Breaking the Base Barrier: Cu(II)-Mediated C-H Heteroarylation of o-Carboranes with Base-Sensitive Heteroaryl Halides.

While cage C-arylation reactions using strong bases are among the most frequently used transformations in carborane chemistry, there has been no general solution to allow for the use of weak bases in the reaction. Moreover, base-metal-promoted C-H heteroarylation with base-sensitive heteroaryl halides remained elusive. Herein, copper-mediated cage C-H (hetero)arylation has been achieved without the need for strong bases, leading to the facile synthesis of a wide range of C-(hetero)arylated carboranes in good to excellent yields with a broad substrate scope and good functional group compatibility.

Mechanistic study of Huangqi Guizhi Wuwu decoction amelioration of doxorubicin-induced cardiotoxicity by reducing oxidative stress and inhibiting cellular pyroptosis.

Huangqi Guizhi Wuwu Decoction (HQGZWWD) has shown promising potential in treating various cardiovascular diseases. This study aimed to elucidate the molecular basis and therapeutic role of HQGZWWD in the treatment of doxorubicin (DOX)-induced myocardial injury. The HPLC fingerprint of HQGZWWD was used to analyze the active components. A DOX-induced myocardial damage rat model was developed, and the therapeutic effects of HQGZWWD were evaluated using echocardiography, myocardial enzyme levels, and hematoxylin and eosin staining. Network pharmacology was used to screen treatment targets, and western blotting and immunohistochemistry were performed to assess cellular pyroptosis levels. Oxidative stress levels were measured using assay kits, and mitochondrial damage was examined using transmission electron microscopy. An in vitro model of DOX-induced cell damage was established, and treatment was administered using serum containing HQGZWWD and N-acetylcysteine (NAC). Oxidative stress levels were detected using assay kits and DCFH-DA, whereas cellular pyroptosis levels were assessed through WB, immunofluorescence, and ELISA assays. HQGZWWD ameliorated DOX-induced myocardial injury. Network pharmacology identified IL-1ß and IL-18 as crucial targets. HQGZWWD downregulated the protein levels of the inflammatory factors IL-1ß and IL-18, inhibited the expression of GSDMD-NT, and simultaneously suppressed the synthesis of Caspase-1, ASC, NLRP3, and Caspase-11. Additionally, HQGZWWD inhibited oxidative stress, and the use of NAC as an oxidative stress inhibitor resulted in significant inhibition of the GSDMD-NT protein in H9C2 cells. These findings highlight the myocardial protective effects of HQGZWWD by inhibiting oxidative stress and suppressing both canonical and non-canonical pyroptotic pathways.

Effects of the Fasting-Postprandial State on Arterial Spin Labeling MRI-Based Cerebral Perfusion Quantification in Alzheimer's Disease.

BACKGROUND: The fasting-postprandial state remains an underrecognized confounding factor for quantifying cerebral blood flow (CBF) in the cognitive assessment and differential diagnosis of Alzheimer's disease (AD). PURPOSE: To investigate the effects of fasting-postprandial state on arterial spin labeling (ASL)-based CBF in AD patients. STUDY TYPE: Prospective. SUBJECTS: Ninety-two subjects (mean age = 62.5 ± 6.4 years; females 29.3%), including 30 with AD, 32 with mild cognitive impairment (MCI), and 30 healthy controls (HCs). Differential diagnostic models were developed with a 4:1 training to testing set ratio. FIELD STRENGTH/SEQUENCE: 3-T, T1-weighted imaging using gradient echo and pseudocontinuous ASL imaging using turbo spin echo. ASSESSMENT: Two ASL scans were acquired to quantify fasting state and postprandial state regional CBFs based on an automated anatomical labeling atlas. Two-way ANOVA was used to assess the effects of fasting/postprandial state and disease state (AD, MCI, and HC) on regional CBF. Pearson's correlation analysis was conducted between regional CBF and cognitive scores (Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]). The diagnostic performances of the fasting state, postprandial state, and mixed state (random mixing of the fasting and postprandial state CBF) in differential diagnosis of AD were conducted using support vector machine and logistic regression models. STATISTICAL TESTS: Two-way ANOVA, Pearson's correlation, and area under the curve (AUC) of diagnostic model were performed. P values <0.05 indicated statistical significance. RESULTS: Fasting-state CBF was correlated with cognitive scores in more brain regions (17 vs. 4 [MMSE] and 15 vs. 9 [MoCA]) and had higher absolute correlation coefficients than postprandial-state CBF. In the differential diagnosis of AD patients from MCI patients and HCs, fasting-state CBF outperformed mixed-state CBF, which itself outperformed postprandial-state CBF. DATA CONCLUSION: Compared with postprandial CBF, fasting-state CBF performed better in terms of cognitive score correlations and in differentiating AD patients from MCI patients and HCs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Clinical and neuroimaging association between neuropsychiatric symptoms and nutritional status across the Alzheimer's disease continuum: a longitudinal cohort study.

OBJECTIVES: To investigate the association between neuropsychiatric symptoms (NPS) and nutritional status, and explore their shared regulatory brain regions on the Alzheimer's disease (AD) continuum. DESIGN: A longitudinal, observational cohort study. SETTING: Data were collected from the Chinese Imaging, Biomarkers, and Lifestyle study between June 1, 2021 and December 31, 2022. PARTICIPANTS: Overall, 432 patients on the AD continuum, including amnestic mild cognitive impairment and AD dementia, were assessed at baseline, and only 165 patients completed the (10.37 ± 6.08) months' follow-up. MEASUREMENTS: The Mini-Nutritional Assessment (MNA) and Neuropsychiatric Inventory (NPI) were used to evaluate nutritional status and NPS, respectively. The corrected cerebral blood flow (cCBF) measured by pseudo-continuous arterial spin labeling of the dietary nutrition-related brain regions was analyzed. The association between the NPS at baseline and subsequent change in nutritional status and the association between the changes in the severity of NPS and nutritional status were examined using generalized linear mixed models. RESULTS: Increased cCBF in the left putamen was associated with malnutrition, general NPS, affective symptoms, and hyperactivity (P < 0.05). The presence of general NPS (ß = -1.317, P = 0.003), affective symptoms (ß = -1.887, P < 0.001), and appetite/eating disorders (ß = -1.714, P < 0.001) at baseline were associated with a decline in the MNA scores during follow-up. The higher scores of general NPI (ß = -0.048), affective symptoms (ß = -0.181), and appetite/eating disorders (ß = -0.416; all P < 0.001) were longitudinally associated with lower MNA scores after adjusting for confounding factors. CONCLUSIONS: We found that baseline NPS were predictors of a decline in nutritional status on the AD continuum. The worse the severity of affective symptoms and appetite/eating disorders, the poorer the nutritional status. Furthermore, abnormal perfusion of the putamen may regulate the association between malnutrition and NPS, which suggests their potentially common neural regulatory basis.

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

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

Development and validation of a nutrition-related genetic-clinical-radiological nomogram associated with behavioral and psychological symptoms in Alzheimer's disease.

BACKGROUND: Few evidence is available in the early prediction models of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD). This study aimed to develop and validate a novel genetic-clinical-radiological nomogram for evaluating BPSD in patients with AD and explore its underlying nutritional mechanism. METHODS: This retrospective study included 165 patients with AD from the Chinese Imaging, Biomarkers, and Lifestyle (CIBL) cohort between June 1, 2021, and March 31, 2022. Data on demoimagedatas, neuropsychological assessments, single-nucleotide polymorphisms of AD risk genes, and regional brain volumes were collected. A multivariate logistic regression model identified BPSD-associated factors, for subsequently constructing a diagnostic nomogram. This nomogram was internally validated through 1000-bootstrap resampling and externally validated using a time-series split based on the CIBL cohort data between June 1, 2022, and February 1, 2023. Area under receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used to assess the discrimination, calibration, and clinical applicability of the nomogram. RESULTS: Factors independently associated with BPSD were: CETP rs1800775 (odds ratio [OR] = 4.137, 95% confidence interval [CI]: 1.276-13.415, P = 0.018), decreased Mini Nutritional Assessment score (OR = 0.187, 95% CI: 0.086-0.405, P <0.001), increased caregiver burden inventory score (OR = 8.993, 95% CI: 3.830-21.119, P <0.001), and decreased brain stem volume (OR = 0.006, 95% CI: 0.001-0.191, P = 0.004). These variables were incorporated into the nomogram. The area under the ROC curve was 0.925 (95% CI: 0.884-0.967, P <0.001) in the internal validation and 0.791 (95% CI: 0.686-0.895, P <0.001) in the external validation. The calibration plots showed favorable consistency between the prediction of nomogram and actual observations, and the DCA showed that the model was clinically useful in both validations. CONCLUSION: A novel nomogram was established and validated based on lipid metabolism-related genes, nutritional status, and brain stem volumes, which may allow patients with AD to benefit from early triage and more intensive monitoring of BPSD. REGISTRATION: Chictr.org.cn, ChiCTR2100049131.

Spatiotemporal Characteristics of Regional Brain Perfusion Associated with Neuropsychiatric Symptoms in Patients with Alzheimer's Disease.

BACKGROUND: Current technology for exploring neuroimaging markers and neural circuits of neuropsychiatric symptoms (NPS) in patients with Alzheimer's disease (AD) is expensive and usually invasive, limiting its use in clinical practice. OBJECTIVE: To investigate the cerebral morphology and perfusion characteristics of NPS and identify the spatiotemporal perfusion circuits of NPS sub-symptoms. METHODS: This nested case-control study included 102 AD patients with NPS and 51 age- and sex-matched AD patients without NPS. Gray matter volume, cerebral blood flow (CBF), and arterial transit time (ATT) were measured and generated using time-encoded 7-delay pseudo-continuous arterial spin labeling (pCASL). Multiple conditional logistic regression analysis was used to identify neuroimaging markers of NPS. The associations between the CBF or ATT of affected brain areas and NPS sub-symptoms were evaluated after adjusting for confounding factors. The neural circuits of sub-symptoms were identified based on spatiotemporal perfusion sequencing. RESULTS: Lower Mini-Mental State Examination scores (p < 0.001), higher Caregiver Burden Inventory scores (p < 0.001), and higher CBF (p = 0.001) and ATT values (p < 0.003) of the right anteroventral thalamic nucleus (ATN) were risk factors for NPS in patients with AD. Six spatiotemporal perfusion circuits were found from 12 sub-symptoms, including the anterior cingulate gyri-temporal pole/subcortical thalamus-cerebellum circuit, insula-limbic-cortex circuit, subcortical thalamus-temporal pole-cortex circuit, subcortical thalamus-cerebellum circuit, frontal cortex-cerebellum-occipital cortex circuit, and subcortical thalamus-hippocampus-dorsal raphe nucleus circuit. CONCLUSIONS: Prolonged ATT and increased CBF of the right ATN may be neuroimaging markers for detecting NPS in patients with AD. Time-encoded pCASL could be a reliable technique to explore the neural perfusional circuits of NPS.

Nanotechnology boosts the efficiency of tumor diagnosis and therapy.

The incidence and mortality of cancer are gradually increasing. The highly invasive and metastasis of tumor cells increase the difficulty of diagnosis and treatment, so people pay more and more attention to the diagnosis and treatment of cancer. Conventional treatment methods, including surgery, radiotherapy and chemotherapy, are difficult to eliminate tumor cells completely. And the emergence of nanotechnology has boosted the efficiency of tumor diagnosis and therapy. Herein, the research progress of nanotechnology used for tumor diagnosis and treatment is reviewed, and the emerging detection technology and the application of nanodrugs in clinic are summarized and prospected. The first part refers to the application of different nanomaterials for imaging in vivo and detection in vitro, which includes magnetic resonance imaging, fluorescence imaging, photoacoustic imaging and biomarker detection. The distinctive physical and chemical advantages of nanomaterials can improve the detection sensitivity and accuracy to achieve tumor detection in early stage. The second part is about the nanodrug used in clinic for tumor treatment. Nanomaterials have been widely used as drug carriers, including the albumin paclitaxel, liposome drugs, mRNA-LNP, protein nanocages, micelles, membrane nanocomplexes, microspheres et al., which could improve the drug accumulate in tumor tissue through enhanced permeability and retention effect to kill tumor cells with high efficiency. But there are still some challenges to revolutionize traditional tumor diagnosis and anti-drug resistance based on nanotechnology.

Nutrition in Alzheimer's disease: a review of an underappreciated pathophysiological mechanism.

Alzheimer's disease (AD) is the leading cause of dementia in older individuals and is an escalating challenge to global public health. Pharmacy therapy of AD is one of the well-funded areas; however, little progress has been made due to the complex pathogenesis. Recent evidence has demonstrated that modifying risk factors and lifestyle may prevent or delay the incidence of AD by 40%, which suggests that the management should pivot from single pharmacotherapy toward a multipronged approach because AD is a complex and multifaceted disease. Recently, the gut-microbiota-brain axis has gained tremendous traction in the pathogenesis of AD through bidirectional communication with multiple neural, immune, and metabolic pathways, providing new insights into novel therapeutic strategies. Dietary nutrition is an important and profound environmental factor that influences the composition and function of the microbiota. The Nutrition for Dementia Prevention Working Group recently found that dietary nutrition can affect cognition in AD-related dementia directly or indirectly through complex interactions of behavioral, genetic, systemic, and brain factors. Thus, considering the multiple etiologies of AD, nutrition represents a multidimensional factor that has a profound effect on AD onset and development. However, mechanistically, the effect of nutrition on AD is uncertain; therefore, optimal strategies or the timing of nutritional intervention to prevent or treat AD has not been established.Thus, this review summarizes the current state of knowledge concerning nutritional disorders, AD patient and caregiver burden, and the roles of nutrition in the pathophysiology of AD. We aim to emphasize knowledge gaps to provide direction for future research and to establish optimal nutrition-based intervention strategies for AD.

Huperzine A-Liposomes Efficiently Improve Neural Injury in the Hippocampus of Mice with Chronic Intermittent Hypoxia.

Background: Chronic intermittent hypoxia (CIH) could cause neuronal damage, accelerating the progression of dementia. However, safe and effective therapeutic drugs and delivery are needed for successful CIH therapy. Purpose: To investigate the neuroprotective effect of Huperzine A (HuA) packaged with nanoliposomes (HuA-LIP) on neuronal damage induced by CIH. Methods: The stability and release of HuA-LIP in vitro were identified. Mice were randomly divided into the Control, CIH, HuA-LIP, and HuA groups. The mice in the HuA and HuA-LIP groups received HuA (0.1 mg/kg, i.p.), and HuA-LIP was administered during CIH exposure for 21 days. HuA-LIP contains the equivalent content of HuA. Results: We prepared a novel formulation of HuA-LIP that had good stability and controlled release. First, HuA-LIP significantly ameliorated cognitive dysfunction and neuronal damage in CIH mice. Second, HuA-LIP elevated T-SOD and GSH-Px abilities and decreased MDA content to resist oxidative stress damage induced by CIH. Furthermore, HuA-LIP reduced brain iron levels by downregulating TfR1, hepcidin, and FTL expression. In addition, HuA-LIP activated the PKAα/Erk/CREB/BDNF signaling pathway and elevated MAP2, PSD95, and synaptophysin to improve synaptic plasticity. Most importantly, compared with HuA, HuA-LIP showed a superior performance against neuronal damage induced by CIH. Conclusion: HuA-LIP has a good sustained-release effect and targeting ability and efficiently protects against neural injury caused by CIH.

Potential Diagnostic Applications of Multi-Delay Arterial Spin Labeling in Early Alzheimer's Disease: The Chinese Imaging, Biomarkers, and Lifestyle Study.

Background: Cerebral blood flow (CBF) alterations are involved in the onset and progression of Alzheimer's disease (AD) and can be a potential biomarker. However, CBF measured by single-delay arterial spin labeling (ASL) for discrimination of mild cognitive impairment (MCI, an early stage of AD) was lack of accuracy. Multi-delay ASL can not only provide CBF quantification but also provide arterial transit time (ATT). Unfortunately, the technique was scarcely applied to the diagnosis of AD. Here, we detected the utility of ASL with 1-delay and 7-delay in ten regions of interest (ROIs) to identify MCI and AD. Materials and Methods: Pseudocontinuous ASL (pCASL) MRI was acquired on a 3T GE scanner in adults from the Chinese Imaging, Biomarkers, and Lifestyle (CIBL) Study of AD cohort, including 26 normal cognition (NC), 37 MCI, and 39 AD. Receiver operating characteristic (ROC) analyses with 1-delay and 7-delay ASL were performed for the identification of MCI and AD. The DeLong test was used to compare ROC curves. Results: For CBF of 1-delay or 7-delay the AUCs showed moderate-high performance for the AD/NC and AD/MCI comparisons (AUC = 0.83∼0.96) (p < 0.001). CBF of 1-delay performed poorly in MCI/NC comparison (AUC = 0.69) (p < 0.001), but CBF of 7-delay fared well with an AUC of 0.79 (p < 0.001). The combination of CBF and ATT of 7-delay showed higher performance for AD/NC, AD/MCI, and MCI/NC comparisons with AUCs of 0.96, 0.89, and 0.89, respectively (p < 0.001). Furthermore, combination of CBF, ATT, sex, age, APOE ε4, and education improved further the accuracy (p < 0.001). In subgroups analyses, there were no significant differences in CBF of 7-delay ASL for identification of AD or MCI between age subgroups (p > 0.05). Conclusion: The combination of CBF and ATT with 7-delay ASL showed higher performance for identification of MCI than CBF of 1-delay, when adding to sex, age, APOE ε4 carrier status, and education years, the diagnostic performance was further increased, presenting a potential imaging biomarker in early AD.

The characteristics of arterial spin labeling cerebral blood flow in patients with subjective cognitive decline: The Chinese imaging, biomarkers, and lifestyle study.

Objective: We aimed to characterize the potential risk factors and cerebral perfusion of patients with subjective cognitive decline (SCD). Methods: This prospective study enrolled consecutive patients from the Chinese Imaging, Biomarkers, and Lifestyle (CIBL) Cohort of Alzheimer's disease between February 2021 and March 2022. Patients who met the SCD diagnostic criteria were categorized into the SCD group, while those without cognitive complaints or any concerns were assigned to the healthy control (HC) group. The demographic and clinical characteristics and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL) in standard cognitive regions were compared between these two groups. A multivariate analysis was performed to identify independent factors associated with SCD. Results: The frequency of family history of dementia in the SCD group was higher compared with the HC group (p = 0.016). The CBF of left hippocampus (p = 0.023), left parahippocampal gyrus (p = 0.004), left precuneus (p = 0.029), left middle temporal gyrus (p = 0.022), right parahippocampal gyrus (p = 0.018), and right precuneus (p = 0.024) in the SCD group were significantly increased than those in the HC group. The multivariate logistic regression analyses demonstrated that the family history of dementia [OR = 4.284 (1.096-16.747), p = 0.036] and the CBF of left parahippocampal gyrus [OR = 1.361 (1.006-1.840), p = 0.045] were independently associated with SCD. Conclusion: This study demonstrated that the family history of dementia and the higher CBF within the left parahippocampal gyrus were independent risk factors associated with patients with SCD, which could help in the early identification of the SCD and in intervening during this optimal period.

Mediation of the APOE Associations With Cognition Through Cerebral Blood Flow: The CIBL Study.

Background: The ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for aging-related cognitive decline. However, the causal connection between ε4 alleles and cognition is not well understood. The objective of this study was to identify the roles of cerebral blood flow (CBF) in cognitive-related brain areas in mediating the associations of APOE with cognition. Methods: The multiple linear regression analyses were conducted on 369 subjects (mean age of 68.8 years; 62.9% of women; 29.3% of APOE ε4 allele carriers). Causal mediation analyses with 5,000 bootstrapped iterations were conducted to explore the mediation effects. Result: APOE ε4 allele was negatively associated with cognition (P < 0.05) and CBF in the amygdala, hippocampus, middle temporal gyrus, posterior cingulate, and precuneus (all P < 0.05). The effect of the APOE genotype on cognition was partly mediated by the above CBF (all P < 0.05). Conclusion: CBF partially mediates the potential links between APOE genotype and cognition. Overall, the APOE ε4 allele may lead to a dysregulation of the vascular structure and function with reduced cerebral perfusion, which in turn leads to cognitive impairment.

Plasma p-tau181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study.

Background: Plasma-based biomarkers would be potential biomarkers for early diagnosis of Alzheimer's disease (AD) because they are more available and cost-effective than cerebrospinal fluid (CSF) or neuroimaging. Therefore, we aimed to evaluate whether phosphorylated tau181 (p-tau181) in plasma could be an accurate AD predictor. Methods: Participants from the ADNI database included 185 cognitively unimpaired subjects with negative Aß (CU-), 66 subjects with pre-clinical AD (CU with positive Aß), 164 subjects with mild cognitive impairment with negative Aß (MCI-), 254 subjects with prodromal AD (MCI with positive Aß), and 98 subjects with dementia. Multiple linear regression models, linear mixed-effects models, and local regression were used to explore cross-sectional and longitudinal associations of plasma p-tau181 with cognition, neuroimaging, or CSF biomarkers adjusted for age, sex, education, and APOE genotype. Besides, Kaplan-Meier and adjusted Cox-regression model were performed to predict the risk of progression to dementia. Receiver operating characteristic analyses were performed to evaluate the predictive value of p-tau181. Results: Plasma p-tau181 level was highest in AD dementia, followed by prodromal AD and pre-clinical AD. In pre-clinical AD, plasma p-tau181 was negatively associated with hippocampal volume (ß = -0.031, p-value = 0.017). In prodromal AD, plasma p-tau181 was associated with decreased global cognition, executive function, memory, language, and visuospatial functioning (ß range -0.119 to -0.273, p-value < 0.05) and correlated with hippocampal volume (ß = -0.028, p-value < 0.005) and white matter hyperintensity volume (WMH) volume (ß = 0.02, p-value = 0.01). In AD dementia, increased plasma p-tau181 was associated with worse memory. In the whole group, baseline plasma p-tau181 was significantly associated with longitudinal increases in multiple neuropsychological test z-scores and correlated with AD-related CSF biomarkers and hippocampal volume (p-value < 0.05). Meanwhile, CU or MCI with high plasma p-tau181 carried a higher risk of progression to dementia. The area under the curve (AUC) of the adjusted model (age, sex, education, APOE genotype, and plasma p-tau181) was 0.78; that of additionally included CSF biomarkers was 0.84. Conclusions: Plasma p-tau181 level is related to multiple AD-associated cognitive domains and AD-related CSF biomarkers at the clinical stages of AD. Moreover, plasma p-tau181 level is related to the change rates of cognitive decline and hippocampal atrophy. Thus, this study confirms the utility of plasma p-tau181 as a non-invasive biomarker for early detection and prediction of AD.

Can Aspirin Use Be Associated With the Risk or Prognosis of Bladder Cancer? A Case-Control Study and Meta-analytic Assessment.

Aspirin, widely used to prevent cardiovascular disease, had been linked to the incidence of bladder cancer (BCa). Existing studies focusing on Chinese populations are relatively rare, especially for Northeast China. Meanwhile, relevant studies on the effects of aspirin on the occurrence or prognosis of BCa are inconsistent or even controversial. First, in the case control study, logistic regression analysis was used to investigate the association between aspirin intake and risk of BCa including 1121 patients with BCa and the 2242 controls. Subsequently, Kaplan-Meier curve and Cox regression analyses were applied to explore the association between aspirin intake and clinicopathological factors which may predict overall survival (OS) and recurrence-free survival (RFS) of BCa patients. Finally, we quantificationally combined the results with those from the published literature evaluating aspirin intake and its effects on the occurrence, outcome of surgery and prognosis of BCa by meta-analysis up to May 1, 2021.Our case-control study demonstrated that the regular use of aspirin was not associated with a reduced incidence of BCa (P=0.175). Stratified analyses of sex showed that aspirin intake did not lead to a lower risk of BCa in female patients (P=0.063). However, the male population who regularly took aspirin had a lower incidence of BCa (OR=0.748, 95% CI= 0.584-0.958, P=0.021). Subgroup analyses stratified by smoking found a significant reduction in the risk of BCa in current smokers with aspirin intake (OR=0.522, 95% CI=0.342-0.797, P=0.002). In terms of prognosis of BCa, patients with a history of aspirin intake did not had a markedly longer OS or RFS than those with no history of aspirin intake by Kaplan-Meier curves. Stratified analysis by sex showed no correlation between aspirin intake and the recurrence or survival of BCa for either male or female patients. However, in people younger than 68, aspirin intake seemed to have prolonged effects for overall survival (HR=3.876; 95% CI=1.326-11.325, P=0.019). Then, we performed a meta-analysis and the combined results from 19 articles and our study involving more than 39524 BCa cases indicated that aspirin intake was not associated with the occurrence of BCa (P=0.671). Subgroup analysis by whether regular use of aspirin, by the mean duration of use of aspirin, by sex, by smoking exposure, by research region and by study type also supported the above results. In terms of the impact of aspirin intake on the prognosis of patients with BCa, 11 articles and our study involving 8825 BCa cases were eligible. The combined results showed that patients with aspirin intake did not have significantly influence on survival, recurrence, progression and metastasis than those without aspirin intake. On the whole, both our retrospective study and literature meta-analysis suggested a lack of a strong relevant association between the use of aspirin and the incidence or prognosis of BCa. Thus, additional long-term follow-up prospective research is warranted to clarify the association of aspirin with BCa incidence and prognosis.

Altered Cerebral Blood Flow in Alzheimer's Disease With Depression.

Background: Depression is common in Alzheimer's disease (AD) with an unclear neural mechanism. This study aimed to investigate the underlying cerebral perfusion associated with depression in AD and evaluate its clinical significance. Method: Twenty-one AD patients and 21 healthy controls (HCs) were enrolled in this study. The depressive symptom was defined according to the Hamilton Depression Rating Scale (HAMD). Nine patients were diagnosed as AD with depression symptoms (HAMD >7). Three-dimensional pseudocontinuous arterial spin labeling MR imaging was conducted to measure regional cerebral blood flow (CBF). Neuropsychological tests covered cognition and depressive scores. Between-group comparisons on clinical variables and regional CBFs, relationship between regional CBF and depressive score, and identification of AD patients with depression were performed using covariance analysis, linear regression, and receiver operating characteristic (ROC) analysis, respectively. Results: Compared with HCs, AD patients without depression exhibited lower gray matter CBF (p = 0.016); compared with AD patients without depression, AD patients with depression had higher CBF in the right supplementary motor area (39.23 vs. 47.91 ml/100 g/min, p = 0.017) and right supramarginal gyrus (35.54 vs. 43.85 ml/100 g/min, p = 0.034). CBF in the right supplementary motor area was correlated with depressive score (ß = 0.46, p = 0.025). The combination of CBF in the right supplementary motor area and supramarginal gyrus and age could identify AD patients with depression from those without depression with a specificity of 100%, sensitivity of 66.67%, accuracy of 85.71%, and area under the curve of 0.87. Conclusions: Our findings suggested that hyperperfusion of the right supplementary motor area and right supramarginal gyrus were associated with depression syndrome in AD, which could provide a potential neuroimaging marker to evaluate the depression state in AD.

Relationship between homocysteine levels and post-stroke cognitive impairment in female and male population: from a prospective multicenter study.

BACKGROUND AND OBJECTIVES: To investigate the relationship between homocysteine levels and post-stroke cognitive impairment (PSCI) in Chinese female and male populations with minor acute ischemic stroke or transient ischemic attack. MATERIALS AND METHODS: A total of 1070 participants with clinically confirmed acute minor ischemic stroke or transient ischemic attack and baseline homocysteine information from a nationwide multicenter prospective registry study in China were included in this study. Of these, 919 patients had cognitive assessments at 3-month follow-ups and 584 participants had cognitive assessments at 12-month follow-ups. The incidence of PSCI was defined as a Montreal Cognitive Assessment score ≤22. The differences in homocysteine levels and the incidence of PSCI were compared between female and male populations. Relationships between homocysteine levels and the incidence of PSCI in female and male populations were analyzed using multiple logistic regression, respectively. RESULTS: Females had lower baseline homocysteine levels than males. Compared to males, females had lower education levels, lower rates of smoking and alcohol intake, and higher rates of diabetes and hypertension. No relationship was observed between elevated homocysteine level and 3-month PSCI incidence in either females or males. After adjusting the confounders, elevated baseline homocysteine significantly increased the 12-month PSCI risk (odds ratio 3.28, 95% confidence interval 1.47-7.34, P = 0.004) in females, but not in males (odds ratio 0.86, 95% confidence interval 0.49-1.49, P = 0.586). CONCLUSION: Elevated homocysteine levels increased the 12-month PSCI risk in females, but not in males with minor acute ischemic stroke or transient ischemic attack.

MicroRNA­21 contributes to renal cell carcinoma cell invasiveness and angiogenesis via the PDCD4/c­Jun (AP­1) signalling pathway.

Accumulating evidence has demonstrated that microRNAs are associated with malignant biological behaviour, including tumorigenesis, cancer progression and metastasis via the regulation of target gene expression. Our previous study demonstrated that programmed cell death protein 4 (PDCD4), which is a tumour suppressor gene, is a target of microRNA­21 (miR­21), which affects the proliferation and transformation capabilities of renal cell carcinoma (RCC) cells. However, the role of miR­21 in the molecular mechanism underlying the migration, invasion and angiogenesis of RCC remains poorly understood. The effects of miR­21 on the invasion, migration and angiogenesis of RCC cells was determined through meta­analysis and regulation of miR­21 expression in vitro. After searching several databases, 6 articles including a total of 473 patients met the eligibility criteria for this analysis. The combined results of the meta­analysis revealed that increased miR­21 expression was significantly associated with adverse prognosis in patients with RCC, with a pooled hazard ratio estimate of 1.740. In in vitro experiments, we demonstrated that a miR­21 inhibitor decreased the number of migrating and invading A498 and 786­O RCC cells, along with a decrease in PDCD4, c­Jun, matrix metalloproteinase (MMP)2 and MMP9 expression. Additionally, inhibition of miR­21 was revealed to reduce tube formation and tube junctions in the endothelial cell line HMEC­1 by affecting the expression of angiotensin­1 and vascular endothelial growth factor A, whereas PDCD4 small interfering RNA exerted opposite effects on the same cells. Overall, these findings, along with evidence­based molecular biology, demonstrated that miR­21 expression promoted the migration, invasion and angiogenic abilities of RCC cells by directly targeting the PDCD4/c­Jun signalling pathway. The results may help elucidate the molecular mechanism underlying the development and progression of RCC and provide a promising target for microRNA­based therapy.