CSF sAPPα and sAPPß levels in Alzheimer's Disease and Multiple Other Neurodegenerative Diseases: A Network Meta-Analysis.

The soluble amyloid protein procurer α (sAPPα) and ß (sAPPß) have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and multiple other neurodegenerative diseases, but have failed to meet expectations with their often discordant and even contradictory findings to date. The aim of the study was to systematically explore this issue. Cochrane Library, PubMed, and CNKI were systematically searched without language or date restrictions. This network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and also adhered to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Twenty studies, comprising ten groups, were eligible and included. Overall, 19 eligible studies with 1634 patients contributed to the analysis of CSF sAPPα levels and 16 eligible studies with 1684 patients contributed to the analysis of CSF sAPPß levels. CSF sAPPß levels are significantly higher in AD than in corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP); higher in Control than in Depression, CBS and PSP; higher in Parkinson's disease dementia (PDD) than in CBS and PSP; higher in mild cognitive impairment progressed to AD dementia during the follow-up period (pMCI) than in Depression and PSP; higher in stable mild cognitive impairment (sMCI) than in Depression. With regard to CSF sAPPα levels, there were no significant difference among groups. However, surprisingly, the resultant rankings graphically showed that pMCI populations have the highest levels of CSF sAPPα and sAPPß. Furthermore, it seemed there was a positive correlation between CSF sAPPα and sAPPß levels. The measurement of CSF sAPPα and sAPPß levels may provide an alternative method for the diagnosis of early-stage AD, pMCI, which is conducive to preventive therapy.

The Synergistic Roles of the Chronic Prenatal and Offspring Stress Exposures in Impairing Offspring Learning and Memory.

In Alzheimer's disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AßPP, Aß42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aß42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene.

Use of CSF α-synuclein in the differential diagnosis between Alzheimer's disease and other neurodegenerative disorders.

BACKGROUND: The etiology and pathogenesis of neurodegenerative disorders has yet to be elucidated, so their differential diagnosis is a challenge. This is especially true in differentiating Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson disease (PD), and multiple system atrophy (MSA). METHODS: A total of 11 eligible articles were identified by search of electronic databases including PubMed, Springer Link, Elsevier, and the Cochrane Library, up to June 2014. In meta-analyses, standardized mean differences (SMD), with 95% confidence intervals (CI), comparing cerebrospinal fluid (CSF) measures of α-synuclein between the above conditions were calculated using random-effects models. RESULTS: CSF α-synuclein concentrations were significantly higher in AD compared to DLB [SMD: 0.32, 95% CI: (0.02, 0.62), z = 2.07, P = 0.038]; PD [SMD: 0.87, 95% CI: (0.15, 1.58), z = 2.38, P = 0.017]; or MSA [SMD: 1.14, 95% CI: (0.15, 2.14), z = 2.25, P = 0.025]. However, no significant difference was found between patients with AD and neurological cognitively normal controls [SMD: 0.02, 95% CI: (-0.21, 0.24), z = 0.13, P = 0.894]. CONCLUSIONS: Results of these meta-analysis suggest that quantification of CSF α-synuclein could help distinguish AD from other neurodegenerative disorders such as DLB, PD, or MSA.

Assessment of CSF Aß42 as an aid to discriminating Alzheimer's disease from other dementias and mild cognitive impairment: a meta-analysis of 50 studies.

Mild Alzheimer's disease (AD) is usually difficult to differentiate from other dementias or mild cognitive impairment (MCI). The aim of our study is to evaluate the clinical importance of cerebrospinal fluid (CSF) ß-amyloid 42 (Aß42) in MCI, AD and other dementias, more specifically: frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease (PD) with dementia (PDD) and vascular dementia (VaD). Fifty eligible articles were identified by search of databases including PubMed, EMBASE, Elsevier, Springer Link and the Cochrane Library, from January 1990 to May 2014. The random effects model was used to calculate the standardized mean difference (SMD) with corresponding 95% CI by STATA 9.0 software. The subgroup analyses were made on the method (ELISA, xMAP). We found that CSF Aß42 concentrations were significantly lower in AD compared to MCI (SMD: -0.68, 95% CI: [-0.80, -0.56], z=11.34, P<0.001), FTD (SMD: -1.09, 95% CI: [-1.41, -0.76], z=6.62, P<0.001), PDD (SMD: -0.75, 95% CI: [-1.39, -0.10], z=2.27, P=0.023), VaD (SMD: -0.95, 95% CI: [-1.30, -0.61], z=5.43, P<0.001). In addition, compared to DLB, Aß42 concentrations are moderately lower in AD (SMD: -0.27, 95% CI: [-0.51, -0.03], z=2.20, P=0.028). Results from this meta-analysis hinted that CSF Aß42 is a good biomarker for discriminating Alzheimer's disease from other dementias and MCI.

Does CSF p-tau181 help to discriminate Alzheimer's disease from other dementias and mild cognitive impairment? A meta-analysis of the literature.

To evaluate the clinical importance of cerebrospinal fluid (CSF) phosphorylated tau 181 (p-tau181) in mild cognitive impairment (MCI), Alzheimer's disease (AD) and other dementias, more specifically: frontotemporal degeneration (FTD), dementia with Lewy bodies (DLB), vascular dementia (VaD) and Parkinson's disease (PD) with dementia (PDD). Fifty eligible articles were identified by search of databases including PubMed, EMBASE, Elsevier, Springer Link and the Cochrane Library, up to December 2013. The random effects model was used to calculate the standardized mean difference (SMD) with corresponding 95% CI by STATA 9.0 software. The subgroup analyses were made on the methods or PD with dementia. We found that CSF p-tau181 concentrations were significantly higher in AD compared to MCI [SMD: 0.61, 95% CI: (0.46, 0.76), z = 8.07, P < 0.001], FTD [SMD: 1.23, 95% CI: (0.89, 1.56), z = 7.19, P < 0.001], DLB [SMD: 1.08, 95% CI: (0.80, 1.37), z = 7.41, P < 0.001], PDD [SMD: 1.05, 95% CI: (0.02, 2.07), z = 2.00, P = 0.045] and VaD [SMD: 1.28, 95% CI: (0.68, 1.88), z = 4.19, P < 0.001]. Results from this meta-analysis implied that CSF p-tau181 is a good biomarker for discriminating Alzheimer's disease from other dementias and mild cognitive impairment.

[Impact of evening exercise on college students' sleep quality].

OBJECTIVE: To investigate the impact of college students' evening exercise on their sleep quality, so as to provide a scientific basis for college students to choose an appropriate method of exercise and improve their sleep quality. METHODS: From September to October in 2012, Multi-stage cluster random sampling method was used to select the 5997 college students in Anhui province. The status of college students' exercise and their sleep quality were investigated by the general situation questionnaire, Physical activity rating scale-3(PARS-3), Rating of perceived exertion(RPE) and Pittsburgh sleep quality index(PSQI). Kruskal-Wallis test was used to analyze the impact of evening exercise on sleep quality and multivariate unconditional logistic regression was used to analyze the factors of sleep quality in evening excise students. RESULTS: The median of PSQI total score among 5806 college students was 5 and 1030(17.7%) students had poor sleep quality. The median of the PSQI scores was the same (5 points) for evening exercise group, daytime exercise group,daytime and evening exercise group and non-exercise group (1406, 1514, 1244, 1642 respectively). The difference was not statistically significant (χ(2) = 2.80, P = 0.42). Compared to non-exercise population, the OR (95%CI) value of evening exercise' impact on sleep quality was 0.90(0.73-1.10). Compared to very light evening exercise, the OR (95%CI) value of moderate and large amount of evening exercise' impact on sleep quality was 0.58 (0.44-0.75) and 0.67 (0.48-0.93) respectively; Compared to other sports, the OR (95%CI) value of badminton, rope skipping and jogging' impact on sleep quality was 0.72 (0.55-0.93), 0.38 (0.21-0.70) and 0.76 (0.60-0.95) respectively and they were all protective factors of sleep quality. Compared to small exercise intensity, the OR (95%CI) value of moderate, vigorous and very vigorous exercise intensity' impact on sleep quality was 1.68 (1.13-2.52), 2.38 (1.48-3.83) and 3.18 (1.72-5.90) respectively and they were harmful factors of sleep quality. CONCLUSION: There was no impact of evening exercise on sleep quality for college students. Type of sports should be adequately chosen for evening exercise. College students can take moderate and large amount of evening exercise but should avoid activities of vigorous intensity.

Protective effects of astragalosides on dexamethasone and Aß25-35 induced learning and memory impairments due to decrease amyloid precursor protein expression in 12-month male rats.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder of the elderly characterized by learning and memory impairment. Stress level glucocorticoids (GCs) and ß-amyloid (Aß) peptide deposition are found to be correlated with dementia progression in patients with AD. The astragalosides (AST) was extracted from traditional Chinese herb Astragalus membranaceous. In this study, 12 months male rats were treated with Aß(25-35) (10 µg/rat, hippocampal CA1 injection) and dexamethasone (DEX, 1.5mg/kg, ig) and AST (8, 16 and 32 mg/kg, ig) or ginsenoside Rg1 (Rg1, 5 mg/kg, ig) for 14 days. We investigated the protective effect of AST against DEX+Aß(25-35) injury in rats and its mechanisms of action. Our results indicate that DEX+Aß(25-35) can induce learning and memory impairments and increase APP and Aß(1-40) expression. AST (16, 32 mg/kg) or Rg1 (5mg/kg) treatment significantly improve learning and memory, down-regulate the mRNA levels of APP and ß-secretase, decrease expression of APP and Aß(1-40) in hippocampus. The results indicated that DEX might increase hippocampal vulnerability to Aß(25-35) and highlight the potential neuronal protection of AST.

Dexamethasone and Aß25-35 accelerate learning and memory impairments due to elevate amyloid precursor protein expression and neuronal apoptosis in 12-month male rats.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder of the elderly characterized by learning and memory impairment. Stress level glucocorticoids (GCs) and ß-amyloid (Aß) peptides deposition are found to be correlated with dementia progression in patients with AD. However, little is known about the simultaneous effects of glucocorticoids and Aß on learning and memory impairment and its mechanism. In this study, 12-month-old male rats were chronically treated with Aß(25-35) (10 µg/rat, hippocampal CA1 injection) and dexamethasone (DEX, 1.5mg/kg) for 14 days to investigate the effects of DEX and Aß(25-35) treatment on learning and memory impairments, pathological changes, neuronal ultrastructure, amyloid precursor protein (APP) processing and neuronal cell apoptosis. Our results showed that DEX or Aß(25-35) treatment alone for 14 days had caused slight damage on learning and memory impairments and hippocampal neurons, but damages were significantly increased with DEX+Aß(25-35) treatment. And the mRNA levels of the APP, ß-secretase and caspase 3 were significantly increased after DEX+Aß(25-35) treatment. The immunohistochemistry demonstrated that APP, Aß(1-40), caspase 3 and cytochrome c in hippocampus CA1 were significantly increased. Furthermore, Hoechst 33258 staining and Aß(1-40) ELISA results showed that DEX+Aß(25-35) treatment induced hippocampus CA1 neuron apoptosis and increased the level of Aß(1-40). The results suggest that the simultaneous effects of GCs and Aß may have important roles in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy may increase the toxicity of Aß and have cumulative impacts on the course of AD development and progression.

Dexamethasone potentiated Aß-induced learning and memory impairment in rats.

OBJECTIVE: To determine whether dexamethasone (DEX) could potentiate amyloid beta-protein (Abeta)-induced learning and memory impairment in rats, and, if so, what the underlying mechanism is. METHODS: Morris water maze was used to investigate whether DEX could potentiate Abeta-induced learning and memory impairment in rats, and the histopathologic changes in CA1 field of hippocampus were examined under a light microscope. Immunohistochemistry was used to observe the change of the phosphorylated tau at Thr-231 in the CA1 field of hippocampus. The effects of DEX on the levels of phospho-tau and p25 induced by Abeta were analyzed by Western blot. RESULTS: The results showed that DEX could potentiate Abeta-induced learning and memory impairment and pathological damage in CA1 field of hippocampus in Sprague Dawley (SD) rats, and could enhance the increased levels of phosphorylated tau induced by Abeta(25-35) in the neuronal cell bodies in CA1 field of hippocampus of SD rats and in the protein extracts from hippocampus. Pretreatment of hippocampal neurons with DEX could up-regulate the increased levels of phosphorylated tau and p25 protein induced by Abeta(25-35) in vitro. CONCLUSIONS: These results suggest that DEX could potentiate Abeta-induced learning and memory impairment and pathological damage in CA1 field of hippocampus in SD rats, which might be related to DEX up-regulating the levels of phosphorylated tau and p25 protein induced by Abeta(25-35). Since Abeta and glucocorticoids increase with aging, DEX potentiating Abeta-induced learning and memory impairment may be one of the etiology of Alzheimer's disease.

Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice.

Alzheimer's disease is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stress level glucocorticoids are correlated with dementia progression in patients with Alzheimer's disease. In this study, twelve month old male mice were chronically treated for 21 days with stress-level dexamethasone (5mg/kg). We investigated the pathological consequences of dexamethasone administration on learning and memory impairments, amyloid precursor protein processing and neuronal cell apoptosis in 12-month old male mice. Our results indicate that dexamethasone can induce learning and memory impairments, neuronal cell apoptosis, and mRNA levels of the amyloid precursor protein, beta-secretase and caspase-3 are selectively increased after dexamethasone administration. Immunohistochemistry demonstrated that amyloid precursor protein, caspase-3 and cytochrome c in the cortex and CA1, CA3 regions of the hippocampus are significantly increased in 12-month old male mice. Furthermore, dexamethasone treatment induced cortex and hippocampus neuron apoptosis as well as increasing the activity of caspase-9 and caspase-3. These findings suggest that high levels of glucocorticoids, found in Alzheimer's disease, are not merely a consequence of the disease process but rather play a central role in the development and progression of Alzheimer's disease. Stress management or pharmacological reduction of glucocorticoids warrant additional consideration of the regimen used in Alzheimer's disease therapies.

Memory and learning impairment induced by dexamethasone in senescent but not young mice.

In this study, the memory and learning impairment induced by dexamethasone in young mice and senescent mice were evaluated by step-down inhibitory avoidance task and passive avoidance test. Colorimetric MTT(tetrazole 3-(4,5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide) assay and TUNEL staining were used to investigate the influence of dexamethasone on hippocampal neuronal cell death with amyloid beta-protein. It was determined the effect of dexamethasone on intracellular calcium ([Ca(2+)](i)) with amyloid beta-protein 25-35 by fluorescence imaging with a confocal laser microscope using fluo-3 acetoxymethylester (AM) as a fluorescent dye. The effect of dexamethasone on amyloid beta-protein 25-35-induced nuclear factor kappaB (NF-kappaB) was analyzed by western blot. The results showed that twenty one days dexamethasone exposure resulted in an impairment of memory and learning in senescent but not young mice. Pretreatment of isolated hippocampal neurons with dexamethasone increased the vulnerability of the hippocampal neurons to amyloid beta-protein 25-35, enhanced [Ca(2+)](i) and down-regulated the increased level of nuclear NF-kappaB p65 proteins induced by amyloid beta-protein 25-35. These results demonstrated that glucocorticoids could potentiate the neurotoxic action of amyloid beta-protein by further increasing the level of [Ca(2+)](i) and down-regulating the level of nuclear NF-kappaB protein. Since amyloid beta-protein increases in the brain with aging, glucocorticoids potentiation of the neurotoxic action of amyloid beta-protein maybe one of the mechanisms responsible for glucocorticoids-induced memory and learning impairment in senescent but not young mice, which maybe relevance to the etiology of Alzheimer's disease.