Juan Deng

Leisure activity and risk of cognitive impairment: The Chongqing aging study

The authors followed 5,437 people aged 55 years and older with normal baseline Mini-Mental State Examination score annually for 5 years. The mean incidence of cognitive impairment was 2.3% per year. Cognitive activities in both the individual item (playing board games and reading) and the composite measure were associated with the reduced risk of cognitive impairment, while watching television was associated with an increased risk of cognitive impairment.

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

Significance Alzheimer’s disease (AD) is a devastating disease that results in the progressive cognitive deficits of elderly and has become one of major social and economic burdens worldwide. There is no effective drug or therapy to prevent or halt the progressive cognitive dysfunctions due to the complex mechanisms such as accumulation of amyloid-β (Aβ), increase in oxidative stress, and formation of neurofibrillary tangle that drive the development of the disease. We found here that Edaravone, a drug that has been used for ischemic stroke, is able to prevent and treat AD by targeting multiple pathways of AD pathogenesis and rescuing the cognitive deficits of a mouse model of AD. Our study suggests Edaravone is a promising drug candidate for AD. 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.

Association between Bone Mineral Density and the Risk of Alzheimer's Disease

Alzheimers disease (AD) and osteoporosis are common chronic degenerative disorders which are strongly associated with advanced age. Some studies suggest that low bone mineral density (BMD) is related to the increased risk of AD. We conducted a 5-year prospective study to exam the association between BMD and the risk of AD in a cohort of Chinese elderly people. Of 3263 community residents aged 65 years and over, 2019 were enrolled into the study and followed up annually for 5 years. At baseline demographic data, smoking and drinking status, medical history, cognitive status, and blood samples were collected. BMD was measured by dual energy X-ray absorptiometry (DEXA) scanning at baseline and during follow-up. Cox proportional hazards analysis was used to evaluate the association with BMD and incidence of AD. Over the follow-up of 5 years, AD developed in 132 subjects. Baseline BMD, bone loss rate, current smoking, and daily drinking were associated with increased risk of AD, while higher baseline plasma leptin level was associated with decreased risk of AD, in both women and men. Low BMD and increased loss rate of BMD were associated with higher risk of AD. Cigarette smoking, alcohol drinking, and lower leptin level are risk factors for AD. Uncovering the relation linking osteoporosis and AD is important for understanding the pathogenesis and developing therapeutic strategies for these two common disorders afflicting elderly people.

Nicotine exacerbates tau phosphorylation and cognitive impairment induced by amyloid-beta 25-35 in rats.

Nicotine was reported to reduce the plaque burden and could be used as a possible anti-Alzheimers disease agent. However, the effect of nicotine on memory and tau pathology in Alzheimers disease has been less studied. The present study investigated the effect of nicotine on tau phosphorylation and cognitive impairment induced by hippocampus injections of amyloid-beta (Abeta) 25-35. Rats were treated with nicotine hydrogen tartrate salt dissolved in normal saline by subcutaneous injection twice per day for 14 days. The age and gender matched rats treated with same amount of normal saline were used as the control. Morris water maze was used to detect the cognitive impairment induced by Abeta25-35. Compared to the sham-operated rats, Abeta25-35 injection significantly prolonged the mean escape latency in vehicle-treated rats in the Morris water maze test and increased the number of tau(pS202) and tau(pT231) immunoreactive cells. The data show that nicotine (1mg/kg in base weight) treatment significantly exacerbates cognitive impairment and tau phosphorylation at Ser-202 and Thr-231 in the hippocampus compared with Abeta25-35 injection groups in the Abeta rat model of Alzheimers disease. The use of nicotine for treatment of Alzheimers disease should be reassessed.

Vascular Risk Aggravates the Progression of Alzheimer's Disease in a Chinese Cohort

To investigate whether vascular risk affects the progression of Alzheimers disease (AD), 415 AD patients aged 65 years old and over without cerebrovascular diseases were enrolled and administered with a structured interview to assess demography, vascular risk factors, and cognitive and functional status at baseline, and 324 AD patients were followed up annually for 5 years. A mixed random effects regression model was used to identify the association between vascular risk, individual vascular risk factors, and the progression of AD. After adjusting for confounding factors, AD patients with vascular risk had faster cognitive and functional decline rates than the subjects without such risk factors. Individual vascular risk factors including hypertension and diabetes mellitus, transient ischemic attack and cerebrovascular accident during the follow-up were independently associated with the progression of AD. Our findings suggest that vascular risk aggravates the progression of AD and may be involved in the etiologic process of AD. As such, control of vascular risk may slow down the progression of AD.

An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect.

BackgroundSenile plaques consisting of amyloid-beta (Aβ) are the major pathological hallmark of Alzheimer’s disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain Aβ deposits, increased levels of soluble Aβ and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of Aβ deposition might facilitate the formation of more toxic Aβ oligomers and enhance neurotoxicity.MethodsThe capacity of antibodies against different epitopes of Aβ to disaggregate preformed Aβ fibrils was investigated. The co-incubation of antibodies and Aβ fibrils was then tested for neurotoxicity both in vitro and in vivo.ResultsAfter the incubation of preformed Aβ fibrils with the N-terminal antibody 6E10, the fibrils were decreased, while the oligomers, mostly dimers and trimers, were significantly increased. However, no such effects were observed for antibodies targeting the middle domain (4G8) and C-terminus of Aβ (8G7). The co-incubates of preformed Aβ fibrils with 6E10 were more neurotoxic, both in vitro and in vivo, than the co-incubates with 4G8 and 8G7.ConclusionsOur results indicate that the antibody targeting the N-terminus of Aβ promoted the transformation of Aβ from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of Aβ deposits by antibodies against the Nterminus of Aβ.

Intracranial artery stenosis and progression from mild cognitive impairment to Alzheimer disease

Objective: To assess the impact of intracranial arterial stenosis on the progression from mild cognitive impairment (MCI) to Alzheimer disease (AD). Methods: A total of 423 participants with MCI were included and evaluated with clinical and neuropsychological examinations annually for 4 years. The incidence of dementia due to AD was investigated. CT angiography was used to measure the stenosis of major intracranial arteries in the studied population. A mixed-effects regression model was used to analyze the association between intracranial arterial stenosis and the progression of MCI, which was assessed with the Mini-Mental State Examination and the Activities of Daily Living scale. Cox proportional hazards models were used to identify the association between intracranial arterial stenosis and dementia progression. Results: At the end of the follow-up, 116 participants had progressed to dementia due to AD, while 223 remained in the MCI stage. Participants with moderate or severe intracranial arterial stenosis had a faster decline in cognition and function relative to participants without such stenosis. The presence of moderate or severe intracranial arterial stenosis significantly increased the risk of dementia progression, even after controlling for age, sex, education, vascular risk factors, and silent MRI lesions. Conclusions: Intracranial arterial stenosis increased the risk of developing AD dementia after MCI.

Relation Between Bone Mineral Density, Bone Loss and the Risk of Cardiovascular Disease in a Chinese Cohort

Cardiovascular disease (CVD) and osteoporosis share some common risk factors such as old age, smoking, alcoholic drinking, hypertension, diabetes mellitus, and hyperlipidemia. Although previous studies have investigated the association of bone mineral density (BMD) with CVD, the results were conflicting. There are limited studies on the association of BMD loss rate with CVD. We therefore conducted a 5-year prospective study to examine the relation among BMD, bone loss, and risk of CVD in a Chinese cohort. Of 9,657 community residents 30 to 75 years old, 6,092 were enrolled in the study and followed annually for 5 years. At baseline demographic data, BMD, smoking and drinking statuses, medical history, and blood samples were collected. Cox proportional hazards analysis was used to evaluate the association of BMD and incidence of CVD. Over the 5-year follow-up period, CVD developed in 118 subjects. Baseline BMD, bone loss rate, current smoking, daily alcoholic ingestion, and higher osteoprotegerin and leptin levels were independently associated with increased risk of CVD, whereas higher baseline adiponectin level was associated with decreased risk of CVD in women and men. In conclusion, uncovering the relation linking osteoporosis and CVD is important for understanding the pathogenesis of these 2 common disorders.

Associations Between ApoEε4 Carrier Status and Serum BDNF Levels—New Insights into the Molecular Mechanism of ApoEε4 Actions in Alzheimer’s Disease

Insufficient neurotrophic support increases the risk for developing Alzheimer’s disease (AD). Mounting evidence has confirmed the association of brain-derived neurotrophic factor (BDNF) and apolipoprotein E (ApoE) with AD. As both BDNF and ApoE are suggested to be involved in modulating brain integrity, the present study is aiming to investigate the associations between these two factors. In this study, 110 AD patients and 120 cognitively normal controls (NC) were recruited for measurement of serum BDNF levels and ApoE genotyping. Serum BDNF levels in the AD group were significantly lower than that in the NC group, reflecting insufficient neurotrophic supply in AD patients. We further found that ApoE ε4+/− and ε4+/+ subjects had significantly lower serum BDNF levels than ε4−/− subjects in the whole cohort and the NC group, suggesting altered BDNF metabolism in ApoE ε4 carriers. Further analysis indicated possible interactions between ApoEε4 and BDNF in their co-effects on AD and mini-mental state examination (MMSE) scores. Our findings imply that the possible involvement of ApoE ε4 in BDNF metabolism might be another molecular mechanism underlying the contribution of ApoE ε4 to the development of AD.

Adverse life event and risk of cognitive impairment: a 5-year prospective longitudinal study in Chongqing, China

Background and purpose:  Current knowledge of factors that increase or decrease the risk of cognitive impairment in elderly people is limited. Recently adverse life events appeared to be associated with the increased risk of cognitive impairment in elderly people. However, this is less studied. We conducted a 5‐year prospective study to evaluate the association between adverse life events and the risk of cognitive impairment in Chinese elderly people.