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Purpose: Learning impairment after electroconvulsive therapy (ECT) is common. Ketamine, an anesthetic used for ECT, has been demonstrated to attenuate cognitive impairment after ECT. However, the mechanism by which ketamine occurs in this case is still unknown. We aimed to explore the role of ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] in the protection against learning impairment and investigate whether autophagy is involved in the protective effect. Materials and Methods: A rat depression model received electroconvulsive shock (ECS; simulated ECT in animal models) daily for 3 days. The Morris water maze was used to assess the spatial learning function of the rats. Western blotting was used to detect the expression of Beclin-1, light chain (LC)3-II/LC3-I, p62, mammalian target of rapamycin (mTOR), and p-mTOR in the hippocampus. Results: The escape latency for the maze in the ECS group was significantly longer than that in the sham ECS group (P=0.042). Meanwhile, the escape latency in the (2R,6R)-HNK+ECS group was significantly shorter than that in the ECS group (P=0.005). The LC3-II/LC3-I ratio and Beclin-1 expression level significantly increased, and the p62 expression level significantly decreased in the ECS group, compared with those in the sham ECS group (all P< 0.001). The (2R,6R)-HNK+ECS group showed lower LC3-II/LC3-I ratio (P< 0.001) and Beclin-1 expression level (P< 0.001) and higher p62 (P< 0.001) and p-mTOR expression levels (P=0.048) than did the ECS group. After small-molecule enhancer of rapamycin 28 (SMER28) administration, the role of (2R,6R)-HNK in protecting against learning impairment and inhibiting autophagy was abrogated, showing no difference in the escape latency; the difference in the LC3-II/LC3-I ratio and p62 expression level between the SMER28+(2R,6R)-HNK+ECS and ECS groups was not as significant as that between the (2R,6R)-HNK+ECS and ECS groups (P< 0.05– 0.01 vs P< 0.001). Conclusion: (2R,6R)-HNK yields cognitive protection by suppressing autophagy through the mTOR signaling pathway in the ECS-treated rat hippocampus. [ABSTRACT FROM AUTHOR]

Background: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer's disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear.Objective: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI.Methods: Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1-40 (Aβ40), Aβ42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment.Results: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores.Conclusion: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations. [ABSTRACT FROM AUTHOR]

Background: Our previous study in animal models revealed that bilirubin could induce Aβ formation and deposition. Bilirubin may be important in neurodegenerative dementia with Aβ deposition. Hence, lowering the concentration of the free bilirubin capable of crossing the blood brain–barrier may benefit the treatment of Alzheimer's disease (AD). Objectives: The objectives of this study were to examine the change in the serum bilirubin and albumin concentrations of dementia patients with Aβ deposition, and to determine the effects of intravenous administration of albumin in the treatment of AD. Methods: Bilirubin and albumin concentrations in dementia patients with Aβ deposition were examined. Cell viability and apoptosis were determined in dopaminergic neuron-like cells MN9D treated with bilirubin in the presence of diverse concentrations of serum. Human albumin at a dose of 10 g every 2 weeks for 24 weeks was administered intravenously to AD patients to examine the effect of albumin on AD symptoms. Results: Significantly higher indirect bilirubin (IBIL) concentrations, lower albumin concentrations, and higher ratio of IBIL to albumin (IBIL/ALB) were observed in dementia patients with Aβ deposition, including AD, dementia with Lewy bodies, and general paresis of insane. In vitro assays showed that bilirubin-induced injury in cultured dopaminergic neuron-like cells negatively depends on the concentration of serum in the culture medium. General linear model with repeated measures analysis indicated a main effect of group on the change in albumin concentrations and Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) scores, and the main effect of time and group, and group-by-time interaction on the change of Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) scores. Analysis of the combined data of the entire 28 weeks of assessment period using the area under curve convincingly showed significantly improvements in the change of albumin concentrations, ADCS-ADL scores, and CDR-SB scores. Conclusion: IBIL and the IBIL/ALB ratio are significantly higher in dementia patients with Aβ deposition, and intravenous administration of albumin is beneficial to AD treatment. Trial Registration: The intervention study was registered at http://www.chictr.org.cn (ChiCTR-IOR-17011539). Date of registration: June 1, 2017. [ABSTRACT FROM AUTHOR]

Recently, extracellular matrix-based tissue-engineered bone is a promising approach to repairing bone defects, and the seed cells are mostly mesenchymal stem cells. However, bone remodelling is a complex biological process, in which osteoclasts perform bone resorption and osteoblasts dominate bone formation. The interaction and coupling of these two kinds of cells is the key to bone repair. Therefore, the extracellular matrix secreted by the mesenchymal stem cells alone cannot mimic a complex bone regeneration microenvironment, and the addition of extracellular matrix by preosteoclasts may contribute as an effective strategy for bone regeneration. Here, we established the mesenchymal stem cell/preosteoclast extracellular matrix -based tissue-engineered bones and demonstrated that engineered-scaffolds based on mesenchymal stem cell/ preosteoclast extracellular matrix significantly enhanced osteogenesis in a 3 mm rat femur defect model compared with mesenchymal stem cell alone. The bioactive proteins released from the mesenchymal stem cell/ preosteoclast extracellular matrix based tissue-engineered bones also promoted the migration, adhesion, and osteogenic differentiation of mesenchymal stem cells in vitro. As for the mechanisms, the iTRAQ-labeled mass spectrometry was performed, and 608 differentially expressed proteins were found, including the IGFBP5 and CXCL12. Through in vitro studies, we proved that CXCL12 and IGFBP5 proteins, mainly released from the preosteoclasts, contributed to mesenchymal stem cells migration and osteogenic differentiation, respectively. Overall, our research, for the first time, introduce pre-osteoclast into the tissue engineering of bone and optimize the strategy of constructing extracellular matrix–based tissue-engineered bone using different cells to simulate the natural bone regeneration environment, which provides new sight for bone tissue engineering. [ABSTRACT FROM AUTHOR]

Objectives: Cognitive impairment in late-life depression is common and associated with a higher risk of all-cause dementia. Late-life depression patients with comorbid cardiovascular diseases (CVDs) or related risk factors may experience higher risks of cognitive deterioration in the short term. We aim to investigate the effect of CVDs and their related risk factors on the cognitive function of patients with late-life depression.Methods: A total of 148 participants were recruited (67 individuals with late-life depression and 81 normal controls). The presence of hypertension, coronary heart disease, diabetes mellitus, or hyperlipidemia was defined as the presence of comorbid CVDs or related risk factors. Global cognitive functions were assessed at baseline and after a one-year follow-up by the Mini-Mental State Examination (MMSE). Global cognitive deterioration was defined by the reliable change index (RCI) of the MMSE.Results: Late-life depression patients with CVDs or related risk factors were associated with 6.8 times higher risk of global cognitive deterioration than those without any of these comorbidities at a one-year follow-up. This result remained robust after adjusting for age, gender, and changes in the Hamilton Depression Rating Scale (HAMD) scores.Conclusions: This study suggests that late-life depression patients with comorbid CVDs or their related risk factors showed a higher risk of cognitive deterioration in the short-term (one-year follow up). Given that CVDs and their related risk factors are currently modifiable, active treatment of these comorbidities may delay rapid cognitive deterioration in patients with late-life depression. [ABSTRACT FROM AUTHOR]

Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p < 0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p < 0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression. [ABSTRACT FROM AUTHOR]

Background: Late-life depression patients are at a high risk of developing Alzheimer's disease, and diminished olfactory identification is an indicator in early screening for Alzheimer's disease in the elderly. However, whether diminished olfactory identification is associated with risk of developing Alzheimer's disease in late-life depression patients remains unclear., Methods: One hundred and twenty-five late-life depression patients, 50 Alzheimer's disease patients, and 60 normal controls were continuously recruited. The participants underwent a clinical evaluation, olfactory test, neuropsychological assessment, and neuroimaging assessment., Results: The olfactory identification impairment in late-life depression patients was milder than that in Alzheimer's disease patients. Diminished olfactory identification was significantly correlated with worse cognitive performance (global function, memory language, executive function, and attention) and reduced grey matter volume (olfactory bulb and hippocampus) in the late-life depression patients. According to a multiple linear regression analysis, olfactory identification was significantly associated with the memory scores in late-life depression group (B=1.623, P<.001). The late-life depression with olfactory identification impairment group had worse cognitive performance (global, memory, language, and executive function) and more structural abnormalities in Alzheimer's disease-related regions than the late-life depression without olfactory identification impairment group, and global cognitive function and logical memory in the late-life depression without olfactory identification impairment group was intact. Reduced volume observed in many areas (hippocampus, precuneus, etc.) in the Alzheimer's disease group was also observed in late-life depression with olfactory identification impairment group but not in the late-life depression without olfactory identification impairment group., Conclusion: The patterns of cognitive impairment and structural abnormalities in late-life depression with olfactory identification impairment patients were similar to those in Alzheimer's disease; olfactory identification may help identify late-life depression patients who are at a high risk of developing Alzheimer's disease.