Jianhua Zhuang

Clusterin in Alzheimer’s disease: a player in the biological behavior of amyloid-beta

Alzheimer’s disease (AD) remains a major killer, and although its pathogenesis varies, one dominant feature is an increase in the expression, formation, and sedimentation of senile plaques of amyloid-beta (Aβ) peptides in the brain. The chaperone protein clusterin has, since its first discovery at the end of the 20th century, been labeled as a cytoprotector. However, epigenetic studies showing that clusterin is associated with the severity and risk of AD, especially in the hippocampus, triggered studies to clarify its role in the pathogenesis of AD. It is true that clusterin can inhibit the aggregation of Aβ and therefore prevent further formation of senile plaques in the AD brain, yet it induces the formation of soluble forms of Aβ which are toxic to neurons. Another problematic finding is that clusterin is involved in a pathway through which Aβ has neurodegenerative effects intracellularly. Although the role of clusterin in the pathogenesis of AD is still not clear, this review specifically discusses the interactions between clusterin and Aβ, to open up the possibility of a potential therapeutic approach for treating AD.

Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in eastern China.

OBJECTIVE Our study was designed to assess symptomatology and occurrences of narcolepsy in eastern China between 2003 and 2012. Herein we report the substantial changes in the occurrence and clinical features of narcolepsy over the last decade in China. METHODS We performed a retrospective analysis of 162 Han Chinese patients with narcolepsy at Changzheng Hospital, Shanghai, China. Clinical histories and precipitating factors were recorded, in addition to narcolepsy and H1N1 winter flu pandemic (pH1N1) occurrences at Changzheng Hospital. The occurrences also were compared between the Changzheng Hospital and the Peoples Hospital, Beijing, China. RESULTS In our sample, narcolepsy occurred 1.73 times more frequently in men than in women. Most of the participants were children, which peaked to 91% in 2010. Excessive daytime sleepiness (EDS), disrupted nocturnal sleep, cataplexy, and weight gain were the four major symptoms. We found that 40% of patients had identifiable precipitating factors. The occurrence of narcolepsy in 2010 showed an approximate three-fold difference from the baseline levels at the Changzheng Hospital, which showed positive relationships with occurrences of pH1N1 in Shanghai and the occurrence of narcolepsy at the Peoples Hospital. CONCLUSIONS Our findings show the interactive effects of geography and H1N1 disease in relation to narcolepsy in Han Chinese populations, and strengthen the theoretic hypothesis that immune and mental factors facilitate the onset of narcolepsy.

Elevation of serum TNF-α levels in mild and moderate Alzheimer patients with daytime sleepiness

OBJECTIVES Sleep disturbance has been noted to accompany Alzheimer disease and is more pronounced as dementia severity increases. The aim of this study was to examine whether sleep disturbance in a cohort of patients with mild/moderate AD was associated with serum levels of IL-1β and TNF-α. METHODS Forty three drug-free AD patients and twenty two healthy controls were evaluated. All subjects underwent two consecutive full-night polysomnography. Their daytime sleepiness was assessed by Epworth Sleepiness Scale (ESS). Serum levels of IL-1β and TNF-α were measured by enzyme linked immunoassays. RESULTS AD patients showed lower sleep efficiency, more awakenings and less slow wave sleep (SWS). IL-1β was detectable only in two AD patients. Serum TNF-α concentrations did not differ significantly between AD patients and controls. When AD patients were classified as AD patients with daytime sleepiness (n=20, ESS>10) or AD patients without daytime sleepiness (n=23, ESS<10) according to their ESS scores, serum levels of TNF-α was significantly higher in AD patients with daytime sleepiness than that in those without daytime sleepiness or controls (32.7±17.9 vs 5.2±2.4, p<0.05; 40.9±22.3 vs 5.7±2.2, p<0.05). Serum level of TNF-α was significantly correlated with ESS score. DISCUSSION These data indicate that daytime sleepiness in mild and moderate AD patients is associated with elevation of serum TNF-α concentrations.

Topiramate as an Adjunctive Treatment for Refractory Partial Epilepsy in the Elderly

This double-blind, placebo-controlled study investigated the efficacy and tolerability of adjunctive topiramate in 86 elderly Chinese patients with refractory partial epilepsy. Patients who had at least four seizures per 4 weeks during an 8-week baseline period, despite medication with up to three standard antiepileptic drugs (AEDs), were randomly assigned to receive topiramate (n = 46) or placebo (n = 40). Topiramate dosages were titrated (target dose 200 mg/day orally) for 8 weeks and maintained at stable levels for another 12 weeks; concomitant AEDs continued at original dosages. All patients completed the study: 47.8% in the topiramate group and 7.5% on placebo reached ≥ 50% reduction in complex partial seizures. In the topiramate group, the most common adverse events were dizziness, somnolence, fatigue, headache and difficulty with memory; most events were transient and mild or moderate in severity. It was concluded that 200 mg/day topiramate was effective and well-tolerated in elderly patients with refractory partial epilepsy.

Chronic Sleep Restriction Induces Cognitive Deficits and Cortical Beta-Amyloid Deposition in Mice via BACE1-Antisense Activation

To clarify the correlation between chronic sleep restriction (CSR) and sporadic Alzheimer disease (AD), we determined in wild‐type mice the impact of CSR, on cognitive performance, beta‐amyloid (Aβ) peptides, and its feed‐forward regulators regarding AD pathogenesis.

Frontal cortical mitochondrial dysfunction and mitochondria-related β-amyloid accumulation by chronic sleep restriction in mice.

Mitochondrial dysfunction induced by mitochondria-related &bgr;-amyloid (A&bgr;) accumulation is increasingly being considered a novel risk factor for sporadic Alzheimer’s disease pathophysiology. The close relationship between chronic sleep restriction (CSR) and cortical A&bgr; elevation was confirmed recently. By assessing frontal cortical mitochondrial function (electron microscopy manifestation, cytochrome C oxidase concentration, ATP level, and mitochondrial membrane potential) and the levels of mitochondria-related A&bgr; in 9-month-old adult male C57BL/6J mice subjected to CSR and as an environmental control (CO) group, we aimed to evaluate the association of CSR with mitochondrial dysfunction and mitochondria-related A&bgr; accumulation. In this study, frontal cortical mitochondrial dysfunction was significantly more severe in CSR mice compared with CO animals. Furthermore, CSR mice showed higher mitochondria-associated A&bgr;, total A&bgr;, and mitochondria-related &bgr;-amyloid protein precursor (A&bgr;PP) levels compared with CO mice. In the CSR model, mouse frontal cortical mitochondrial dysfunction was correlated with mitochondria-associated A&bgr; and mitochondria-related A&bgr;PP levels. However, frontal cortical mitochondria-associated A&bgr; levels showed no significant association with cortical total A&bgr; and mitochondrial A&bgr;PP concentrations. These findings indicated that CSR-induced frontal cortical mitochondrial dysfunction and mitochondria-related A&bgr; accumulation, which was closely related to mitochondrial dysfunction under CSR.

Low-Dose Atypical Antipsychotic Risperidone Improves the 5-Year Outcome in Alzheimer's Disease Patients with Sleep Disturbances.

Sleep disturbances (SD) accelerate the progression of Alzheimers disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers.

Estradiol deficiency is a risk factor for idiopathic benign paroxysmal positional vertigo in postmenopausal female patients

Although it is generally considered that benign paroxysmal positional vertigo (BPPV) is associated with changes in female sex hormone levels, no direct data have been reported until now. The purpose of this article was to provide direct data showing the distinct relationship between female sex hormone fluctuations and BPPV in postmenopausal female patients.

Interleukin-1β Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer's Disease.

Sleep alleviates Alzheimer’s disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1β and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1β and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33–14.10, p = 0.015). Compared to the IL-1β CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13–2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1β TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1β levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1β-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1β-31TT genotype and homozygous APOEε4 combined are associated with increased risk of developing AD with sleep disturbance.

Correlation between Endothelial Dysfunction, Rho-Associated Protein Kinase Activity, C-Reactive Protein and Obstructive Sleep Apnoea Syndrome in Male Patients

Objective: This study investigated the association between obstructive sleep apnoea syndrome (OSAS) and flow-mediated dilatation (FMD), Rho-associated protein kinase (ROCK) activity, and C-reactive protein (CRP) concentrations in male patients. Methods: Consecutive patients with symptoms suggestive of OSAS were recruited and divided into non-OSAS (n = 18) and OSAS (n = 32) groups. FMD was measured in the brachial artery; blood samples were taken to measure ROCK activity and CRP concentrations. Results: ROCK activity and CRP concentrations were significantly higher, and FMD was significantly lower, in the OSAS group than in the non-OSAS group. There was a correlation between ROCK activity and FMD. In stepwise multiple regression analyses, the proportion of sleep time spent with an oxygen saturation < 90% was a significant determinant of ROCK activity, while body mass index was the only significant determinant of CRP concentration. The oxygen desaturation index was a significant determinant of FMD. Conclusions: OSAS increased ROCK activity and was a major determinant of endothelial dysfunction.