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Background: Imbalance between the production and clearance of amyloid-β (Aβ) promotes the development of Alzheimer’s disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aβ production. The profiles of autoantibodies are dysregulated in AD patients. Objective: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD. Methods: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma. Results: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aβ load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%. Conclusion: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD.

Amyloid-β (Aβ) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aβ produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aβ clearance remain largely unknown. The kidney is thought to be responsible for Aβ clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aβ in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aβ clearance via the kidney were assessed. We detected Aβ in the kidneys and urine of both humans and animals and found that the Aβ level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aβ deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aβ levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aβ from the blood, suggesting that facilitation of Aβ clearance via the kidney represents a novel potential therapeutic approach for AD.

IMPORTANCE: Determining the long-term impact of COVID-19 on cognition is important to inform immediate steps in COVID-19 research and health policy. OBJECTIVE: To investigate the 1-year trajectory of cognitive changes in older COVID-19 survivors. DESIGN, SETTING, AND PARTICIPANTS: This cohort study recruited 3233 COVID-19 survivors 60 years and older who were discharged from 3 COVID-19–designated hospitals in Wuhan, China, from February 10 to April 10, 2020. Their uninfected spouses (N = 466) were recruited as a control population. Participants with preinfection cognitive impairment, a concomitant neurological disorder, or a family history of dementia were excluded, as well as those with severe cardiac, hepatic, or kidney disease or any kind of tumor. Follow-up monitoring cognitive functioning and decline took place at 6 and 12 months. A total of 1438 COVID-19 survivors and 438 control individuals were included in the final follow-up. COVID-19 was categorized as severe or nonsevere following the American Thoracic Society guidelines. MAIN OUTCOMES AND MEASURES: The main outcome was change in cognition 1 year after patient discharge. Cognitive changes during the first and second 6-month follow-up periods were assessed using the Informant Questionnaire on Cognitive Decline in the Elderly and the Telephone Interview of Cognitive Status-40, respectively. Based on the cognitive changes observed during the 2 periods, cognitive trajectories were classified into 4 categories: stable cognition, early-onset cognitive decline, late-onset cognitive decline, and progressive cognitive decline. Multinomial and conditional logistical regression models were used to identify factors associated with risk of cognitive decline. RESULTS: Among the 3233 COVID-19 survivors and 1317 uninfected spouses screened, 1438 participants who were treated for COVID-19 (691 male [48.05%] and 747 female [51.95%]; median [IQR] age, 69 [66-74] years) and 438 uninfected control individuals (222 male [50.68%] and 216 female [49.32%]; median [IQR] age, 67 [66-74] years) completed the 12-month follow-up. The incidence of cognitive impairment in survivors 12 months after discharge was 12.45%. Individuals with severe cases had lower Telephone Interview of Cognitive Status-40 scores than those with nonsevere cases and control individuals at 12 months (median [IQR]: severe, 22.50 [16.00-28.00]; nonsevere, 30.00 [26.00-33.00]; control, 31.00 [26.00-33.00]). Severe COVID-19 was associated with a higher risk of early-onset cognitive decline (odds ratio [OR], 4.87; 95% CI, 3.30-7.20), late-onset cognitive decline (OR, 7.58; 95% CI, 3.58-16.03), and progressive cognitive decline (OR, 19.00; 95% CI, 9.14-39.51), while nonsevere COVID-19 was associated with a higher risk of early-onset cognitive decline (OR, 1.71; 95% CI, 1.30-2.27) when adjusting for age, sex, education level, body mass index, and comorbidities. CONCLUSIONS AND RELEVANCE: In this cohort study, COVID-19 survival was associated with an increase in risk of longitudinal cognitive decline, highlighting the importance of immediate measures to deal with this challenge.

The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic targets of AD. This study included 2 arms of in vivo investigations: 1) 6-month-old female APPswe/PS1 mice were intravenously treated with AAV-PHP.eB-shRNA (α1-ARs)-GFP or AAV-PHP.eB-GFP for 3 months. 2) 3-month-old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or an equal volume of saline for 6 months. SH-SY5Y cell lines bearing human amyloid precursor protein were treated with terazosin or saline for investigating possible mechanisms. α1-ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total Aβ plaques, than control mice. α1-ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction et al., and rescued behavioral deficits in APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3β, thus reducing Aβ production. This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.

Background The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer’s disease (AD) has rarely been investigated. Clarifying pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic target of AD. Methods This study included 2 arms of in vivo investigations: 1) 6-month-old female APPswe/PS1 mice were intravenously treated with AAV-PHP.eB-shRNA (ARs)-GFP or AAV-PHP.eB-GFP for 3 months. 2) 3-month-old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or equal saline for 6 months. SH-SY5Y cell lines bearing human Amyloid precurssor protein were treated with terazosin or saline for investigating possible mechanisms. Results α1-ARs knockdown mice exhibited improved behavioral performances than control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total plaques, than control mice. The α1-ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including Tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction, and rescued behavioral deficits of APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3β, thus reduced Aβ production. Conclusions This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.

Background Understanding the long-term effects of coronavirus disease 2019 (COVID-19) on cognitive function is essential for monitoring the cognitive decline in the elderly population. This study aims to assess the current cognitive status and the longitudinal cognitive decline in elderly patients recovered from COVID-19. Methods This cross-sectional study recruited 1539 COVID-19 inpatients aged over 60 years who were discharged from three COVID-19-designated hospitals in Wuhan, China, from February 10 to April 10, 2020. In total, 466 uninfected spouses of COVID-19 patients were selected as controls. The current cognitive status was assessed using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) and the longitudinal cognitive decline was assessed using an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Cognitive assessments were performed 6 months after patient discharge. Results Compared with controls, COVID-19 patients had lower TICS-40 scores and higher IQCODE scores [TICS-40 median (IQR): 29 (25 to 32) vs. 30 (26 to 33), p p p p p p p p p p Conclusions Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with an increased risk of long-term cognitive decline in elderly population. COVID-19 patients, especially severe patients, should be intensively monitored for post-infection cognitive decline.

Background Alzheimer’s disease (AD) is the most popular neurodegenerative disease affecting cognitive functions of the elderly population. Neuronal apoptosis is an important pathological process during the development of AD. The Bcl-2-interacting mediator of cell death (Bim) mediates Amyloid-beta (Aβ)-induced neuronal apoptosis. Naturally occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. Methods This study investigated the clinical relevance of plasma NAbs-Bim to AD in 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects. Furthermore, the pathophysiological functions of NAbs-Bim were explored in APP/PS1 mice and SY5Y cell lines overexpressing human amyloid precursor protein (APP). Results We found that plasma levels of NAbs-Bim were lower in AD patients in comparison with patients with non-AD dementia and cognitively normal controls. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burdens and positively associated with cognitive functions. NAbs-Bim purified from intravenous immunoglobulin rescued behavioral deficits of APP/PS1 mice. NAbs-Bim ameliorated Aβ deposition, Tau hyperphosphorylation, microgliosis and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim exerted neuroprotective effects against AD through neutralizing Bim-directed neuronal apoptosis and amyloidogenic processing of amyloid precursor protein. Conclusions The decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim may hold promise for the treatment of AD.

To analyze the medication regularity of traditional Chinese medicine(TCM) prescriptions for gastropyretic excessiveness diabetes recorded in Chinese Medicine Prescriptions Dictionary. A total of 103 eligible prescriptions were input into the system platform, and the Apriori algorithm was used to analyze their medication regularity. The 103 prescriptions for gastropyretic excessiveness diabetes were selected from the system, and 29 herb medicines were found with frequency of usage more than 8. Totally 33 commonly used herbal pairs(support degree≥10), twenty-three 3-herb core combinations(support degree≥8, confidence values≥0.5), and twenty-one 4-herb core combinations(confidence values≥0.5) were discovered after the medication regularity analysis by Apriori algorithm. The herbal medicine combinations with the highest correlation degree were discovered after the association rule analysis on the 103 prescriptions(support degree≥10, confidence values≥0.5). The four properties, five tastes, channel distributions and frequency of dose of the 103 prescriptions were also obtained after the corresponding analysis. According to the analysis and summary of the above data, the combination of Trichosanthis Radix, Anemarrhenae Rhizoma, Coptidis Rhizoma and Ophiopogonis Radix could reflect the medication regularity of TCM prescriptions for gastropyretic excessiveness diabetes to a certain degree, which is of great significance in guiding value in clinic.

Hyperphosphorylated tau is an important pathological agent in Alzheimer’s disease (AD). Tau effluxes from the brain to the blood could potentially stimulate the production of naturally occurring antibodies (NAbs). We aimed to investigate whether NAbs to tau (NAbs-tau) was generated in human blood and to figure out the alteration of plasma NAbs-tau level in AD patients. About 192 AD patients and 192 age-matched and non-demented controls (NC) were enrolled in the present study. Immunofluorescence staining and western blot assays were used to confirm the existence of NAbs-tau in human blood. The plasma level of NAbs-tau in NC and AD group was analyzed by ELISA. Immunofluorescence staining and western blot assays confirmed the existence of NAbs-tau in human blood. However, no significant difference in the plasma level of NAbs-tau was observed between NC and AD group. Furthermore, the plasma level of NAbs-tau had no significant correlation with MMSE scores. The present study confirmed that NAbs-tau exists in human blood but does not differ in level between the NC and AD group. Plasma NAbs-tau is not a reliable biomarker for AD. Refereed/Peer-reviewed

Background: Understanding the long-term effects of coronavirus disease 2019 (COVID-19) on cognitive function is essential for the prevention of cognitive decline in elderly population. This study aims to assess cognitive status and longitudinal decline at 6 months post-infection in elderly patients recovered from COVID-19. Methods: This cross-sectional study recruited 1013 COVID-19 inpatients aged over 60 years who were discharged from three COVID-19-designated hospitals in Wuhan, China, from February 10 to March 13, 2020. In total, 262 uninfected living spouses of COVID-19 patients were selected as controls. Subjects were examined for their current cognitive status using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) and longitudinal cognitive decline using an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Cognitive assessments were performed 6 months after patient discharge. Findings: COVID-19 patients had significantly lower TICS-40 scores (patients: 29.73±6.13; controls: 30.74±5.95, p=0.016) and higher IQCODE scores (patients: 3.40±0.81; controls: 3.15±0.39, p

The p75 neurotrophin receptor (p75NTR) is an amyloid-beta (A beta) receptor that both mediates A beta neurotoxicity and regulates A beta production and deposition, thus playing an important role in the pathogenesis of Alzheimer's disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-A beta scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of A beta and pro-neurotrophins. Identification of the specific A beta binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct synthesis. A beta aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of A beta to p75ECD. The A beta neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the A beta aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that A beta could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized A beta neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are A beta binding domains of p75NTR and capable of antagonizing A beta neurotoxicity, and therefore are potential therapeutic targets to block the interaction of A beta and p75NTR in the pathogenesis of AD. Refereed/Peer-reviewed

Study Objective To describe the new“chopsticks technique”single-site laparoscopic surgery technique, and compare the Perioperative outcomes of “chopsticks technique” single-site laparoscopy versus traditional laparoscopy for endometrial cancer. Design A retrospective case-control study based on propensity score matching. Setting Department of gynecology at a tertiary medical center. Patients or Participants From August 2018 to August 2020, a total of 78 patients who accepted the laparoscopic staging of endometrial cancer were retrospectively analyzed. 26 cases conducted “chopsticks technique”single-site laparoscopic surgery(LESS) were matched with a cohort of 52 cases who underwent traditional multi-site laparoscopic surgery (CLS). Interventions A propensity score matching was performed to reduce the bias due to the imbalanced baseline features between the two groups and the perioperative outcomes were compared between matched cohorts. Measurements and Main Results A retrospective case–control study was conducted matched by age, BMI, history of surgery, FIGO staging. After matching, the variables were well balanced with no differences at baseline between groups. The operations in both groups were successfully completed without conversion to laparotomy. There were no statistically significant differences in the amount of intraoperative blood loss, pelvic lymph nodes, number of para-aortic lymph nodes removed, postoperative exhaust time, postoperative indwelling drainage time, postoperative hospital stay between the two groups (P>0.05). Meanwhile, Compared with the traditional multi-port laparoscopic group CLS, the “chopsticks technique” single-site laparoscopic group (LESS) has longer operation time (197.3±55.7 vs. 164.7±62.7, p=0.043) , a pain score of 24-hour after surgery (3 (3,2) vs3 (4,2) , p=0.031) and a more satisfactory postoperative cosmetic effect (6.9±0.5 vs. 6.12±0.7, p=0.023) , of which the difference was statistically significant (P Conclusion It is safe and feasible for staging endometrial cancer to employ the“chopsticks technique”single-site laparoscopic with minimum scars from abdominal incisions, which results in less pain and outstanding cosmetic effects. However, further prospective, randomized studies with larger samples are needed.

The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery. Refereed/Peer-reviewed

Previous studies have suggested that cardiovascular functions might play a critical role in Alzheimer's disease (AD) pathogenesis. However, the relationship among heart function, blood flow of cerebral vessels, and AD remains unclear. In the present study, AD patients (n = 34) and age- and gender-matched cognitively normal controls (n = 34) were recruited. Demographic and comorbidity information was collected. The ejection fraction was measured using echocardiography, and the mean velocity, pulsatility index (PI), and resistance index (RI) of the basilar artery (BA), left terminal internal carotid artery (LTICA), and right terminal internal carotid artery (RTICA) were measured using transcranial Doppler. The data of lacunae, white matter changes, and plaques in the aortic arch and carotid arteries were collected from brain magnetic resonance imaging and computed tomography angiography images. Compared with normal controls, AD patients had lower ejection fractions and cerebral blood flow velocities and higher RI and PI in the BA, LTICA, and RTICA, as well as more plaques in the aortic and carotid arteries. In the multivariate logistic regression analysis, the ejection fraction and the mean velocity of the BA and LTICA were independently associated with AD after adjusting for age, gender, education, vascular risk factors, arterial plaques, and brain ischemic lesions detected in the brain images. These findings suggest that heart function and vascular condition may play important roles in AD pathogenesis. Improving cardiovascular functions could be a promising approach for the prevention and treatment of AD.

Study Objective This study evaluated the feasibility, safety and short-term clinical outcomes from extraperitoneal sacral hysteropexy by transvaginal natural orifice transluminal endoscopic surgery in treating uterine prolapse. Design Retrospective study. Setting The First Affiliated Hospital of Third Military Medical University, Chongqing, China Patients or Participants The medical records of patients with POP-Q stage 2 or greater uterine prolapse who were treated with vNOTES-ESH between December 2016 to June 2018(to ensure 1-year follow-up or more) in the Southwest Hospital at the Third Military Medical University were reviewed retrospectively. Interventions Extraperitoneal sacral hysteropexy were performed by vNOTES. Measurements and Main Results 21 patients underwent surgery; 20 were successfully completed, and one that could not maintain pressure at the extraperitoneal cavity site due to peritoneal rupture during surgery who underwent multi-port laparoscopic surgery. Median patient age was 50 years. The body mass index (BMI) was 23.7 kg/m2, the median operative time was 126 min, and the median intraoperative blood loss was 60 mL. One case had presacral hemorrhage that was circumvented by bipolar electrocoagulation. Preoperative POP-Q scores were: Aa-0, Ba-1, C-2, Ap-3, and Bp-3. The average post-operative follow-up was 12 months. The POP-Q scores were: Aa-2, Ba-2, C-7, Ap-3, and Bp-3. Associated symptoms disappeared or improved significantly without sexual discomfort or pain on intercourse, mesh erosion, exposure, infection or other complications. The objective cure rate was 100 percent. Conclusion vNOTES was a feasible approach in completing extraperitoneal sacral hysteropexy for apical support, with promising short-term efficacy and safety. However, further studies across multiple sites are needed in evaluating long-term efficacy and safety profile of vNOTES extraperitoneal sacrocolpopexy.

Study Objective This study aimed to describe the new “chopstick technique” in laparoendoscopic single-site radical hysterectomy (LESS-RH) and explore its feasibility, safety and perioperative outcomes in the treatment of early stage cervical cancer. Design Retrospective study. Setting The First Affiliated Hospital of Third Military Medical University, Chongqing, China. Patients or Participants Women with federation international of gynecology and obstetrics (FIGO) stage Ia1 with lymph vascular space invasion or stage Ia2-IIa2 cervical cancer. Interventions “Chopstick technique” was performed in LESS-RH and pelvic lymph node dissection. The demographic characteristics and perioperative efficacy of the patients were summarized and analyzed. Measurements and Main Results LESS-RH was attempted in 84 patients, and 83 (98%) patients underwent the procedure successfully. One patient underwent conversion to traditional laproscopic surgery secondary to phase IV endometriosis. “Chopstick technique” was used in all the 83 cases, wherein 40 cases used the single-incision three-channel laparoscopy platform, and 43 used the multichannel-tipped single port laparoscopy platform (HangT Port). The average operation time was 225.0±50.2min and the median intraoperative blood loss was 100mL. During the operations in the first 20 cases, 2 patients had intraoperative vascular injuries and 1 patient had bladder injury, and all were repaired under LESS. One case had ureterovaginal fistula 14 days after operation, and was successfully repaired by ureteroneocystostomy. The average number of pelvic lymph node dissections was 21, and the pathological examination of incisal edge was negative. Deep stromal invasion in 43 cases, LVSI in 16 cases,positive parametrium in 1 case, positive pelvic nodes in 15 cases. 33 patients were treated with postoperative chemotherapy and radiotherapy and 19 patients with intermediate risk factors were treated with radiotherapy postoperatively. Conclusion “Chopstick technique” under LESS was considered feasible for treating cervical cancer.

Parkinson’s disease (PD) is attributed to interactions among genes and environmental and lifestyle factors, but the genetic architecture of PD is complex and not completely understood. To evaluate whether the genetic profile modifies PD development and cerebrospinal fluid (CSF) pathological biomarkers, we enrolled 418 PD patients and 426 age- and sex-matched normal controls. Forty-six single nucleotide polymorphisms (SNPs) that were reported to be significantly associated with PD in large-scale genome-wide association studies (GWASs) were genotyped and analysed. The alleles associated with PD were used to build polygenic risk score (PRS) models to represent polygenic risk. The Cox proportional hazards model and receiver operating characteristic (ROC) analyses were used to evaluate the prediction value of the PRS for PD risk and age at onset. The CSF α-synuclein levels were measured in a subgroup of control subjects (n = 262), and its relationship with the PRS was analysed. We found that some SNPs identified from other populations had significant correlations with PD in our Chinese cohort. The PRS we built had prediction value for PD risk and age at onset. The CSF α-synuclein level had no correlation with the PRS in normal subjects.

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Clearance of Aβ is a promising therapeutic strategy for AD. We have previously demonstrated that peripheral organs play important roles in the clearance of brain-derived Aβ. In the present study, we recruited 46 patients with liver cirrhosis and 46 normal controls and found that plasma Aβ40 and Aβ42 levels were significantly higher in the cirrhosis patients than in the normal controls. Notably, cirrhosis patients with hepatitis B virus (HBV) infection had higher plasma Aβ40 and Aβ42 levels than HBV-negative cirrhosis patients. Besides, cirrhosis patients had significantly higher plasma levels of interleukin-1β (IL-1β) and IL-6. Plasma tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ) levels were not significantly different between the groups. Moreover, we found significant correlations of hepatic functions with plasma Aβ40 and Aβ42 levels. Plasma IL-6 levels were also significantly correlated with plasma Aβ40 levels. However, in the linear regression model, we found significant correlation of plasma Aβ40 levels with hepatic functions, but not with plasma IL-6 levels. Our results indicate that the hepatic dysfunctions might result in decreased peripheral Aβ clearance by the liver. Protecting hepatic functions might be helpful for the clearance of brain-derived Aβ in the blood.

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by parenchymal and vascular beta-amyloid (Aβ) burden, tau pathology, neuroinflammation, and loss of neurons and synapses. There is a clear sex difference in the prevalence of AD. However, sex differences in AD-type pathologies have not been systematically documented. Applying 12-month-old female and male APP/PS1 mice as a model, we investigated the sex dimorphism in these major pathological indices. Compared with male APP/PS1 mice, the females exhibited higher parenchymal Aβ burdens, with the sex difference in hippocampus being the most significant. Female APP/PS1 mice had more severe cerebral amyloid angiopathy and subsequent microhemorrhage. In addition, female APP/PS1 mice also showed higher levels of phosphorylated tau and proinflammatory cytokines, more severe astrocytosis and microgliosis, and greater neuronal and synaptic degenerations. The present study systematically described a sex dimorphism in AD-type pathologic indices, suggesting that gender should be taken into account in designing studies involving these pathological indices and when interpreting the relevant findings in those studies.

Study Objective To investigate the feasibility and safety of transvaginal natural orifice transluminal endoscopic surgery (vNOTES) for endometrial carcinoma (EC). Design Retrospective study. Setting The First Affiliated Hospital of Third Military Medical University, Chongqing, China Patients or Participants Women with federation international of gynecology and obstetrics (FIGO) stage IA endometrial cancer. Interventions vNOTES surgery consist of hysterectomy, bilateral salpingo- oophorectomy and bilateral pelvic and para-aortic lymph node dissection were performed by by a gynecologic oncologist. Clinicopathologic, surgical, and perioperative outcomes were analyzed. Measurements and Main Results All the 12 patients were successfully operated. Vaginal hysterectomy was performed in five patients, and vNOTES hysterectomy was performed in seven patients. All the 12 cases underwent bilateral salpingo-oophorectomy under vNOTES. Pelvic lymph node dissection was performed in six patients, sentinel lymph node biopsy was performed in four patients, and pelvic lymph node dissection plus para-aortic lymphadenectomy was performed in two patients. The median operative time was 172 minutes (94-235 minutes), the median blood loss was 117 (50-200) ml, and the median postoperative hospital stay was 5 (4-9) days. The median time for postoperative recovery of gastrointestinal function was 21 hours (12-40 hours), the median pain score at postoperative 12 hours was 2 (1-4) and 1 (1-2) at postoperative 24 hours. The median follow-up time was 5 months. The vaginal stump incision healed well in all the patients. Conclusion vNOTES is a safe and effective method for comprehensive surgical staging of EC. Larger studies are needed to confirm whether the increased technical difficulty of this procedure justifies its use in routine gynecologic oncology practice.

Introduction The etiology of Parkinson's disease (PD) remains unclear. The aim of this study was to examine the association between common pathogenic infections and PD. Methods Antibody titers to common infectious pathogens including cytomegalovirus (CMV), Epstein Barr virus (EBV)，herpes simplex virus type-1 (HSV-1), Borrelia burgdorferi (B. burgdorferi), Chlamydophila pneumoniae (C. pneumoniae) and Helicobacter pylori (H. pylori) were measured by ELISA in serum of 131 PD patients and 141 normal controls. Infectious burden (IB) was defined as a composite serologic measure of exposure to these common pathogens. Results Seropositivities toward zero-two, three-four and five-six of these pathogens were found in 11%, 74% and 15% of normal controls while in 4%, 61% and 35% of PD patients, respectively. IB, bacterial burden and viral burden were independently associated with PD. Schwab and England (S&E) scores were negatively correlated with IB in patients with PD. Serum α-synuclein protein levels and inflammatory cytokines (interleukin-1β and interleukin-6) in individuals with higher IB were also significantly higher. Conclusions IB consisting of CMV, EBV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with PD. This study supports the role of infection in the etiology of PD.

Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis. Refereed/Peer-reviewed

Amyloid precursor protein (APP) is cleaved by β-secretase and γ-secretase complex, and subsequently generates amyloid-β peptide (Aβ). The Aβ cascade is widely accepted as playing a role in the pathogenesis Alzheimer's disease (AD). Meanwhile, procession of APP by α-secretase (mainly a disintegrin and metalloproteinase 10, ADAM10) precludes Aβ production, and produces soluble APP-α which is considered to be neuroprotective against AD. To explore the relationship between APP, ADAM10 gene polymorphism and sporadic AD (sAD), we conducted a case-control study in a Chinese Han cohort including 200 sAD patients and 243 control participants. Four target single nucleotide polymorphisms (SNPs) in or near the promoter of the APP gene and two in the promoter of the ADAM10 gene were selected and genotyped with a polymerase chain reaction-ligase detection reaction method. After adjustments for age, sex, and APOE ε4 status, only one target SNP, rs463946 was associated with the risk of sAD in the dominant (OR 1.52, 95 % CI 1.01-2.29, P = 0.045) and overdominant models (OR 1.59, 95 % CI 1.04-2.43, P = 0.031); the results also showed a borderline association of rs364048 (OR 1.53, 95 % CI 1.00-2.34, P = 0.048) and rs466433 (OR 1.53, 95 % CI 1.00-2.34, P = 0.048) with the risk of sAD in the overdominant model. However, these associations did not remain after multiple comparison correction. As for the ADAM10 gene, the two target SNPs (rs514049 and rs653765) were not associated with the risk of sAD either. No significant association was found between different haplotypes of the two genes and the risk of sAD. Conclusively, we did not find the association between APP, ADAM10 gene polymorphism, and the risk of sAD in our cohort of Chinese Han people.

Network science is an emerging interdiscipline that can solve practical issues by researching and analyzing properties of complex networks. In this paper, a modified algorithm based on PageRank is developed to construct the evaluation model in directed-weighted networks. This model can effectively determine the node importance in networks. Discussions about how to construct networks with the use of relationship between data and how to determine the weight of edges form the major concern of the present studies. Schemes for solving the above issues can differ in different networks. We successfully apply this model to citation, co-author and weibo follower networks. Through the results, we find that this optimized model can efficiently evaluate the importance of nodes in different complex networks and has strong applicability.

Several psychiatric disorders are associated with aberrant white matter development, suggesting oligodendrocyte and myelin dysfunction in these diseases. There are indications that radial glial cells (RGCs) are involved in initiating myelination, and may contribute to the production of oligodendrocyte progenitor cells (OPCs) in the dorsal cortex. Liver X receptors (LXRs) are involved in maintaining normal myelin in the central nervous system (CNS), however, their function in oligodendrogenesis and myelination is not well understood. Here, we demonstrate that loss of LXRβ function leads to abnormality in locomotor activity and exploratory behavior, signs of anxiety and hypomyelination in the corpus callosum and optic nerve, providing in vivo evidence that LXRβ deletion delays both oligodendrocyte differentiation and maturation. Remarkably, along the germinal ventricular zone-subventricular zone and corpus callosum there is reduced OPC production from RGCs in LXRβ(-/-) mice. Conversely, in cultured RGC an LXR agonist led to increased differentiation into OPCs. Collectively, these results suggest that LXRβ, by driving RGCs to become OPCs in the dorsal cortex, is critical for white matter development and CNS myelination, and point to the involvement of LXRβ in psychiatric disorders.

Objective To investigate the serum levels of inflammatory cytokines IL-6, IL-1β, TNF-α and IFN-γ, and explore the correlation between the inflammatory factor levels and the cognitive function in patients with Alzheimer's disease (AD). Methods One hundred and ten AD patients and 120 cognitively normal subjects were recruited in the present study. Serum levels of IL-6, IL-1β, TNF-α and IFN-γ were determined with enzyme-linked immunosorbent assay (ELISA). Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDR) were used to assess the cognitive function and activities of day living of the subjects. Wilcoxon rank sum test was used to compare the inflammatory cytokine levels between AD patients and healthy controls. Non-conditional logistic regression model was used to screen the potential influence factors of AD. Partial correlation analysis was performed to study the correlation between inflammatory cytokine levels of all subjects and MMSE scores in the whole sample, and the correlation between the serum levels of inflammatory cytokines and CDR scores was examined in the AD cohort. Results The serum levels of IL-1β (129.46 vs 102.70, P=0.002) and IL-6 (125.25 vs 106.56, P=0.033) were significantly higher in AD patients than that of normal control, while the values of TNF-α (116.40 vs 114.67, P=0.844) and IFN-γ (115.90 vs 115.14, P=0.931) were not significantly different between the two groups. The serum levels of IL-1β was correlated with MMSE score (r=–0.184, P=0.007) in the whole sample. No significant correlation was observed between serum inflammatory factors and CDR scores in AD patients. IL-1β was identified as a risk factor (OR=1.018, 95%CI 1.005-1.030), and duration of receiving education as a protective factor (OR=0.891, 95%CI 0.834-0.953) for AD. Conclusion The serum levels of inflammatory factors may be correlated with the cognitive function but not with the severity of dementia in AD patients. DOI: 10.11855/j.issn.0577-7402.2014.02.11

Neural stem/progenitor cells (NSCs) proliferate and differentiate under tight regulation by various factors in the stem cell niche. Recent studies have shown that the precursor of nerve growth factor (NGF), proNGF, abounds in the central nervous system (CNS) and that its expression level in the brain is substantially elevated with aging as well as in several types of CNS disorders. In this study, we found for the first time that proNGF inhibited the proliferation of NSCs isolated from postnatal mouse hippocampus and caused cell cycle arrest in the G0/G1 phase without affecting apoptosis. In addition, proNGF reduced the differentiation of NSCs to oligodendrocytes. The effects of proNGF were blocked by the fusion protein of p75 neurotrophin receptor extracellular domain and human IgG Fc fragment (p75NTR/Fc), and by p75NTR knockout, suggesting that proNGF/p75NTR interaction was involved in the effects of proNGF on NSC proliferation and differentiation. proNGF decreased the phosphorylation level of extracellular signal responsive kinase 1/2 (ERK 1/2) in a p75NTR-dependent manner under both self-renewal and differentiation conditions. The inhibition of ERK 1/2 phosphorylation by U0126 significantly reduced the proliferation and oligodendrogenesis of NSCs, indicating that ERK 1/2 inhibition by proNGF partially explains its effects on NSC proliferation and oligodendrogenesis. These results suggest that the proNGF/p75NTR signal plays a key role in the regulation of NSCs' behavior. Refereed/Peer-reviewed

Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co-receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimer's disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6-month-old swedish-amyloid precursor protein/PS1dE9 transgenic mice. Aβ42 enhanced the protein and mRNA expression levels of sortilin in a dose- and time-dependent manner in SH-SY5Y cells, but had no effect on sorLA. In addition, proBDNF also significantly increased the protein and mRNA expression of sortilin in these cells. The recombinant extracellular domain of p75NTR (P75ECD-FC), or the antibody against the extracellular domain of p75NTR, blocked the up-regulation of sortilin induced by Amyloid-β protein (Aβ), suggesting that Aβ42 increased the expression level of sortilin and mRNA in SH-SY5Y via the p75NTR receptor. Inhibition of ROCK, but not Jun N-terminal kinase, suppressed constitutive and Aβ42-induced expression of sortilin. In conclusion, this study shows that sortilin expression is increased in the AD brain in human and mice and that Aβ42 oligomer increases sortilin gene and protein expression through p75NTR and RhoA signaling pathways, suggesting a potential physiological interaction of Aβ42 and sortilin in Alzheimer's disease. Sortilin is the co-receptor of p75NTR which signals the cell death induced by Aβ and proneurotrophins. We found that sortilin is increased in the AD brain and up-regulated by Aβ and pro-brain-derived neurotrophic factor (proBDNF). Aβ-induced upregulation of sortilin is mediated by p75NTR and the down-streaming RhoA-ROCK signaling pathway. The Aβ/Sortilinp/75NTR signaling may play a role in the pathogenesis of AD. Refereed/Peer-reviewed

Transient receptor potential canonical 6 (TRPC6) inhibits β-amyloid (Aβ) production. Hyperforin, the TRPC6 agonist, reduces Aβ levels and improves cognitive performance in Alzheimer's disease (AD) models. However, it's unknown whether TRPC6 expression is changed in AD patients. In this case-control study, we measured TRPC6 expression levels in the peripheral blood cells of four independent AD sets from five hospitals and one mild cognitive impairment (MCI) set from a local community (229 AD, 70 MCI, 40 Parkinson disease and 359 controls from China, total n=698) using quantitative real-time PCR assay. We found a specific reduction of TRPC6 mRNA levels in four AD sets and one MCI set. The median TRPC6 mRNA levels were lower in the following: (1) combined AD patients than in age-matched controls (0.78 vs 1.73, P

The neurotrophin receptor p75 (p75NTR) is a receptor for amyloid-beta (Aβ) and mediates Aβ-induced neurodegenerative signals. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against Aβ in Alzheimer's disease (AD). We have previously demonstrated that the shedding of p75ECD from the cell surface is down-regulated in AD brains and restoration of the p75ECD level in the brain, through intracranial administration of p75ECD by adeno-associated virus vectors, attenuates AD-like pathologies in an AD mouse model. In this study, we further investigated the feasibility and efficacy of peripheral administration of AAV-p75ECD on brain amyloid burden and associated pathogenesis. We found that intramuscular delivery of AAV-p75ECD increased the level of p75ECD in the blood, significantly improved the behavioral phenotype of amyloid precursor protein/PS1 transgenic mice, and reduced brain amyloid burden, attenuated Tau hyperphosphorylation, and neuroinflammation. Furthermore, intramuscular delivery of AAV-p75ECD was well tolerated. Our results indicate that peripheral delivery of p75ECD represents a safe and effective therapeutic strategy for AD. (Figure presented.) The ectodomain of p75NTR (p75ECD) is a physiological protective factor against amyloid-beta (Aβ) in Alzheimer's disease (AD). Intramuscular delivery of AAV-p75ECD increased the p75ECD levels in the blood, reduced brain amyloid burden through a ‘peripheral sink’ mechanism and alleviates AD-type pathologies. Peripheral delivery of p75ECD represents a promising therapeutic strategy for AD. Refereed/Peer-reviewed

We investigated the regulation of primary neurite growth and expression of specific growth-associated genes by lens epithelium-derived growth factor (LEDGF) in rat retinal ganglion cells (RGCs). A pAd-LEDGFp52 adenovirus vector and a siRNA-LEDGFp52 eucaryotic expression vector were transfected into cultured RGCs. Transfection with pAd-LEDGFp52 significantly increased the number of neurites and their lengths compared with untransfected control RGCs. The expression of growth associated protein 43 (GAP43), microtubule-associated protein 2 (MAP2), and low-molecular-weight neurofilament (NF-L) genes and proteins were also significantly up-regulated. In contrast, the introduction of siRNA-LEDGFp52 significantly decreased the number and length of neurites, and significantly down-regulated the expression GAP43, NF-L and MAP2 genes and proteins compared with controls. Our findings suggest that LEDGFp52 might act as a dendritic arborization gene as well as an axonal elongation gene in RGCs and that it might be beneficial to the functional recovery of regenerating RGCs.

Chronic obstructive pulmonary disease (COPD) is associated with cognitive decline, but the molecular link between COPD and dementia or Alzheimer's disease (AD) remains unclear. This study was aimed to investigate whether serum Aβ levels are correlated with COPD. 77 cognitively normal COPD patients and 45 age- and gender-matched normal controls were admitted to the study. Serum Aβ40 and Aβ42 levels were measured using ELISA kits. Serum C-reactive protein (CRP), interleukin 6 (IL-6), and procalcitonin (PCT) measurements were done using standard laboratory methods. Pulmonary function tests were performed to assess the pulmonary function and determine the degree of lung damage. Significantly increased levels of serum Aβ40, Aβ42, and total Aβ levels were found in patients with COPD in comparison with normal controls. In COPD patients, serum Aβ levels were higher in subjects with serum CRP, IL-6, and PCT upper the limit of normal. Moreover, serum Aβ levels were dramatically higher in COPD patients with worse pulmonary function. Our study suggests that cognitively normal COPD patients may undergo AD-related pathological changes, and COPD might facilitate AD-type pathogenesis.

Mounting evidence suggests that ischemic stroke (IS) is associated with Alzheimer's disease (AD). IS and vascular risk factors increase the risk for AD. However, whether AD pathologies exist in IS and the effects of these pathologies on stroke remain unknown. In the present study, we aimed to investigate the alterations of serum Aβ after acute IS (AIS), and its correlations with the neurological deficits, infarction volume, and site after stroke. AIS patients (n = 35) were recruited within 24 h of symptom onset. Age- and gender-matched AD patients (n = 48) and cognitively normal controls (NC, n = 37) were also enrolled. Serum Aβ40 and Aβ42 and the National Institute of Health Stroke Scale Score (NIHSS) were measured on day 1, 3, and 7 after stroke onset. We found that serum Aβ40 and Aβ42 levels were increased at day 1 and reached peak levels at day 3, and decreased to pre-stroke levels at day 7. Serum Aβ40 levels at day 1 were correlated with the NIHSS scores and infarction volume of AIS patients. Serum Aβ42 levels at day 1 were significantly higher in IS patients with dominant gray matter infarction. Serum Aβ40 levels at day 1 were predictive for NIHSS at day 7. Our results indicate that AIS can induce the generation of Aβ in the brain, which may in turn be involved in the pathogenesis of neurological deficits after stroke. Serum Aβ might be predictive for the short-term neurological deficits after AIS.

Amyloid-beta (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD), and it is a major therapeutic target for AD. It is proposed that removal of Aβ in blood can facilitate Aβ clearance from the brain, representing a promising therapeutic approach for AD. However, the efficacy and mechanisms for Aβ clearance by peripheral organs and tissues remain largely unknown. In the present study, 47 chronic kidney disease (CKD) patients (16 newly diagnosed patients who had never been dialyzed and 31 patients who were receiving dialysis) and 43 normal controls (NC) were enrolled. We found that serum Aβ levels were significantly higher in CKD patients than NC. CKD patients who were receiving dialysis had lower serum Aβ levels than patients without receiving dialysis, being comparable to NC. Furthermore, serum Aβ levels were correlated with renal functions reflected by estimated glomerular filtration rate (eGFR) and residual GFR (rGFR). Our study suggests that kidney is involved in peripheral clearance of Aβ, and dialysis might be a potential therapeutic approach of Aβ removal.

This study has identified a gene mutation in a Chinese family with Alzheimer’s disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD.

Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer’s disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies. Refereed/Peer-reviewed

Increasing evidence shows that sortilin (encoded by SORT1 gene), a member of the vacuolar protein sorting 10 family of sorting receptors, can modulate amyloid-β peptides (Aβ) metabolism and clearance, as well as mediate the neurotoxicity of the Aβ oligomer and proneurotrophins, thus playing diverse roles in the pathogenesis of Alzheimer’s disease. To assess the association between single nucleotide polymorphism (SNP) of the SORT1 gene and sporadic Alzheimer’s disease (sAD) in the Chinese Han population, a case–control study was carried out including 220 sAD patients and 245 controls. One tag SNP was selected from the entire SORT1 gene through construction of linkage disequilibrium blocks, and three SNPs located in the vicinity of SORT1 that affect its expression were also selected. The four target SNPs were genotyped using a multiplex PCR-ligase detection reaction method, yielding no significant association between them or haplotypes containing three of them, and the risk of sAD. The results of this study indicate that polymorphisms of the SORT1 gene are unlikely to confer the risk of sAD in the Chinese Han population. Refereed/Peer-reviewed