Somatosensory processing has been shown to be correlated with brain development and cognitive function, but whether and how tactile sensory deficits affect cognition decline remains unclear. Here we show that tactile function is impaired in individuals with Alzheimer's disease (AD), and this impairment is inversely correlated with Montreal Cognitive Assessment scores and positively correlated with Tau pathology. We observed similar deficits in presymptomatic 3×Tg AD mice and find that cholecystokinin (CCK)-expressing neurons in the spinal cord are highly vulnerable to Tau pathology. Expressing mutant Tau-P301S in spinal cord CCK-expressing neurons aberrantly activates the transcription factor c-Maf, inhibits CCK neurons and induces tactile deficits, whereas silencing Tau or c-Maf restores tactile sensation and improves cognition in AD model mice. Together, these gain- and loss-of-function studies demonstrate that Tau pathology in spinal cord CCK neurons contributes to tactile dysfunction and cognitive function. Targeting tactile sensation may be a promising strategy for predicting the progression of cognitive impairment in AD.

This study aims to explore the protective effect of electroacupuncture (EA) on myocardial ischemia-reperfusion injury (MIRI) and decipher the molecular mechanism. Forty male SD rats were randomly allocated into four groups: sham, model (ischemia/reperfusion, I/R, MI group), I/R combined with ST36 (ST36 group), and I/R combined with sham acupuncture (MI+sham group). The MIRI model was established by ligation and reperfusion of the left anterior descending coronary artery. EA stimulation was applied at Neiguan (PC6) and Zusanli (ST36) in the ST36 group. Echocardiography, Evans blue-TTC double staining, ELISA and multi-omics techniques were adopted to evaluate therapeutic efficacy and analyze molecular characteristics. The results demonstrated that EA markedly reduced myocardial infarct size, improved cardiac systolic function, and decreased serum levels of IL-6, IL-1, and TNF-α as well as the expression of high mobility group box 1 (HMGB1) in the myocardial tissue. A total of 6 676 proteins were identified via differential proteomics analysis. One hundred and eighty-seven differentially expressed proteins were identified between the MI group and the sham group, among which the expression of 141 proteins was reversed after EA intervention. These proteins were mainly enriched in signaling pathways related to mitochondrial autophagy and apoptosis. Metabolomics analysis screened out 454 differential metabolites, which were predominantly involved in sphingolipid metabolism and alanine-aspartate-glutamate metabolism pathways. This study indicates that EA alleviates myocardial damage in the rat model of MIRI by suppressing inflammatory responses and regulating signaling pathways associated with myocardial structural maintenance, energy metabolism, and cell survival. The therapeutic mechanism of EA involves the synergistic modulation of multiple targets and pathways, providing experimental evidence for the comprehensive treatment of MIRI.

Abstract Purpose This study aimed to identify the effectiveness of free water MRI (FW-MRI) features for predicting amyloid-beta (Aβ) statuses in Alzheimer’s disease (AD) by constructing diagnostic models using machine learning analysis. Methods This study retrospectively included 96 patients of mild cognitive impairment (MCI) and AD (69 Aβ-positive and 27 Aβ-negative). Clinical characteristics, FW-corrected and standard diffusion indices, and structural MRI indices were collected. Three supervised machine learning algorithms, including random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGB), were adopted to construct a diagnostic model for distinguishing Aβ deposition in AD. SHapley Additive exPlanation (SHAP) value was used as an interpretable algorithm to identify influential characteristics based on the best-performing model. Results In the single-modality model, FW-DTI achieved better classification performance than conventional DTI, which obtained accuracies all above 80% among three machine learning approaches on the internal dataset (RF = 0.800, SVM = 0.867, XGB = 0.800). In the multi-modality model, the XGB model integrated FW-DTI, voxel-based morphometry, and clinical features outperformed the RF and SVM models, achieving an accuracy of 86.7% and an area under the curves (AUC) value 93.2% in the training cohort, and an accuracy of 77.8% and AUC value of 83.1% in the external testing cohort. The model demonstrated high sensitivity but relatively low specificity, indicating a tendency toward positive predictions. Furthermore, FW-DTI indices were shown to have the highest predictive value for Aβ deposition. Conclusion Integrating FW-DTI with structural and clinical features effectively differentiated Aβ positivity in AD, with FW-DTI indices contributing the highest predictive risks, demonstrating the potential of FW-DTI in AD diagnosis.

AIM:This prospective study examined whether lecanemab was associated with changes in neuropsychiatric symptoms (NPS) and investigated their associations with cerebral amyloid burden in patients with early-stage Alzheimer's disease (AD). METHODS:Fourteen eligible participants underwent amyloid positron emission tomography, magnetic resonance imaging, and neuropsychological assessments at baseline and following 6 months of lecanemab treatment. Neuropsychological assessments included the Clinical Dementia Rating, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton Depression Rating Scale, Hamilton Anxiety Scale (HAMA), and Neuropsychiatric Inventory (NPI). RESULTS:MMSE and MoCA remained stable, while amyloid burden decreased after 6 months of treatment (p < 0.05). HAMA, total NPI score, and NPI sub-scores for psychosis, hyperactivity, and apathy were also decreased (p < 0.05). Improvements in NPS were associated with lower amyloid burden in the hippocampus, amygdala, thalamus, inferior frontal gyrus (IFG), and anterior cingulate gyrus. These clinical improvements were associated with increased fractal dimension in the middle cingulate cortex and decreased sulcal depth in the IFG. CONCLUSIONS:These findings suggest that, in early AD, lecanemab treatment may be associated with benefits beyond cognitive stabilization, including possible improvement in NPS, which may relate to amyloid clearance and structural changes in relevant brain regions.

BACKGROUND:Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated with sex in AD remain unclear. METHODS:RNA sequencing (RNA-seq) and transcriptomic analyses were performed on peripheral blood samples from total of 54 patients, including male AD patients (n = 15), female AD patients (n = 10), male MCI patients (n = 7), female MCI patients (n = 11), male healthy controls (n = 6), female healthy controls (n = 5). The snRNA-seq dataset (GSE167494, GSE157827) of prefrontal cortex tissues was obtained from the Gene Expression Omnibus (GEO). We conducted an investigation into differentially expressed genes and pathways in the peripheral blood cells as well as prefrontal cortex tissues of both male and female AD patients with consideration to sex-related factors. Additionally, we analyzed the distribution and characteristics of cells in the cerebral cortex as well as the interaction and communication between cells of male and female AD patients. Connectivity Map (CMap) was utilized for predicting and screening potential sex-specific drugs for AD. RESULTS:The transcriptome profile and associated biological processes in the peripheral blood of male and female AD and MCI patients exhibit discernible differences, including upregulation of BASP1 in AD male patients and arousing TNS1 in AD female patients. The distribution of various cell types in the prefrontal cortex tissues differs between male and female AD patients, like neuron and oligodendrocyte decreased and endothelial cell and astrocyte increased in female compared with male, while a multitude of genes exhibit significant differential expression. The results of cell communication analysis, such as collagen signaling pathway, suggest that sex disparities impact intercellular interactions within prefrontal cortex tissues among individuals with AD. By drug repositioning, several drugs, including torin-2 and YM-298198, might have the potential to therapeutic value of MCI or AD, while drugs like homoharringtonine and teniposide have potential opposite effects in different sexes. CONCLUSION:The characteristics of the transcriptome in peripheral blood and single-cell transcriptome in the prefrontal cortex exhibit significant differences between male and female patients with AD, which providing a basis for future sex stratified treatment of AD.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and hyperphosphorylated tau pathology. Although palmitoylation has been implicated in AD, its specific mechanisms remain poorly defined. To investigate this, seven transcriptomic datasets were obtained from the GEO database. Differential expression and Gene Set Enrichment Analysis (GSEA) were performed across five training sets (GSE5281, GSE29378, GSE36980, GSE122063, and GSE132903). By intersecting differentially expressed genes (DEGs) with palmitoylation-related genes from GeneCards, 65 AD-associated palmitoylation-related genes (AD-PRGs) were identified. Functional enrichment analyses (KEGG and GO) were performed on these genes. Furthermore, seven key AD-PRGs (CALM1, VAMP2, SYT1, MET, BAG3, TJP1, NOTCH1) were prioritized using protein-protein interaction (PPI) networks and three machine learning algorithms (LASSO, SVM-RFE, and Random Forest). A diagnostic model constructed from these seven genes exhibited strong predictive performance, with AUC values of 0.834 in the training set and 0.907/0.865 in two external validation sets (GSE33000, GSE44770). Single-gene GSEA indicated associations with synaptic function and oxidative phosphorylation pathways. Protein docking analyses using GRAMM (Global RAnge Molecular Matching) and PISA (Proteins, Interfaces, Surfaces, and Assemblies) further suggested interactions between these key genes and Aβ/tau, supporting their involvement in AD pathogenesis. Additionally, regulatory network analysis identified 23 miRNAs, 33 transcription factors, and 14 potential therapeutic agents targeting these key genes. Our findings underscore the importance of palmitoylation in synaptic dysfunction-notably VAMP2 and SYT1 roles in vesicle recycling and neurotransmitter release-and offer promising targets for novel therapeutic strategies in AD.

ABSTRACT This study aims to identify the risk factors associated with clinical outcomes and the proteomic changes in organs related to fatal SARS‐CoV‐2 infection within the super‐elderly population. This retrospective analysis included all elderly individuals with COVID‐19 admitted to the Second Medical Center of PLA General Hospital from December 2022 to January 2023. The follow‐up period ended on March 30, 2023. During this time, epidemiological, demographic, laboratory, and outcome data were analyzed descriptively. Proteomic sequencing was performed on super‐elderly patients who died from COVID‐19 at different stages of the disease. A total of 352 elderly COVID‐19 patients, with a mean age of 89.84 ± 8.54 years, were included in this study. During a median follow‐up period of 98 days, 79 patients died. Deceased patients were older and more likely to have cardiovascular and cerebrovascular diseases, with a lower prevalence of lipid‐lowering therapy. The number of deaths in the acute and post‐acute phases were 34 and 45, respectively. Proteomics data suggest that the immune systems of patients who died in the acute phase underwent a more rapid and severe onslaught. Patients in the post‐acute phase showed higher levels of viral genome replication and a more robust immune response. However, the over‐activation of the immune system led to systemic organ dysfunction. Effective management of comorbidities may improve the prognosis of COVID‐19 in super‐elderly patients. The continuous replication of the SARS‐CoV‐2 virus and its subsequent impact on the immune system are critical determinants of survival time in this demographic.

Hypertension is closely related to cognitive impairment; however, the correlation between blood pressure control and cognitive impairment in the hypertensive population is unclear. We aimed to explore the relationship between blood pressure control and cognitive impairment in older adults with hypertension. Using the cross-sectional data from the 2018 Chinese Longitudinal Healthy Longevity Survey, 5,860 people with self-reported history of hypertension were divided into the hypotension, intermediate blood pressure, and hypertension groups. Cognitive impairment was defined as a score of < 18 on the Chinese version of the Mini-Mental State Examination. Demographics of the population were also collected. Bivariate Logistic regression analysis and restricted cubic spline (RCS) model were used to analyze the relationship between blood pressure control and cognitive impairment. After adjusting for confounding factors, binary logistic regression analysis showed that the intermediate group was significantly associated with an increased risk of cognitive impairment than the hypotension group, whereas the hypertension group was significantly correlated with a reduced risk of cognitive impairment. No significant correlation was found between blood pressure control and cognitive impairment in patients aged <80 years, with hearing impairment, or with cerebrovascular diseases, whether in the hypotension or hypertension groups. There was a significant correlation between hypotension and cognitive impairment, and no correlation between hypertension and cognitive impairment in people aged ≥ 80 years, Han ethnicity and those who used antihypertensive drugs. Furthermore, RCS model analysis showed that there was a non-linear relationship between systolic blood pressure and cognitive impairment in individuals aged ≥ 80 years and those using antihypertensive drugs. There was a linear relationship between diastolic blood pressure and cognitive impairment. Blood pressure control in the hypertensive group was significantly associated with a lower risk of cognitive impairment.

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-hydroxyvitaminD[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: VitaminDdeficiencywas 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.

BACKGROUND:Hederagenin (HG), derived from ivy seeds, is known to offer protection against Alzheimer's disease (AD). However, the specific molecular pathways through which it counters ferroptosis-induced neurotoxicity are not fully elucidated. This investigation seeks to delineate the processes by which HG mitigates neurotoxic effects in HT22 cells subjected to glutamate (Glu)-induced ferroptosis. METHODS:HT22 cell ferroptosis was prompted by Glu exposure. Cell viability was assessed using CCK-8 and LDH assays, while Fe2+ fluorescence and assays of iron-related proteins served to gauge intracellular Fe2+ concentrations. Evaluations of mitochondrial structure and functionality employed JC-1 staining and transmission electron microscopy. Assessments of ROS, lipid peroxidation, MDA, 4-HNE, and the GSSG/GSH ratio were conducted to ascertain HG's antioxidative efficacy. The expression of proteins within the PPARα/Nrf2/GPX4 pathway was quantified via western blotting, with molecular docking (MD), and molecular dynamics simulations (MDS) used to explore protein interactions. RESULTS:HG diminished the cellular toxicity triggered by Glu in HT22 cells, lowered Fe2+ within cells, and rejuvenated mitochondrial morphology and performance. Concurrently, it modulated proteins critical to Fe2+ metabolism, diminished ROS and lipid peroxidation, and elevated GSH/GSSG ratios. Enhanced PPARα/Nrf2/GPX4 protein levels were corroborated by western blot results. Furthermore, molecular docking revealed favorable binding of HG to the proteins PPARα, Nrf2, and GPX4, with binding energies of -7.751, -7.535, and -7.414 kcal/mol, respectively. MDS confirmed robust interactions between HG and these pivotal targets. CONCLUSION:The evidence suggests that HG effectively mitigates Glu-induced ferroptosis in HT22 cells by activating the PPARα/Nrf2/GPX4 signaling pathway. These findings endorse HG's potential as a nutritional adjunct for AD management.

Microglia/macrophages (MG/Mφ) play a central role in the pathogenesis of multiple sclerosis (MS). However, the intricacies of the immunomodulatory microenvironment in MS, particularly the heterogeneity and regulatory mechanisms of MG/Mφ subpopulations, remain elusive. The commonly used treatment options for MS have several drawbacks, such as significant side effects and uncertain efficacy. The exploration of developing new drugs targeting MG/Mφ for the treatment of MS remains to be investigated. We identified three distinct subpopulations of MG/Mφ, among which MG/Mφ_3 significantly increased as the experimental autoimmune encephalomyelitis (EAE) progressed. Ifenprodil and RO-25–6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity. The interaction modes of these compounds with the common binding pocket in the GluN1b–GluN2B amino terminal domain heterodimer were elucidated. Virtual docking, based on the N-methyl-d-aspartate (NMDA) receptor, showed that homo-skeleton compounds of ifenprodil potentially exhibit low binding free energy with the receptor, including eliprodil and volinanserin. In vitro cell models corroborated the effective inhibition of inflammatory factor expression and minimal cytotoxicity of eliprodil and volinanserin. CoMFA (standard error of estimate = 0.378, R2 = 0.928, F values = 241.255, Prob. of R2 = 0) and topomer CoMFA (q2 = 0.553, q2 stderr = 0.77, intercept = − 1.48, r2 = 0.908, r2 stderr = 0.35) were established based on the inhibitors of NMDA receptor. The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ.

Background: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's 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 Material and Methods: According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid ss-protein positive (A ss+) and negative (A ss-) patients were recruited according to the A ss-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 A ss+ 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 A ss+ and 73 A ss- 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.

BACKGROUND (31-blockers could improve clinical outcomes in patients with coronary artery disease by lowering the heart rate, blood pressure, and myocardial contractility. Moreover, recent studies have suggested that (31-blockers may also have the potential to reduce bleeding risk. OBJECTIVES This study aimed to evaluate the association between (31-blockers and bleeding risk in the patients prescribed with potent dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). METHODS Patients with ACS or undergoing PCI treated by DAPT of ticagrelor and aspirin were consecutively recruited. Follow-up for all eligible patients was conducted for 1 year. Major bleeding outcomes were defined as events that were type >= 2 based on the Bleeding Academic Research Consortium (BARC) criteria. RESULTS A total of 1,113 eligible ticagrelor-treated patients were recruited. During the 1-year follow-up interval, 142 (12.6%) patients experienced BARC >= 2 bleedings including 23 patients (2.1%) suffering BARC >= 3 bleedings, with the most common site of bleeding located in the gastrointestinal tract. (31-blockers treatment was associated with a lower risk of BARC >= 2 bleedings (11.2% vs. 23.3%, adjusted HR: 0.42, 95% CI: 0.28-0.62, P < 0.01). Moreover, metoprolol (11.1% vs. 23.3%, adjusted HR: 0.56, 95% CI: 0.37-0.83, P < 0.01) and bisoprolol (11.3% vs. 23.3%, adjusted HR: 0.56, 95% CI: 0.33-0.96, P 1/4 0.04) had similar effects on the reduction of bleeding risk. CONCLUSION (31-blockers might be beneficial for the reduction of bleeding risk in potent dual antiplatelet therapy patients with ACS or undergoing PCI. (Hellenic Journal of Cardiology 2024;79:15-24) (c) 2023 Hellenic Society of Cardiology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

AimPatients with unstable angina pectoris (UAP) usually present anxiety or depression during percutaneous coronary intervention (PCI). This study sought to investigate the instant and short-term effects of acupuncture for anxiety and depression in UAP patients with PCI.MethodsA total of 210 UAP patients who underwent PCI were recruited and randomly assigned (1:1:1) to acupuncture, placebo, or control groups. Enzyme-linked immunosorbent assay was used to detect the levels of fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), interleukin-6 (IL-6), high-sensitivity C-reactive protein (Hs-CRP), advanced oxidation protein products (AoPPs), and oxidized low-density lipoprotein (OX-LDL). Serial questionnaires with the Hamilton Anxiety (HAMA) scale and the Pittsburgh Sleep Quality Index were evaluated, and heart rate variability indicators were obtained.ResultsPrimary end-point: low frequency/high frequency (HF) was lower in the electroacupuncture group (p = 0.014), while standard deviation of normal-to-normal intervals, average standard deviation of normal-to-normal intervals, percentage of successive intervals that differ more than 50 ms, and HF were increased with acupuncture (p = 0.018, p = 0.043, p = 0.016, and p = 0.002, respectively). Secondary end-point: significant improvements in anxiety levels (HAMA) were observed in the three groups (p < 0.001). The fasting insulin and HOMA-IR levels were similar between the control group and the acupuncture group (p = 0.285 and p = 0.165, respectively). The levels of IL-6 and AoPPs differed among the three groups (p = 0.021 and p < 0.001, respectively). However, no significant differences were found in fasting plasma glucose, fasting c-peptide, Hs-CRP, and OX-LDL levels among the three groups (p = 0.585, p = 0.611, p = 0.902, and p = 0.756, respectively).ConclusionsIn this study, short-term acupuncture may potentially relieve clinical symptoms before PCI treatment. Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT03789344).

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

BackgroundMitochondrial dysfunction (MD) is increasingly recognized as a key pathophysiological contributor in Alzheimer disease (AD). As differential MD genes expression may serve as either a causative factor or a consequence in AD, and expression of these genes could be influenced by epigenetic modifications or interact with inflammatory cytokines, hence, the precise role of MD in AD remains uncertain.MethodsMeta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD. We utilized three-step SMR to analyze the AD genome-wide association study summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs from the blood and brain tissues, respectively. Through SMR and colocalization analysis, we further explored the interactions between brain eQTLs and inflammatory cytokines.ResultsFive datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes. Among these, seven genes from blood samples such as NDUFS8 and SPG7 and thirty-two genes from brain tissue including CLU and MAPT were identified as candidate AD-causal MD genes and regulated by methylation level. Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor.ConclusionsThis study highlighted that the AD-causal MD genes could be regulated by epigenetic changes and interact with inflammatory cytokines, providing evidence for AD prevention and intervention.

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, Ruminococcus 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.

阿尔茨海默病(Alzheimer's disease,AD)是老年期痴呆最主要的病因,我国 AD患者已近 1000 万,但目前尚无有效的药物可以治疗,早期诊断并进行干预是延缓疾病进展的主要手段.通过腰椎穿刺和正电子发射断层显像(PET)确认颅内β淀粉样蛋白(Aβ)沉积是 AD 在轻度认知障碍(MCI)阶段早期精准诊断的必要条件.但由于有创检查、费用高昂以及辐射暴露等原因,多数医院仍采用结构 MRI诊断疾病.然而,内侧颞叶萎缩等结构 MRI 改变在 AD 早期诊断的准确性只有 60％,临床急需更敏感的 MRI 生物标志物[1].近年,弥散张量成像(DTI)因能无创的探测脑微结构改变广泛应用于临床研究.但是由于萎缩相关部分容积效应、DTI指标生物意义难以明确等原因,限制了DTI作为AD生物标志物的应用.自由水DTI(FW-DTI)成像在很大程度上弥补了上述缺陷,本综述对 FW-DTI作为 AD诊断的潜在影像标志物进行分析、归纳和总结.

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 (Aβ) positivity in mild cognitive impairment (MCI) subtypes. STUDY TYPE:Retrospective. POPULATION:Thirty-eight Aβ-negative cognitively healthy (CH) controls (68.74 ± 8.28 years old, 55% female), 15 Aβ-negative MCI patients (MCI-n) (68.87 ± 8.83 years old, 60% female), 29 Aβ-positive MCI patients (MCI-p) (73.03 ± 7.05 years old, 52% female), and 29 Aβ-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 Aβ PET (18F-florbetaben or 11C-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.

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer’s disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.