Chang-Yue Gao

A 2‐year follow‐up study of cigarette smoking and risk of dementia

The report focused on investigating the relationship between cigarette smoking and dementia in elderly people through prospective studies. We did a 2‐year follow‐up study of elderly people. A total of 2820 participants aged 60 years old and over from six communities of Chongqing agreed to take part. Dementia was diagnosed with MMSE (Mini‐Mental State Examination) and DSM‐III‐R (Diagnostic and Statistical Manual of Mental Disorders). Participants were classified as never smokers, past smokers, and current smokers. During follow‐up, we recorded incident cases of dementia. The association of smoking and dementia was investigated using proportional hazards regression analysis. A total of 121 incident cases of dementia were detected, of which 84 (69%) were Alzheimers disease, 17 (14%) were vascular dementia, and 21(17%) were other dementia. Compared with never smokers, current smokers had an increased risk of Alzheimers disease (RR = 2.72; 95% CI = 1.63–5.42) and vascular dementia (RR = 1.98; 95% CI = 1.53–3.12) adjusting for age, sex, education, blood pressure, and alcohol intake. Compared with light smokers, the adjusted risk of Alzheimers disease was significantly increased among smokers with a medium level of exposure (RR = 2.56; 95% CI = 1.65–5.52), with an even higher risk of Alzheimers disease in the heavy smoking group (RR = 3.03; 95% CI = 1.25–4.02). Smoking was associated with the risk of dementia. This study suggests that both smoking status and amount is associated with dementia.

A study on the association between infectious burden and Alzheimer's disease

Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between infectious burden (IB) and Alzheimers disease (AD) was examined.

A 2-year follow-up study of alcohol consumption and risk of dementia

BACKGROUND This report focused on investigating the relationship between alcohol consumption and dementia in elderly people through prospective studies. METHODS We conducted a 2-year follow-up study of elderly people from six communities in Chongqing, China. Dementia was detected using the Mini-Mental State Examination (MMSE) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R). The relationship between alcohol consumption and dementia was investigated using multiple logistic regression models, adjusting for the potential confounders age, sex, educational level and cigarette smoking. RESULTS Light-to-moderate drinking was associated with a significantly lower risk of dementia compared with non-drinking. Excessive drinking was related to a higher risk of dementia. The effect of light-to-moderate drinking seemed most prominent among vascular dementia, 0.63 (0.55-0.72) for Alzheimers disease, 0.31 (0.19-0.51) for vascular dementia and 0.45 (0.12-1.69) for other dementia. In a model adjusting for confounding variables, a light-to-moderate intake of beer was associated with a significantly higher risk of dementia than a non-drinker of beer. For wine, a significantly lower risk of dementia existed for a light-to-moderate drinker. CONCLUSIONS Light-to-moderate drinking was associated with a significantly lower risk of dementia compared with a non-drinker.

Study on frequency and predictors of dementia after ischemic stroke: The Chongqing Stroke Study

Abstract.Objective:We studied a large hospitalized cohort of patients aged 55 years and over with acute ischemic stroke to identify the frequency and predictors of poststroke dementia.Methods:A total of 434 consecutive patients with ischemic stroke were enrolled in this study. During admission, the demographic data, vascular risk factors, stroke features, and neurological status information were collected. All subjects were examined by a battery of neuropsychological tests during admission and 3 months after stroke. Logistic regression analysis was used to find the predictors of poststroke dementia.Results:(1) The frequency of poststroke dementia was 27.2%, that of stroke-related dementia was 21.6%, and that of dementia after first-ever stroke was 22.7% 3 months after stroke. (2) Univariate analysis indicated that older age, low educational level (≤ 6 years), everyday drinking, diabetes mellitus, atrial fibrillation, prior stroke, left carotid territory infarction, embolism, multiple stroke lesions, dysphasia, and gait impairment were more frequent in the patients with poststroke dementia. (3) Multivariate analyses demonstrated that age (OR 1.179, 95%CI 1.130–1.230), low educational level (OR 1.806, 95 %CI 1.024–3.186), everyday drinking (OR 3.447, 95 %CI 1.591–7.468), prior stroke (OR 2.531, 95 %CI 1.419–4.512), atrial fibrillation (OR 3.475, 95%CI 1.712–7.057), dysphasia (OR 5.873, 95 %CI 2.620–13.163), and left carotid territory infarction (OR 1.975, 95%CI 1.152–3.388) were associated with poststroke dementia.Conclusions:The frequency of dementia is about one-forth of patients with ischemic stroke 3 months after stroke. Independent predictors of poststroke dementia include age, low educational level, everyday drinking, prior stroke, dysphasia, atrial fibrillation, and left carotid territory infarction.

p75NTR Regulates Aβ Deposition by Increasing Aβ Production But Inhibiting Aβ Aggregation with Its Extracellular Domain

Accumulation of toxic amyloid-β (Aβ) in the cerebral cortex and hippocampus is a major pathological feature of Alzheimers disease (AD). The neurotrophin receptor p75NTR has been proposed to mediate Aβ-induced neurotoxicity; however, its role in the development of AD remains to be clarified. The p75NTR/ExonIII−/− mice and APPSwe/PS1dE9 mice were crossed to generate transgenic AD mice with deletion of p75NTR gene. In APPSwe/PS1dE9 transgenic mice, p75NTR expression was localized in the basal forebrain neurons and degenerative neurites in neocortex, increased with aging, and further activated by Aβ accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Aβ levels in the brain and serum, but increased the accumulation of insoluble Aβ and Aβ plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or α-, β-, and γ-secretase activities, or in levels of BACE1, neprilysin (NEP), and insulin-degrading enzyme (IDE) proteins. Aβ production by cortical neurons of APPSwe/PS1dE9 mice was reduced by deletion of p75NTR gene in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Aβ42 peptide in vitro, and reduced local Aβ plaques after hippocampus injection in vivo. In addition, deletion of p75NTR attenuated microgliosis but increased the microhemorrhage profiles in the brain. The deletion of p75NTR did not significantly change the cognitive function of the mice up to the age of 9 months. Our data suggest that p75NTR plays a critical role in regulating Aβ levels by both increasing Aβ production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology.

Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: A meta-analysis

It remains controversial regarding the association between Apolipoprotein E (ApoE) gene polymorphism and the risk of vascular dementia (VaD). The present meta-analysis was performed to derive a more precise estimation of the relationship. The meta-analysis was performed by searching PubMed, Embase and Web of Science databases. A total of 29 studies included 1763 VaD cases and 4534 controls were identified. The results showed evidence for significant association between ApoE ɛ4 mutation and VaD risk (for ɛ3/ɛ4 vs. ɛ3/ɛ3: OR=1.65, 95% CI=1.40-1.94, p-value<0.00001; for ɛ4/ɛ4 vs. ɛ3/ɛ3: OR=3.17, 95% CI=2.09-4.80, p-value<0.00001; for ɛ4 allele vs. ɛ3 allele: OR=1.72, 95% CI=1.40-2.12, p-value<0.00001). The similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests an association between ApoE ɛ4 mutation and increased risk of VaD. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.

Inhibition of reactive oxygen species generation attenuates TLR4-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells.

Reactive oxygen species (ROS) are associated with inflammation and vasculature dysfunction. This study aimed to investigate the potential role of the ROS on vascular Toll-like receptor 4 (TLR4)-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells (VSMCs). A wire-induced carotid injury model was used in male TLR4-deficient (TLR4−/−) and wild-type C57BL/6J mice to induce neointima formation. In the presence or absence of the ROS scavenger apocynin for 14 days, increased TLR4 and proinflammatory cytokines were observed in wire injury-induced carotid neointima and in platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs. The TLR4−/− protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to PDGF-BB. Apocynin attenuated intimal hyperplasia. Pre-treatment with apocynin significantly inhibited intracellular ROS generation, accompanied by a significant suppression of TLR4 and proinflammatory cytokines expression, and VSMC proliferation and migration. However, the results were not obvious in TLR4−/− condition. These findings highlight the importance of ROS inhibition in TLR4-mediated proinflammatory and proliferative phenotype of VSMCs, and suggest ROS as an essential therapeutic target for TLR4-associated vascular inflammation and vascular diseases.

PPARγ attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells

AIMS Peroxisome proliferator-activated receptor γ (PPARγ) has been reported to attenuate intimal hyperplasia. This study aimed to test the hypothesis that PPARγ inhibits intimal hyperplasia through suppressing Toll-like receptor 4 (TLR4)-mediated inflammation in vascular smooth muscle cells. METHODS AND RESULTS TLR4(-/-) mice on a C57BL/6J background were used. Increased TLR4 and pro-inflammatory cytokines were observed in wire-injury-induced carotid neointima and in platelet-derived growth factor (PDGF)-activated vascular smooth muscle cells. The TLR4 deficiency protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to lipopolysaccharide and PDGF. Rosiglitazone attenuated intimal hyperplasia. Overexpression of PPARγ suppressed PDGF-induced proliferation and migration and inhibited TLR4-mediated inflammation in vascular smooth muscle cells, while PPARγ silencing exerted the opposite effect. Lipopolysaccharide counteracted the inhibitory effect of PPARγ on PDGF-induced proliferation and migration. Eritoran suppressed the proliferation and migration induced by PDGF and PPARγ silencing. Vascular smooth muscle cells derived from TLR4(-/-) mice showed impaired proliferation and migration upon PDGF activation and displayed no response to PPARγ manipulation. CONCLUSION PPARγ inhibits vascular smooth muscle cell proliferation and migration by suppressing TLR4-mediated inflammation and ultimately attenuates intimal hyperplasia after carotid injury.

Association of Soluble Intercellular Adhesion Molecule 1 with Neurological Deterioration of Ischemic Stroke: The Chongqing Stroke Study

Background: Adhesion molecules play important roles in the pathophysiology of ischemic stroke. The aim of the present study was to investigate whether serum levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cellular adhesion molecule 1 (sVCAM-1) and soluble E-selectin were associated with neurological deterioration of ischemic stroke. Methods: 238 consecutive patients with ischemic stroke examined within 24 h from onset were enrolled into the study. The stroke severity was daily assessed with the NIH Stroke Scale (NIHSS) within the first week after admission. Serum levels of sICAM-1, sVCAM-1 and sE-selectin after admission were measured using enzyme-linked immunosorbent assay. Multivariate logistic regression was used to analyze the association of serum levels of sICAM-1, sVCAM-1 and sE-selectin on admission with the neurological deterioration of ischemic stroke, adjusted for potential confounders. Results: 52 (21.8%) out of 238 stroke patients suffered from neurological deterioration. Serum levels of sICAM-1 on admission of stroke patients were significantly higher than those of healthy controls. Compared with patients without deterioration, patients with neurological deterioration had higher levels of sICAM-1, but not of sVCAM-1 and sE-selectin. On multivariate logistic regression, the serum level of sICAM-1 on admission was associated with neurological deterioration of stroke (OR 2.92, 95% CI 1.41–6.05). Other variables associated with neurological deterioration were fasting serum glucose (OR 1.65, 95% CI 1.24–2.20), baseline fibrinogen (OR 1.31, 95% CI 1.13–1.52) and NIHSS score (OR 1.23, 95% CI 1.15–1.32). Conclusions: The serum level of sICAM-1 on admission is associated with neurological deterioration of ischemic stroke.

Effects of proNGF on neuronal viability, neurite growth and amyloid-beta metabolism.

Alzheimer’s disease (AD) is characterized pathologically by the deposition of amyloid-β peptides (Aβ), neurofibrillary tangles, distinctive neuronal loss and neurite dystrophy. Nerve growth factor (NGF) has been suggested to be involved in the pathogenesis of AD, however, the role of its precursor (proNGF) in AD remains unknown. In this study, we investigated the effect of proNGF on neuron death, neurite growth and Aβ production, in vitro and in vivo. We found that proNGF promotes the death of different cell lines and primary neurons in culture, likely dependent on the expression of p75NTR. We for the first time found that proNGF has an opposite role in neurite growth to that of mature NGF, retarding neurite growth in both cell lines and primary neurons. proNGF is localized to the Aβ plaques in AD mice brain, however, it had no significant effect on Aβ production in vitro and in vivo. Our findings suggest that proNGF is an important factor involving AD pathogenesis.