Clinical and Polysomnographic Characteristics of Nonobese and Obese Chinese Patients With Obstructive Sleep Apnea.

PURPOSE: Obesity is a risk factor associated with the onset and exacerbation of obstructive sleep apnea (OSA). However, the majority of OSA patients in Asian populations are nonobese. To date, there have been insufficient large-scale studies of the differences in the clinical and polysomnographic features of obese and nonobese OSA patients in this population, and few studies have sought to identify predictors of OSA severity in affected obese and nonobese patients. METHODS: We conducted a case-matched retrospective study, including 652 consecutive Chinese OSA patients (326 nonobese and 326 obese) to assess differences in demographic, clinical, and polysomnographic data between these two groups. Independent predictors of OSA severity were identified through multivariate linear regression analysis. RESULTS: The age and gender distributions of our obese and nonobese OSA patient cohorts did not differ significantly ( P > 0.05), and rates of comorbidities were comparable in these two patient groups ( P > 0.05). Nonobese patients were more likely to report atypical symptoms of OSA, including insomnia ( P < 0.001), irritability ( P < 0.05), and depressive symptoms ( P < 0.01), whereas obese patients were more likely to report typical symptoms of OSA, such as habitual snoring ( P < 0.001), witnessed apnea ( P < 0.05), and daytime sleepiness ( P < 0.001). Relative to nonobese patients, those who were obese exhibited significantly higher apnea-hypopnea index during total sleep time ( P < 0.001), apnea-hypopnea index during nonrapid eye movement sleep ( P < 0.001), and apnea-hypopnea index during rapid eye movement sleep ( P < 0.001), in addition to lower average oxygen saturation ( P < 0.001), minimal oxygen saturation ( P < 0.001), and a higher oxygen desaturation index ( P < 0.001) and arousal index ( P < 0.001). Total sleep time was, on average, shorter for nonobese patients ( P < 0.05), who also exhibited decreased sleep efficiency and more frequent awakening relative to obese patients ( P < 0.05). A multivariate linear regression analysis revealed that neck circumference and waist circumference were independent predictors of OSA severity in obese patients ( P < 0.05). CONCLUSIONS: On average, OSA was typically less severe in nonobese patients, who were also more likely to experience atypical OSA symptoms relative to obese patients. These results also suggest that the differential contributions of body fat accumulation and distribution to OSA severity may offer insights into the pathogenesis, clinical manifestations, and optimal management of this condition in nonobese and obese patient populations. It is vital that clinicians consider these differences to properly diagnose and treat this debilitating condition.

Gender differences in clinical manifestations and polysomnographic findings in Chinese patients with obstructive sleep apnea.

PURPOSE: The gender differences in patients with obstructive sleep apnea (OSA) are not fully understood so far, as previous studies had conflicting results. No reports have addressed the differences in OSA between Chinese men and women. Therefore, the purpose of this study was to investigate the clinical and polysomnographic differences between Chinese men and women with OSA. METHODS: This case-paired control retrospective study included 580 consecutive Chinese patients (290 males and 290 females) newly diagnosed as OSA by overnight polysomnography from the Sleep Disorders Center of Tangdu Hospital affiliated to the Fourth Military Medical University of China. Demographic, clinical, and polysomnographic data of men and women with OSA were compared. Order logistic regression analysis was used to determine the risk factors for OSA severity. RESULTS: Male and female patients had similar age (57.3 ± 9.2 vs. 58.2 ± 8.9, p > 0.05) and body mass index (BMI) (25.4 ± 3.4 vs. 25.5 ± 3.9, p > 0.05). Women more commonly presented with insomnia (70.3% vs. 40.3%, p < 0.001), poor sleep quality (58.3% vs. 40.7%, p < 0.001), and headache on awakening (23.1% vs. 13.8%, p < 0.01) than men, while men more frequently reported habitual snoring (69.0% vs. 52.1%, p < 0.001) compared with women. The apnea-hypopnea index (AHI) during total sleep time and non-rapid eye movement sleep was higher in men compared with women (25.8 ± 20.4 vs. 19.3 ± 16.8; 22.0 ± 18.2 vs. 15.1 ± 15.4; p < 0.001, respectively), whereas AHI during rapid eye movement sleep was higher in women than in men (4.2 ± 3.6 vs. 3.7 ± 4.3, p < 0.01). Compared with men, women had lower sleep efficiency (75.4 ± 15.7 vs. 78.1 ± 15.5, p < 0.05), longer REM latency (128.9 ± 88.6 vs. 107.7 ± 72.4, p < 0.01), and greater wakefulness after sleep onset (WASO) (98.3 ± 70.2 vs. 88.0 ± 70.3, p < 0.05). No significant differences in the lowest oxygen desaturation and oxygen desaturation index (ODI) were observed between men and women (80.4 ± 10.8 vs. 80.8 ± 9.0; 17.0 ± 20.9 vs. 13.1 ± 16.5; p > 0.05, respectively). In addition, ordinal logistic regression analysis identified neck circumference as an independent risk factor for OSA severity in male patients (OR, 1.161; 95% CI, 1.020-1.325; p < 0.05) and in female patients (OR, 1.163; 95% CI, 1.013-1.338; p < 0.05). CONCLUSIONS: Overall, female patients had less severe OSA when compared with male patients. The female patients more commonly reported "atypical" OSA symptoms, while male patients more frequently reported "typical" OSA symptoms. In clinical practices, physicians dealing with OSA need to take the gender disparity into consideration for more precise diagnosis and treatment, as women may be atypically symptomatic at a less severe OSA.

The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.

MicroRNAs are small non-coding RNAs that repress the expression of their target proteins. The roles of microRNAs in the development of Alzheimer's disease (AD) are not clear. In this study we show that miR-200c represses the expression of PTEN protein. PTEN downregulation by miR-200c supports the survival and differentiation of cultured neurons. AD is a progressive neurodegenerative disease signified by beta amyloid (Aß) peptide aggregation and deposition. In a mouse model of AD that is induced by APPswe and PS1ΔE9 double transgenes, we found Aß deposition results in neuronal ER stress that induces miR200c. Pharmacological blockade of ER stress inhibited Aß-induced miR-200c overexpression in AD brains. MiR-200c was detected in the serum of both AD mice and human AD patients. These findings suggest that miR-200c functions as part of the neuronal cell-intrinsic adaptive machinery, and supports neuronal survival and differentiation in response to Aß induced ER-stress by downregulating PTEN.

Mithramycin A Alleviates Cognitive Deficits and Reduces Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease.

Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models. However, whether the Sp1 activation plays a critical role in the AD pathogenesis and selective inhibition of Sp1 activation may have a disease-modifying effect on the AD-like phenotypes remain elusive. In this study, we reported that Sp1 mRNA and protein expression were markedly increased in the brain of APPswe/PS1dE9 transgenic mice, whereas chronic administration of mithramycin A (MTM), a selective Sp1 inhibitor, potently inhibited Sp1 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, we found that MTM treatment resulted in a significant improvement of learning and memory deficits, a dramatic reduction in cerebral Aß levels and plaque burden, a profound reduction in tau hyperphosphorylation, and a marked increase in synaptic marker in the APPswe/PS1dE9 mice. In addition, MTM treatment was powerfully effective in inhibiting amyloid precursor protein (APP) processing via suppressing APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin-1 (PS1) mRNA and protein expression to preclude Aß production in the APPswe/PS1dE9 mice. Furthermore, MTM treatment strongly inhibited phosphorylated CDK5 and GSK3ß signal pathways to reduce tau hyperphosphorylation in the APPswe/PS1dE9 mice. Collectively, our findings provide evidence that Sp1 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. The present study highlights that selective Sp1 inhibitors may be considered as disease-modifying therapeutic agents for AD.

Morin reverses neuropathological and cognitive impairments in APPswe/PS1dE9 mice by targeting multiple pathogenic mechanisms.

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive cognitive impairment and multiple distinct neuropathological features. Currently, there are no available therapies to delay or block the disease progression. Thus, the disease-modifying therapies are urgent for this devastating disorder by simultaneously targeting multiple distinct pathological processes. Morin, a natural bioflavonoid, have been shown to be strongly neuroprotective in vitro and in vivo. In this study, we first investigated the disease-modifying effects of chronic morin administration on the neuropathological and cognitive impairments in APPswe/PS1dE9 double transgenic mice. Our results showed that chronic morin administration prevented spatial learning and memory deficits in the APPswe/PS1dE9 mice. Morin treatment in the APPswe/PS1dE9 mice markedly reduced cerebral Aß production and Aß plaque burden via promoting non-amyloidogenic APP processing pathway by increasing ADAM10 expression, inhibiting amyloidogenic APP processing pathway by decreased BACE1 and PS1 expression, and facilitating Aß degradation by enhancing Aß-degrading enzyme expression. In addition, we also found that morin treatment in the APPswe/PS1dE9 mice markedly decreased tau hyperphosphorylation via its inhibitory effect on CDK5 signal pathway. Furthermore, morin treatment in the APPswe/PS1dE9 mice markedly reduced the activated glial cells and increased the expression of synaptic markers. Collectively, our findings demonstrate that chronic morin treatment restores cognitive functions and reverses multiple distinct neuropathological AD-like hallmarks in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective actions and neurobiological mechanisms of morin against AD, suggesting that morin is a potently promising disease-modifying agent for treatment of AD.

MicroRNAs 99b-5p/100-5p Regulated by Endoplasmic Reticulum Stress are Involved in Abeta-Induced Pathologies.

Alzheimer's disease (AD) is the most common cause of dementia. Amyloid ß (Abeta, Aß) deposition and intracellular tangles are the pathological hallmarks of AD. MicroRNAs (miRNAs) are small non-coding RNAs, which have been found to play very important roles, and have the potential to serve as diagnostic markers during neuronal pathogenesis. In this study, we aimed to determine the roles of miR-99b-5p and miR-100-5p in Aß-induced neuronal pathologies. We detected the expression levels of miR-99b-5p and miR-100-5p in the brains of APPswe/PS1ΔE9 double-transgenic mice (APP/PS1 mice) at different age stages and found that both miRNAs were decreased at early stages while increased at late stages of APP/PS1 mice when compared with the age-matched wild type (WT) mice. Similar phenomenon was also observed in Aß-treated cultured cells. We also confirmed that mammalian target of rapamycin (mTOR) is one of the targets of miR-99b-5p/100-5p, which is consistent with previous studies in cancer. MiR-99b-5p/100-5p has been found to promote cell apoptosis with the Aß treatment. This effect may be induced via the mTOR pathway. In our study, we find both miR-99b-5p and miR-100-5p affect neuron survival by targeting mTOR. We also speculate that dynamic change of miR-99b-5p/100-5p levels during Aß-associated pathologies might be attributed to Aß-induced endoplasmic reticulum stress (ER stress), suggesting the potential role of the "ER stress-miRNAs-mTOR" axis in Aß-related AD pathogenesis.

Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice.

OBJECTIVE: Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. METHODS: Using behavioral, histological, and biochemical methods, outcomes of SP600125 treatment on neuropathology and cognitive deficits were studied in APPswe/PS1dE9 mice. RESULTS: Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, ß-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. INTERPRETATION: Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.

Genome-wide analysis of miRNA signature in the APPswe/PS1ΔE9 mouse model of alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia. One of the pathological hallmarks of AD is amyloid ß (Aß) deposition. MicroRNAs (miRNAs) are small non-coding RNAs whose expression levels change significantly during neuronal pathogenesis and may be used as diagnostic markers. Some miRNAs are important in AD development by targeting genes responsible for Aß metabolism. However, a systematic assessment of the miRNA expression profile induced by Aß-mediated neuronal pathogenesis is still lacking. In the present study, we examined miRNA expression profile by using the APPswe/PS1ΔE9 mouse model of AD. Two sibling pairs of mice were examined, showing 30 and 24 miRNAs with significantly altered expression levels from each paired control, respectively. Nine known miRNAs were common in both groups. Prediction of putative target genes and functional annotation implied that these altered miRNAs affect many target genes mainly involved in PI3K/Akt signaling pathway. This study provides a general profile of miRNAs regulated by Aß-associated signal pathways, which is helpful to understand the mechanism of Aß-induced neuronal dysfunction in AD development.

Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion.

BACKGROUND AND PURPOSE: Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion. EXPERIMENTAL APPROACH: We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses. KEY RESULTS: BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin. CONCLUSION AND IMPLICATIONS: Our results provide new insights into the pharmacological actions of rutin and suggest that rutin has multi-targeted therapeutical potential on cognitive deficits associated with conditions with chronic cerebral hypoperfusion such as vascular dementia and Alzheimer's disease.

Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion has been identified to be a risk factor for cognitive decline in aging, vascular dementia, and Alzheimer's disease. Substantial evidence has shown that chronic cerebral hypoperfusion may cause cognitive impairment, but the underlying neurobiological mechanism is poorly understood so far. In this study, we used a rat model of chronic cerebral hypoperfusion by permanent bilateral common carotid artery occlusion (BCCAO) to investigate the alterations of neuronal damage, glial activation oxidative stress and central cholinergic dysfunction, and their causal relationship with the cognitive deficits induced by chronic cerebral hypoperfusion. We found that BCCAO rats exhibited spatial learning and memory impairments and working memory dysfunction 12 weeks after BCCAO compared with sham-operated rats, simultaneously accompanied by significantly increased neuronal damage and glial cell activation in the cerebral cortex and hippocampus. Twelve weeks of BCCAO treatment in rats resulted in central cholinergic dysfunction and increased oxidative damage compared with sham-operated rats. Correlational analyses revealed that spatial learning and memory impairments and working memory dysfunction were significantly correlated with the measures of neuronal damage, central cholinergic dysfunction and oxidative damage in the cerebral cortex and hippocampus of rats with BCCAO. Moreover, the measures of neuronal damage and central cholinergic dysfunction were significantly correlated with the indexes of oxidative damage in rats with BCCAO. Collectively, this study provides novel evidence that neuronal damage and central cholinergic dysfunction is likely due to increased oxidative stress under the condition of chronic cerebral hypoperfusion. Furthermore, the results of the present study suggest that neuronal damage, central cholinergic dysfunction and oxidative damage in the brain following the reduction of cerebral blood flow could be involved in cognitive deficits induced by chronic cerebral hypoperfusion.

Extraocular muscle characteristics related to myasthenia gravis susceptibility.

BACKGROUND: The pathogenesis of extraocular muscle (EOM) weakness in myasthenia gravis might involve a mechanism specific to the EOM. The aim of this study was to investigate characteristics of the EOM related to its susceptibility to myasthenia gravis. METHODS: Female F344 rats and female Sprague-Dawley rats were assigned to experimental and control groups. The experimental group received injection with Ringer solution containing monoclonal antibody against the acetylcholine receptor (AChR), mAb35 (0.25 mg/kg), to induce experimental autoimmune myasthenia gravis, and the control group received injection with Ringer solution alone. Three muscles were analyzed: EOM, diaphragm, and tibialis anterior. Tissues were examined by light microscopy, fluorescence histochemistry, and transmission electron microscopy. Western blot analysis was used to assess marker expression and ELISA analysis was used to quantify creatine kinase levels. Microarray assay was conducted to detect differentially expressed genes. RESULTS: In the experimental group, the EOM showed a simpler neuromuscular junction (NMJ) structure compared to the other muscles; the NMJ had fewer synaptic folds, showed a lesser amount of AChR, and the endplate was wider compared to the other muscles. Results of microarray assay showed differential expression of 54 genes in the EOM between the experimental and control groups. CONCLUSION: Various EOM characteristics appear to be related to the increased susceptibility of the EOM and the mechanism of EOM weakness in myasthenia gravis.

S14G-humanin inhibits Aß1-42 fibril formation, disaggregates preformed fibrils, and protects against Aß-induced cytotoxicity in vitro.

The aggregation of soluble amyloid-beta (Aß) peptide into oligomers/fibrils is one of the key pathological features in Alzheimer's disease (AD). The Aß aggregates are considered to play a pivotal role in the pathogenesis of AD. Therefore, inhibiting Aß aggregation and destabilizing preformed Aß fibrils would be an attractive therapeutic target for prevention and treatment of AD. S14G-humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to be a strong neuroprotective agent against various AD-related insults. Recent studies have shown that HNG can significantly improve cognitive deficits and reduce insoluble Aß levels as well as amyloid plaque burden without affecting amyloid precursor protein processing and Aß production in transgenic AD models. However, the potential mechanisms by which HNG reduces Aß-related pathology in vivo remain obscure. In the present study, we found that HNG could significantly inhibit monomeric Aß1-42 aggregation into fibrils and destabilize preformed Aß1-42 fibrils in a concentration-dependent manner by Thioflavin T fluorescence assay. In transmission electron microscope study, we observed that HNG was effective in inhibiting Aß1-42 fibril formation and disrupting preformed Aß1-42 fibrils, exhibiting various types of amorphous aggregates without identifiable Aß fibrils. Furthermore, HNG-treated monomeric or fibrillar Aß1-42 was found to significantly reduce Aß1-42-mediated cytotoxic effects on PC12 cells in a dose-dependent manner by MTT assay. Collectively, our results demonstrate for the first time that HNG not only inhibits Aß1-42 fibril formation but also disaggregates preformed Aß1-42 fibrils, which provides the novel evidence that HNG may have anti-Aß aggregation and fibrillogenesis, and fibril-destabilizing properties. Together with previous studies, we concluded that HNG may have promising therapeutic potential as a multitarget agent for the prevention and/or treatment of AD.

Protective effect of scFv-DAF fusion protein on the complement attack to acetylcholine receptor: a possible option for treatment of myasthenia gravis.

INTRODUCTION: Autoantibody-induced complement activation, which causes disruption of the postsynaptic membrane, is recognized as a key pathogenic factor in myasthenia gravis (MG). Therefore, specific targeting of complement inhibitors to the site of complement activation is a potential therapeutic strategy for treatment of MG. METHODS: We assessed expression of single-chain antibody fragment-decay accelerating factor (scFv-DAF), comprising a single-chain fragment scFv1956 based on the rat complement inhibitor DAF in prokaryotic systems, and studied its inhibitory effect on complement deposition in vitro. RESULTS: The recombinant conjugate scFv-DAF completely retained the wild-type binding activity of scFv1956 to AChR and inhibited complement activation of DAF in vitro. CONCLUSIONS: We found that scFv-DAF could bind specifically to TE671 cells, and it is significantly more potent at inhibiting complement deposition than the untargeted parent molecule DAF. scFv-DAF may be a candidate for in vivo protection of the AChR in MG.

Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: involvement of oxidative stress and cholinergic dysfunction.

A large body of evidence has shown that cognitive deficits occur early, before amyloid plaque deposition, suggesting that soluble amyloid-ß protein (Aß) contributes to the development of early cognitive dysfunction in Alzheimer disease (AD). However, the underlying mechanism(s) through which soluble Aß exerts its neurotoxicity responsible for cognitive dysfunction in the early stage of AD remains unclear so far. In this study, we used preplaque APPswe/PS1dE9 mice ages 2.5 and 3.5 months to examine alterations in cognitive function, oxidative stress, and cholinergic function. We found that only soluble Aß, not insoluble Aß, was detected in these preplaque APPswe/PS1dE9 mice. APPswe/PS1dE9 mice 2.5 months of age did not show any significant changes in the measures of cognitive function, oxidative stress, and cholinergic function, whereas 3.5-month-old APPswe/PS1dE9 mice exhibited spatial memory impairment in the Morris water maze, accompanied by significantly decreased acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) as well as increased malondialdehyde (MDA) and protein carbonyls. In 3.5-month-old preplaque APPswe/PS1dE9 mice, correlational analyses revealed that the performance of impaired spatial memory was inversely correlated with soluble Aß, MDA, and protein carbonyls, as well as being positively correlated with ACh, ChAT, SOD, and GSH-px; soluble Aß level was inversely correlated with ACh, ChAT, SOD, and GSH-px, as well as being positively correlated with MDA and protein carbonyls; ACh level showed a significant positive correlation with ChAT, SOD, and GSH-px, as well as a significant inverse correlation with MDA and protein carbonyls. Collectively, this study provides direct evidence that increased oxidative damage and cholinergic dysfunction may be early pathological responses to soluble Aß and involved in early memory deficits in the preplaque stage of AD. These findings suggest that early antioxidant therapy and improving cholinergic function may be a promising strategy to prevent or delay the onset and progression of AD.

Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice.

Increased accumulation of amyloid-beta peptide (Aß) and neuroinflammation is known to exist within the Alzheimer's disease (AD) brain. However, it remains unclear which form of Aß pathologies triggers neuroinflammation and whether increased neuroinflammation contributes to cognitive deficits in AD. In the present study we found that increased inflammatory responses might occur early in preplaque APPswe/PS1dE9 mice, and were significantly enhanced in both early- and late-plaque APPswe/PS1dE9 mice. Correlational analysis revealed that multiple inflammatory indexes significantly correlated with soluble Aß level, rather than amyloid plaque burden or insoluble Aß level, in APPswe/PS1dE9 mice. Moreover, multiple inflammatory indexes highly correlated with the impaired spatial learning and memory in APPswe/PS1dE9 mice. Collectively, these results provide evidence that inflammatory responses might be likely triggered by soluble toxic Aß species. Importantly, we demonstrate for the first time that multiple inflammatory pathways might be involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice, suggesting that a pharmacological approach targeting multiple inflammatory pathways may be a novel promising strategy to prevent or delay AD.

S14G-humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical cognitive decline and pathological deposition of amyloid-beta protein (Aß) in the brain. So far, there has been no causative therapy for this devastating disease. S14G-Humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to have strong neuroprotective ability against AD-related insults in vitro and prevent cognitive impairments in Aß-infused animal models. In addition, a recent study has reported a beneficial effect of intranasal HNG treatment on memory deficit and Aß accumulation in triple transgenic (3xTg-AD) mice at the early plaque-bearing stage. However, whether HNG treatment has the disease-modifying efficacy on AD with pre-existing well-established amyloid plaque pathology remains unclear. In this study, we employed 9-month-old APPswe/PS1dE9 mice with pre-existing robust amyloid plaque pathology to investigate the effects of chronic HNG treatment on the progression of cognitive dysfunction and Aß-associated neuropathology. We found that vehicle-treated APPswe/PS1dE9 mice showed impaired spatial learning and memory compared with vehicle- and HNG-treated wild-type mice, while intraperitoneal HNG treatment for 3 months significantly improved spatial learning and memory deficits in APPswe/PS1dE9 mice compared with vehicle control treatment. Coincidental with this, HNG treatment significantly reduced cerebral Aß plaque deposition, insoluble Aß levels, and neuroinflammatory responses in APPswe/PS1dE9 mice compared with control treatment. Cumulatively, these findings demonstrate that chronic administration of HNG is able to attenuate cognitive deficits and reduce Aß loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial Aß neuropathology, indicating that HNG has potential as a pharmacotherapeutic intervention in the development of cognitive deficits and neuropathology seen in the cases of established AD.

Soluble Aß levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease.

Amyloid-beta peptide (Aß) is believed to be central in the pathogenesis of Alzheimer's disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of Aß pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aß pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble Aß1-40 and Aß1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aß1-40 and Aß1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total Aß plaque load and fibrillar Aß plaque load), total Aß levels (Aß1-40 and Aß1-42), as well as insoluble Aß levels (Aß1-40 and Aß1-42). Stepwise multiple regression analysis identified hippocampal soluble Aß1-40 and Aß1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aß1-40 and Aß1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble Aß in middle-aged APPswe/PS1dE9 mice, in which soluble Aß levels are only a tiny fraction of the amount of total Aß levels. Consequently, our findings provide further evidence that soluble Aß might primarily contribute to cognitive deficits in AD, suggesting that reducing the levels of soluble Aß species would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble Aß.

NREM-AHI greater than REM-AHI versus REM-AHI greater than NREM-AHI in patients with obstructive sleep apnea: clinical and polysomnographic features.

PURPOSE: Previous studies show a high prevalence of obstructive sleep apnea (OSA) patients with a higher non-rapid eye movement (NREM) apnea-hypopnea index (AHI) (NREM-AHI) than rapid eye movement (REM) AHI (REM-AHI). However, the clinical significance of this phenomenon in patients with OSA is unknown. This study aimed to investigate whether there were significant differences in clinical and polysomnographic features between the NREM-AHI > REM-AHI group and the REM-AHI > NREM-AHI group and to determine whether NREM-AHI > REM-AHI or REM-AHI > NREM-AHI is a specific clinical entity. METHODS: One hundred forty-two patients with OSA, including 114 males and 28 females, were assessed for specific sleep-related complaints using a semistructured clinical questionnaire, for daytime sleepiness using the Epworth Sleepiness Scale (ESS), for depression using the Beck Depression Inventory (BDI), and for health-related quality of life using the Medical Outcomes Study Short-Form 36 Health Survey questionnaire (SF-36). Anthropometric, clinical, and polysomnographic characteristics were examined between patients with NREM-AHI > REM-AHI and those with REM-AHI > NREM-AHI. RESULTS: A higher NREM-AHI than REM-AHI was found in 54.9% of the 142 patients with OSA. Overall, males predominated in each group, and there were no significant differences in age, body mass index, medical history, and drug intake between the NREM-AHI > REM-AHI group and the REM-AHI > NREM-AHI group. A high occurrence of NREM-AHI > REM-AHI (94.9%) or REM-AHI > NREM-AHI (90.6%) was found in moderate-to-severe cases each group. Although several indexes of OSA were worse in the NREM-AHI > REM-AHI group than in the REM-AHI > NREM-AHI group, no significant differences in specific sleep-related complaints, ESS score, BDI score, the incidence of daytime sleepiness or depression, and scores of sub-dimensions and the total score on SF-36 were present between the two groups. As compared separately, no significant differences in clinical features were observed in the clinical data for males and females between the two groups. CONCLUSIONS: Our results show that either NREM-AHI > REM-AHI or REM-AHI > NREM-AHI is more common in moderate-to-severe OSA cases, and there are no significant differences in clinical features between the NREM-AHI > REM-AHI group and the REM-AHI > NREM-AHI group. These findings may suggest that either NREM-AHI > REM-AHI or REM-AHI > NREM-AHI should be considered as a part of the spectrum of OSA, rather than a specific clinical entity.

[Clinical manifestations and neuroimaging characteristics of children with moyamoya disease].

OBJECTIVE: To study the clinical manifestations and neuroimaging characteristics of pediatric moyamoya disease. METHODS: The clinical data of 17 children with moyamoya disease were retrospectively studied. RESULTS: The onset age was between 3 and 14 years. The main clinical manifestations included motor weakness of extremities or hemiplegia, sensory disturbance and headache. Cranial CT or/and MRI examinations predominately showed cerebral infarct. Magnetic resonance angiography (MRA) and digital subtraction angiography (DSA) showed stenosis or occlusion at the terminus of the siphon portions of internal carotid arteries and proximal portions of anterior or middle cerebral arteries, and abnormal vascular networks at the base of brain. CONCLUSIONS: Cerebral ischemia is main clinical manifestations in children with moyamoya disease, presenting motor weakness of extremities or hemiplegia, sensory disturbance and headache. DSA is essential to the diagnosis of the disease.