure in the patients with amnesic mild cognitive impairment(aMCI) and vascular mild cognitive impairment (vMCI).Methods A total of 36 aMCI patients,20 vMCI patients,and 34 sex and age matched healthy controls (HC) in the outpatient and inpatient departments of the First Affiliated Hospital of Anhui Medical University were enrolled in this study.Neuropsychological scales,including the Mini-Mental State Examination,the Montreal Cognitive Assessment,and the Activity of Daily Living Scale,were employed to assess the participants.Plasma samples of all the participants were collected for the measurement of Aß42 and Aß40 levels.All the participants underwent magnetic resonance scanning to obtain diffusion tensor imaging (DTI) data.The DTI indexes of 48 white matter regions of each individual were measured (based on the ICBM-DTI-81 white-matter labels atlas developed by Johns Hopkins University),including fractional anisotropy (FA) and mean diffusivity (MD).The cognitive function,plasma Aß42,Aß40,and Aß42/40 levels,and DTI index were compared among the three groups.The correlations between the plasma Aß42/40 levels and DTI index of aMCI and vMCI patients were analyzed.Results The Mini-Mental State Examination and the Montreal Cognitive Assessment scores of aMCI and vMCI groups were lower than those of the HC group (all P<0.001).There was no significant difference in the Activity of Daily Living Scale score among the three groups (P=0.654).The plasma Aß42 level showed no significant difference among the three groups (P=0.227).The plasma Aß40 level in the vMCI group was higher than that in the HC group (P=0.014),while it showed no significant difference between aMCI and HC groups (P=1.000).The plasma Aß42/40 levels in aMCI and vMCI groups showed no significant differences from that in the HC group (P=1.000,P=0.105),while the plasma Aß42/40 level was lower in the vMCI group than in the aMCI group (P=0.016).The FA value of the left anterior limb of internal capsule in the vMCI group was lower than those in HC and aMCI groups (all P=0.001).The MD values of the left superior corona radiata,left external capsule,left cingulum (cingulate gyrus),and left superior fronto-occipital fasciculus in the vMCI group were higher than those in HC (P=0.024,P=0.001,P=0.003,P<0.001) and aMCI (P=0.015,P=0.004,P=0.019,P=0.001) groups,while the MD values of the right posterior limb of internal capsule (P=0.005,P=0.001) and left cingulum (hippocampus) (P=0.017,P=0.031) in the aMCI and vMCI groups were higher than those in the HC group.In the aMCI group,plasma Aß42/40 level was positively correlated with FA of left posterior limb of internal capsule (r=0.403,P=0.015) and negatively correlated with MD of the right fonix (r=-0.395,P=0.017).In the vMCI group,plasma Aß42/40 level was positively correlated with FA of the right superior cerebellar peduncle and the right anterior limb of internal capsule (r=0.575,P=0.008;r=0.639,P=0.002),while it was negatively correlated with MD of the right superior cerebellar peduncle and the right anterior limb of internal capsule (r=-0.558,P=0.011;r=-0.626,P=0.003).Conclusions Plasma Aß levels vary differently in the patients with aMCI and vMCI.The white matter regions of impaired microstructural integrity differ in the patients with different dementia types in the early stage.The plasma Aß levels in the patients with aMCI and vMCI are associated with the structural integrity of white matter,and there is regional specificity between them.

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.

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.

Initiator-Free Photocuring 3D-Printable PVA-Based Hydrogel with Tunable Mechanical Properties and Cell Compatibility.

Poly(vinyl alcohol) (PVA)-based hydrogels have attracted great attention and been widely used in biological tissue engineering. With the development of modern medicine, precision medicine requires the customization of medical materials. However, lacking of photocurable functional groups or the performance of rapid phase transition makes PVA-based hydrogels difficult to be customizable molded through photocuring 3D printing technique. In this research, customizable PVA-based hydrogels with high performance through 3D photocurable printing and freezing-thawing (F-T) process are obtained. The ability of 3D-printable is endowed by the introduction of polyvinyl alcohol-styrylpyridine (PVA-SBQ), which can be photo-crosslinked quickly without photoinitiator. Meanwhile, the tunable mechanical properties are achieved by adjusting the mass ratio of PVA-SBQ to PVA, and PVA can offer the physical crosslinking points through freezing-thawing (F-T) process. The hydrogels with high resolution are prepared by digital light procession 3D printing with the mass ratio 1:1 of PVA-SBQ to PVA solution. Attributed to the absence of initiator, and no small molecule residues inside the hydrogels, the hydrogels have good biocompatibility and have the potential to be applicated in the field of biological tissue engineering.

Pan-cancer analysis of PCAT6 and its effect on oesophageal squamous cell carcinoma cell proliferation and migration.

Bioinformatics methods were used to analyze the role of PCAT6 in a variety of tumors and verify its role in oesophageal squamous cell carcinoma (ESCC) EC109 cells. The pan-cancer dataset was downloaded from the University of California Santa Cruz (UCSC) database to analyze the expression of PCAT6 in pan-cancer and its relationship with prognosis, clinical features, and immune infiltration. The expression and prognosis of PCAT6 in ESCC were verified by Gene Expression Omnibus (GEO) and Kaplan-Meier database. CCK8, colony formation, wound healing, Transwell cell invasion (CI), and cell migration (CM) assays were used to detect the effect of PCAT6 knockdown on the ability of ESCC cell proliferation (CP), CI and CM. Gene Set Enrichment Analysis was used to analyze the signaling pathways involved in the regulation of PCAT6. Quantitative real-time PCR and western blotting were used to examine the expression of cancer stem cell-related markers and the activation of JAK/STAT pathway in ESCC after PCAT6 knockdown. PCAT6 is significantly up-regulated in a variety of tumor tissues, and its expression is closely related to prognosis, clinical features and immune infiltration. High expression of PCAT6 leads to poor prognosis in ESCC patients. In ESCC EC109 cells, PCAT6 knockdown inhibited the ability of CP, CI, CM, and stemness, and inhibited the activation of JAK/STAT signaling pathway. PCAT6 expression is elevated in a variety of tumors. PCAT6 plays an oncogene role in ESCC by activating the JAK/STAT signaling pathway.

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.

Progress in blood biomarkers of subjective cognitive decline in preclinical Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease that gradually impairs cognitive functions. Recently, there has been a conceptual shift toward AD to view the disease as a continuum. Since AD is currently incurable, effective intervention to delay or prevent pathological cognitive decline may best target the early stages of symptomatic disease, such as subjective cognitive decline (SCD), in which cognitive function remains relatively intact. Diagnostic methods for identifying AD, such as cerebrospinal fluid biomarkers and positron emission tomography, are invasive and expensive. Therefore, it is imperative to develop blood biomarkers that are sensitive, less invasive, easier to access, and more cost effective for AD diagnosis. This review aimed to summarize the current data on whether individuals with SCD differ reliably and effectively in subjective and objective performances compared to cognitively normal elderly individuals, and to find one or more convenient and accessible blood biomarkers so that researchers can identify SCD patients with preclinical AD in the population as soon as possible. Owing to the heterogeneity and complicated pathogenesis of AD, it is difficult to make reliable diagnoses using only a single blood marker. This review provides an overview of the progress achieved to date with the use of SCD blood biomarkers in patients with preclinical AD, highlighting the key areas of application and current challenges.

Bilateral Hippocampal Volume Mediated the Relationship Between Plasma BACE1 Concentration and Memory Function in the Early Stage of Alzheimer's Disease: A Cross-Sectional Study.

BACKGROUND: ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in the formation of amyloid-ß (Aß) protein. Increasing evidence suggests that BACE1 concentration is a potential biomarker for Alzheimer's disease (AD). OBJECTIVE: To evaluate the correlations between plasma BACE1 concentration, cognition, and hippocampal volume at different stages of the AD continuum. METHODS: Plasma BACE1 concentrations were measured in 32 patients with probable dementia due to AD (ADD), 48 patients with mild cognitive impairment (MCI) due to AD, and 40 cognitively unimpaired (CU) individuals. Memory function was evaluated using the auditory verbal learning test (AVLT), and voxel-based morphometry was used to analyze bilateral hippocampal volumes. Correlation and mediation analyses were performed to investigate the associations between plasma BACE1 concentration, cognition, and hippocampal atrophy. RESULTS: The MCI and ADD groups exhibited elevated BACE1 concentrations compared with the CU group after adjusting for age, sex, and apolipoprotein E (APOE) genotype. Increased BACE1 concentration was found in AD continuum patients who were APOE ɛ4 carriers (p < 0.05). BACE1 concentration was negatively associated with the scores of the subitems of the AVLT and hippocampal volume (p < 0.05, false discovery rate correction) in the MCI group. Moreover, bilateral hippocampal volume mediated the relationship between BACE1 concentration and recognition in the MCI group. CONCLUSION: BACE1 expression increased in the AD continuum, and bilateral hippocampal volume mediated the effect of BACE1 concentration on memory function in patients with MCI. Research has indicated that the plasma BACE1 concentration might be a biomarker at the early stage of AD.

Brain Gray Matter Volume Mediated the Correlation Between Plasma P-Tau and Cognitive Function of Early Alzheimer's Disease in China: A Cross-Sectional Observational Study.

BACKGROUND: The primary manifestations of Alzheimer's disease (AD) include cognitive decline and brain gray matter volume (GMV) atrophy. Recent studies have found that plasma phosphorylated-tau (p-tau) concentrations perform better in diagnosing, differentiating, and monitoring the progression of AD. However, the correlation between plasma p-tau, GMV, and cognition remains unclear. OBJECTIVE: To investigate whether GMV plays a mediating role in the association between plasma p-tau concentrations and cognition. METHODS: In total, 99 participants (47 patients with AD and 52 cognitively unimpaired [CU] individuals) were included. All participants underwent neuropsychological assessments, laboratory examinations, and magnetic resonance imaging scans. Plasma p-tau217 and p-tau181 concentrations were measured using an enzyme-linked immunosorbent assay kit. Voxel-based morphometry was performed to assess participants' brain GMV. Partial correlation and mediation analyses were conducted in AD group. RESULTS: Plasma p-tau concentrations were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p-tau217 concentrations, GMV, and Mini-Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p-tau217 concentrations and MMSE scores. A significant correlation between plasma p-tau181 and MMSE scores was not identified. CONCLUSION: The findings indicate that p-tau217 is a promising biomarker for central processes affecting brain GMV and cognitive function. This may provide potential targets for future intervention and treatment of tau-targeting therapies in the early stages of AD.

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.