The association of changes of sleep architecture related to donepezil: A systematic review and meta-analysis.

BACKGROUND: Donepezil had been recognized to have impact on sleep quality in demented patients. However, there was insufficient evidences about the actual effect of donepezil in the sleep architectures. Our meta-analysis aimed to evaluate the changes of sleep architectures related to donepezil use. METHODS: Followed the PRISMA2020 and AMSTAR2 guidelines, electronic search had been performed on the databases of PubMed, Embase, ScienceDirect, ClinicalKey, Cochrane CENTRAL, ProQuest, Web of Science, and ClinicalTrials.gov. The outcome measurement was changes of sleep parameters detected by polysomnography. A random-effects meta-analysis was conducted. RESULTS: Total twelve studies had been involved. The percentage of REM sleep would significantly increase after donepezil treatment (Hedges' g = 0.694, p < 0.001). Compared to placebo/controls, subjects with donepezil would had significantly increased percentage of REM sleep stage (Hedges' g = 0.556, p = 0.018). Furthermore, donepezil was also associated with the decreased stage 2 sleep percentage, sleep efficiency, or total sleep time in different analysis conditions. CONCLUSION: Our meta-analysis provided detailed changes of sleep architectures related to donepezil treatment. Further larger sample size studies with stricter control of potential moderators are needed to clarify these issues.

Clinical-based oral rehabilitation programme improved the oral diadochokinesis and swallowing function of older patients with dementia: A randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of a clinical-based oral function intervention on oral function and care behaviours in older patients with mild dementia. METHOD: Participants were randomly assigned to the experimental group (EG) and control group (CG). Both groups received a leaflet on oral health-related knowledge, and the EG also received an oral function intervention, which was a brief one-on-one lesson concerning oral exercise and preventive oral care. Oral exercise included turning the head, pouting lips, bulging cheeks, stretching tongue, articulation exercise and salivary gland massages. A reminder phone call was made every 2 weeks. Perceived xerostomia and dysphagia, plaque index (PI), Winkel tongue-coating index (WTCI), repetitive saliva-swallowing test (RSST), oral diadochokinesis (DDK) and oral care behaviours were recorded at baseline and at 3-month follow-up. Generalised Estimating Equations (GEE) were used to analyse the indicated effects. RESULTS: The EG (n = 59) exhibited greater improvement to the CG (n = 55) in RSST [ß = 0.7; effect size (ES) = 0.45], the syllables /pa/ (ß = 3.1; ES = 0.37) and /ka/ (ß = 2.7; ES = 0.40) in oral DDK, PI (ß = -0.2; ES = 0.52) and WTCI (ß = -0.8; ES = 0.38). Moreover, the EG exhibited better preventive behaviours in regular dental visits [adjusted odds ratio (aOR) = 2.2], daily mouth cleaning frequency (aOR = 1.6) and mouth cleaning before sleep (aOR = 1.3). CONCLUSION: The brief clinical-based intervention was effective in improving the swallowing function, oral DDK and plaque control of older patients with mild dementia at 3-month follow-up.

Factors associated with type 2 diabetes in patients with vascular dementia: a population-based cross-sectional study.

BACKGROUND: Incidence of dementia is growing rapidly and affects many people worldwide. Type 2 diabetes mellitus (DM) might link cognitive decline and dementia, but the reasons for this association remain unclear. Our study explored the factors associated with type 2 DM in patients with dementia. METHODS: Patients (n = 40,404) with vascular dementia were identified in Taiwan's 1997 to 2008 National Health Insurance Research Database and divided into a DM group and non-DM group. Eleven comorbidities were identified and categorized into four groups: cardiovascular and cerebrovascular diseases, digestive system diseases, renal and metabolic system diseases, and cancer. The associations of these factors with type 2 DM were explored through multivaraible logistic regression. RESULTS: Of the patients with dementia, 22.5% had DM. Associated with a higher likelihood of DM in this population were female sex (adjusted odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.36-1.52), young age (range of adjusted OR: 0.55-1.13), low income (range of adjusted OR: 1.09-1.18), and renal and metabolic system diseases (OR: 2.81, 95% CI: 2.64-2.98). CONCLUSIONS: The findings of this study suggest that clinicians should encourage patients with dementia to receive regular glucose impairment screening if they are female, have low socioeconomic status, or have renal or metabolic diseases.

Basal sympathetic predominance in periodic limb movements in sleep after continuous positive airway pressure.

PURPOSE: This study investigated the basal autonomic regulation in patients with obstructive sleep apnea (OSA) showing periodic limb movements in sleep (PLMS) emerging after therapy with continuous positive airway pressure (CPAP). METHODS: Data of patients with OSA undergoing a first polysomnography for diagnosis and a second polysomnography for therapy with CPAP were reviewed. Patients with OSA showing PLMS on the first polysomnography were excluded. By using heart rate variability analysis, epochs without any sleep events and continuous effects from the second polysomnography were retrospectively analyzed. RESULTS: Of 125 eligible patients, 30 with PLMS after therapy with CPAP (PLMS group) and 30 not showing PLMS on both polysomnography (non-PLMS group) were randomly selected for the analysis. No significant differences in the demographic characteristics and variables of polysomnographies were identified between the groups. Although one trend of low root mean square of successive differences (RMSSD) between intervals of adjacent normal heart beats (NN intervals) in the PLMS group was observed, patients in the PLMS group had significantly low normalized high-frequency (n-HF) and high-frequency (HF) values, but high normalized low frequency (n-LF) and high ratio of LF to HF (LF/HF ratio). After adjustment for confounding variables, PLMS on the second polysomnography was significantly associated with RMSSD (ß = - 6.7587, p = 0.0338), n-LF (ß = 0.0907, p = 0.0148), n-HF (ß = - 0.0895, p = 0.0163), log LF/HF ratio (ß = 0.4923, p = 0.0090), and log HF (ß = - 0.6134, p = 0.0199). CONCLUSIONS: Patients with OSA showing PLMS emerging after therapy with CPAP may have a basal sympathetic predominance with potential negative cardiovascular effects.

Statin therapy prevents the onset of Parkinson disease in patients with diabetes.

OBJECTIVE: We studied the association between the statin dosage and the risk of Parkinson disease (PD) in diabetic patients in Taiwan. METHODS: One million patients were randomly sampled from a National Health Insurance (NHI) database and followed from 2001 to 2008. Diabetic patients were screened by diagnosis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and statin dosage was determined according to the NHI pharmacy database. PD was diagnosed on the basis of ICD-9-CM codes and anti-Parkinson medication use. Statin users was classified by statin dose-duration-day > 28 and matched with nonusers of statins using a coarsened exact matching method. There were 50,432 patients, and half of them were statin users. We examined the risk of PD between statin users and nonusers of statins and further tested the trends of the relative risk between the statin dosage and PD. RESULTS: The PD incidence rate was lower in statin users than in nonusers of statins. The crude hazard ratio of PD incidence in statin users was 0.65 (95% confidence interval [CI] = 0.57-0.74) in females and 0.60 (95% CI = 0.51-0.69) in males compared with nonusers of statins. After Cox regression analysis, all statins except lovastatin exerted protective effects on PD incidence and had a significant dose-dependent trend. INTERPRETATION: In Taiwanese diabetic patients, the risk of PD is lower in statin users than in nonusers of statins. Statin users, except lovastatin users, are dose-dependently associated with a decreased incidence of PD compared with nonusers of statins. This finding provides a new indication for statin beyond lipid control and cardiovascular events in diabetic patients. Ann Neurol 2016;80:532-540.

Clinical implication of hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator.

To determine the clinical implications of hemorrhagic transformation (HT) after thrombolysis, 241 eligible patients receiving alteplase for acute ischemic stroke were studied. HT was classified, according to the European Cooperative Acute Stroke Study criteria, as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH). Symptomatic intracranial hemorrhage (SICH) was defined according to the National Institute of Neurological Disorders and Stroke study. A novel classification, clinically significant intracranial hemorrhage (CSICH) was defined as HTs associated with an unfavorable clinical outcome (modified Rankin Scale 5-6) at 3 months. For all subtypes of HT, we found that patients receiving alteplase were more often in the standard-dose group (0.90 ± 0.02 mg/kg) than in the lower dose group (0.72 ± 0.07 mg/kg). PH and SICH were related to an unfavorable clinical outcome, while HI was not. There was a positive trend between age and CSICH in patients receiving the standard dose (P = 0.0101), and between alteplase dose and CSICH in patients ≥70 years old (P = 0.0228). All PHs (including asymptomatic PHs) and symptomatic HIs have been found to be associated with unfavorable outcome, and for this reason defined as CSICH. Independent predictors of CSICH were age ≥70 years and the standard dose of alteplase. Further studies of thrombolysis for ischemic stroke with different doses of alteplase are warranted.

Basal sympathetic predominance in periodic limb movements in sleep with obstructive sleep apnea.

Because the impact of periodic limb movements in sleep (PLMS) is controversial, no consensus has been reached on the therapeutic strategy for PLMS in obstructive sleep apnea (OSA). To verify the hypothesis that PLMS is related to a negative impact on the cardiovascular system in OSA patients, this study investigated the basal autonomic regulation by heart rate variability (HRV) analysis. Sixty patients with mild-to-moderate OSA who underwent polysomnography (PSG) and completed sleep questionnaires were analysed retrospectively and divided into the PLMS group (n = 30) and the non-PLMS group (n = 30). Epochs without any sleep events or continuous effects were evaluated using HRV analysis. No significant difference was observed in the demographic data, PSG parameters or sleep questionnaires between the PLMS and non-PLMS groups, except for age. Patients in the PLMS group had significantly lower normalized high frequency (n-HF), high frequency (HF), square root of the mean of the sum of the squares of difference between adjacent NN intervals (RMSSD) and standard deviation of all normal to normal intervals index (SDNN-I), but had a higher normalized low frequency (n-LF) and LF/HF ratio. There was no significant difference in the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Short-Form 36 and the Hospital Anxiety and Depression Scale between the two groups. After adjustment for confounding variables, PLMS remained an independent predictor of n-LF (ß = 0.0901, P = 0.0081), LF/HF ratio (ß = 0.5351, P = 0.0361), RMSSD (ß = -20.1620, P = 0.0455) and n-HF (ß = -0.0886, P = 0.0134). In conclusion, PLMS is related independently to basal sympathetic predominance and has a potentially negative impact on the cardiovascular system of OSA patients.

More severe hypoxemia is associated with better subjective sleep quality in obstructive sleep apnea.

BACKGROUND: Perceived sleep quality may play an important role in diagnosis and therapy for obstructive sleep apnea (OSA). However, few studies have assessed factors that are associated with perceived sleep quality in OSA patients. Hypoxemia depresses the central nervous system and attenuates the perceived respiratory load in asthmatic patients. This study aimed to investigate the factors related to perceived sleep quality, focusing on the role of hypoxemia. METHODS: Polysomnography studies of 156 OSA patients were reviewed. Traditional polysomnographic parameters, including parameters of oxy-hemoglobin saturation (SpO2), were calculated, and the sleep questionnaire and scales were used. Considering the possible pitfalls of absolute values of SpO2 and individualized responses to hypoxemia, the amplitude of desaturation was further computed as "median SpO2 minus lowest 5 % SpO2 "and "highest 5 % SpO2 minus median 5 % SpO2". Correlations between these parameters and perceived sleep quality, represented as the Pittsburgh sleep quality index (PSQI), were performed. Multiple linear regression analysis was also conducted to investigate the factors associated with the PSQI. RESULTS: Although the PSQI was not correlated with the apnea-hypopnea index (r = -0.113, p = 0.162) and oxygen desaturation index (r = -0.085, p = 0.291), the PSQI was negatively correlated with "median SpO2 minus lowest 5 % SpO2" (r = -0.161, p = 0.045). After adjusting for age, total sleep time, the periodic limb movements index, tendency of depression, and the lowest 5 % SpO2, the "median SpO2 minus lowest SpO2" was still a significant predictor for a lower PSQI (ß = -0.357, p = 0.015). CONCLUSIONS: More severe hypoxemia is associated with better perceived sleep quality among OSA patients. This paradox may be associated with hypoxemia-related impairment of perception. The effect of hypoxemia did not appear to be significant in relatively mild hypoxemia but become significant in severe hypoxemia." Median SpO2 minus lowest 5 % SpO2" may also be a better predictor of perceived sleep quality than the apnea-hypopnea index because of the disproportionate effects of hypoxemia. Additionally, further studies are necessary to confirm the role of hypoxemia on perceived sleep quality and identify the possible threshold of hypoxemia in OSA patients.

Different doses of recombinant tissue-type plasminogen activator for acute stroke in Chinese patients.

BACKGROUND AND PURPOSE: The relationship between the dose of recombinant tissue-type plasminogen activator (r-tPA) and its safety/efficacy for ischemic stroke has not been well evaluated in the East Asian population. We assessed the safety/efficacy of different doses of r-tPA for acute ischemic stroke in Chinese patients. METHODS: A total of 1004 eligible patients were classified according to the dose of r-tPA received for managing acute ischemic stroke: 0.9 mg/kg (n=422), 0.8 mg/kg (n=202), 0.7 mg/kg (n=199), and 0.6 mg/kg (n=181). The safety outcome was symptomatic intracerebral hemorrhage and death within 3 months. The efficacy outcome was good functional outcome (modified Rankin Scale ≤1) at 3 months. RESULTS: There was a significant trend for symptomatic intracerebral hemorrhage with age (P=0.002). With multivariate logistic regression analysis, a dose of 0.9 mg/kg was a predictor of symptomatic intracerebral hemorrhage (P=0.0109), and a dose ≤0.65 mg/kg was a predictor of good functional outcome (P=0.0369). In patients aged 71 to 80 years, there was a significant trend of increasing symptomatic intracerebral hemorrhage (P=0.0130) and less good functional outcome (P=0.0179) with increasing doses of r-tPA. There was also a trend of increasing mortality (P=0.0971) at 3 months in these patients. CONCLUSIONS: These results did not support the dose of 0.9 mg/kg of r-tPA being optimal for all patients in the East Asian population. In elderly patients (71-80 years), a lower dose of 0.6 mg/kg is associated with a better outcome. Confirmation of the results through randomized trial is required.

Rotating night shifts too quickly may cause anxiety and decreased attentional performance, and impact prolactin levels during the subsequent day: a case control study.

BACKGROUND: We investigated circadian changes and effects on mood, sleep-related hormones and cognitive performance when nurses worked consecutive night shifts in a rapidly rotating shift system. Daytime cognitive function, sleep propensity and sleep-related hormones (growth hormone, cortisol, prolactin, thyrotropin) were compared after participants worked two and four consecutive night shifts. METHODS: Twenty-three off-duty nurses, 20 nurses working two consecutive night shifts and 16 nurses working four consecutive night shifts were enrolled. All participants completed the Maintenance of Wakefulness Test, State-Trait Anxiety Inventory, Stanford Sleepiness Scale, visual attention tasks (VAT), Wisconsin Card Sorting Test, and modified Multiple Sleep Latency Test. Hormone levels were also measured four times throughout the day, at 2-h intervals. RESULTS: During the day, the participants in the night shift groups were less able to maintain wakefulness, had poor performance on VAT, and higher thyrotropin levels than did those in the off-duty group. Participants who worked two night shifts were better able to maintain wakefulness, had higher anxiety scale scores, poorer initial performance and lack of learning effect on VAT, and higher prolactin levels compared with those who worked four night shifts. There were no differences in cortisol levels between the two- and four- shift groups. CONCLUSIONS: Rotating night shifts too quickly may cause anxiety and decreased attentional performance, and may impact daytime prolactin levels after night shifts. It is possible that the two-shift group had a higher cortisol level than did the four-shift group, which would be consistent with the group's higher state anxiety scores. The negative findings may be due to the small sample size. Further studies on the effects of consecutive night shifts on mood and cortisol levels during the daytime after sleep restriction would be valuable.

Concentration of donepezil to the cognitive response in Alzheimer disease.

BACKGROUND: Donepezil has been approved, and higher dosages are recommended for the treatment of Alzheimer disease (AD). However, a few studies have reported different cognitive responses in patients with AD treated with donepezil without measuring the concentration. METHODS: We evaluated the relationships between the therapeutic responses and plasma concentrations of donepezil in various cognitive domains using the Cognitive Ability Screening Instrument among 37 patients with newly diagnosed mild stage AD taking donepezil 5 mg/d. RESULTS: Among the 9 cognitive domains in the Cognitive Ability Screening Instrument, the long-term memory domain had the highest improvement ratio (81.1%) compared with the other domains. An increased donepezil plasma concentration [mean (SD), 75.14 (32.16) ng/mL] was significantly associated with the improvement of long-term memory (P = 0.045; odds ratio, 0.959; 95% confidence interval, 0.920-0.999) after adjusting for age, sex, education, and apolipoprotein E genotype. CONCLUSIONS: Although there are some limitations in our study, these findings indicate that a higher concentration of donepezil improves long-term memory in patients with mild stage AD and imply the possible benefits in the advanced stage of AD for relatively preserved long-term memory.

Temporal changes of urinary oxidative metabolites of di(2-ethylhexyl)phthalate after the 2011 phthalate incident in Taiwanese children: findings of a six month follow-up.

A major incident involving phthalates-contaminated foodstuffs occurred in Taiwan in May 2011, leading to the quick removal of tainted food items from store shelves. We investigated changes in urinary oxidative di(2-ethylhexyl)phthalate (DEHP) metabolites, our proxy for exposure to DEHP-tainted foodstuffs in children ≤10 years, during the six months following withdrawal of the tainted food. Our hospital screened 60 possibly exposed children between May and June 2011. The children's food intake information was collected, and they were administered one-spot urine samples at baseline and at the two and six month follow-ups. All three samples were measured for four oxidative DEHP metabolites, mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), mono-(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP), and mono-(2-carboxymethylhexyl) phthalate (2cx-MMHP) by triple quadrupole liquid chromatography tandem mass spectrometry. Fifty-two children had been exposed. After excluding those without a full set of urine samples or adequate food intake information, 23 exposed children were studied. We found significantly positive correlations between DEHP daily intake and urinary 5OH-MEHP, 5oxo-MEHP, and 5cx-MEPP (p < 0.05). At the six month follow-up, all four metabolite concentrations had significantly decreased compared to the baseline. In conclusion, urinary DEHP metabolites decreased progressively in children after tainted food withdrawal, indicating that the main sources of phthalate contamination for children had been successfully controlled.

The Associations between Polysomnographic Parameters and Memory Impairment among Patients with Obstructive Sleep Apnea: A 10-Year Hospital-Based Longitudinal Study.

Obstructive sleep apnea (OSA) has been associated with cognitive decline via several mechanisms, including intermittent hypoxemia, sleep fragmentation, and neuroinflammation. The neurological consequences of OSA have evolved into a major biopsychosocial concern in the elderly, especially memory impairment. We aimed to identify the polysomnographic (PSG) parameters capable of predicting memory impairment among OSA patients at or over age 50 with OSA. We reviewed the 10-year electronic medical records of OSA patients and compared the initial PSG parameters between those presenting and not presenting self-reported memory impairment. We conducted subgroup analyses based on OSA severity and performed multivariate analysis to correlate PSG parameters with memory impairment. The result showed that 25 out of the 156 (16%) investigated patients experienced self-reported memory impairment during follow-up. As compared to OSA patients without self-reported memory impairment, those reported with self-reported memory impairment had a higher oxygen desaturation index (ODI) (23.9 ± 17.8 versus 18.2 ± 12.0, p = 0.048). Regarding the associations between apnea-hypopnea index (AHI) as well as ODI and self-reported memory impairment among OSA subgroups classified by severity, the associations were only evident in the severe OSA subgroup in both univariate (p < 0.001; p = 0.005) and multivariate analyses (p = 0.014; p = 0.018). We concluded that AHI and ODI are the most relevant PSG parameters in predicting memory impairment in severe OSA patients.

Lipids and lipoproteins may play a role in the neuropathology of Alzheimer's disease.

Alzheimer's disease (AD) and other classes of dementia are important public health problems with overwhelming social, physical, and financial effects for patients, society, and their families and caregivers. The pathophysiology of AD is poorly understood despite the extensive number of clinical and experimental studies. The brain's lipid-rich composition is linked to disturbances in lipid homeostasis, often associated with glucose and lipid abnormalities in various neurodegenerative diseases, including AD. Moreover, elevated low-density lipoprotein (LDL) cholesterol levels may be related to a higher probability of AD. Here, we hypothesize that lipids, and electronegative LDL (L5) in particular, may be involved in the pathophysiology of AD. Although changes in cholesterol, triglyceride, LDL, and glucose levels are seen in AD, the cause remains unknown. We believe that L5-the most electronegative subfraction of LDL-may be a crucial factor in understanding the involvement of lipids in AD pathology. LDL and L5 are internalized by cells through different receptors and mechanisms that trigger separate intracellular pathways. One of the receptors involved in L5 internalization, LOX-1, triggers apoptotic pathways. Aging is associated with dysregulation of lipid homeostasis, and it is believed that alterations in lipid metabolism contribute to the pathogenesis of AD. Proposed mechanisms of lipid dysregulation in AD include mitochondrial dysfunction, blood-brain barrier disease, neuronal signaling, inflammation, and oxidative stress, all of which lead ultimately to memory loss through deficiency of synaptic integration. Several lipid species and their receptors have essential functions in AD pathogenesis and may be potential biomarkers.

Apolipoprotein E polymorphism and behavioral and psychological symptoms of dementia in patients with Alzheimer disease.

The aims of this study were to identify subsyndromes of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer disease (AD), and to investigate whether the apolipoprotein E (ApoE) gene confers a risk of distinct BPSD subsyndromes. BPSD of 96 patients with AD were assessed using the Neuropsychiatric Inventory. Factor analysis with principal component analysis and varimax rotation was used to construct the BPSD subsyndromes. ApoE genotypes were determined using the TaqMan technology. The results showed that the 5 subsyndromes can be determined, including: agitation/aggression-delusion, euphoria-disinhibition, depression-apathy, hallucination-nighttime behavior, and appetite. ApoE ε4 carriers had higher factor scores in the agitation/aggression-delusion subsyndrome. We demonstrated that ApoE ε4 confers a higher risk for the subsyndrome of agitation/aggression delusion in AD.

Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase-Containing Neurons in the Brain of Middle-Aged Rats.

Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or a 45% high-fat diet (HFD) for 30 weeks (i.e., until 67 weeks of age). To study the effects of chronic dyslipidemia on the brain, we analyzed spontaneous locomotor activity, cognitive function, and brain tissues in both groups of rats after 30 weeks. Compared with age-matched rats fed a ND, Wistar-Kyoto rats fed a HFD had dyslipidemia and showed decreased movement but normal recognition of a novel object. In our brain analyses, we observed a significant decrease in astrocytes and tyrosine hydroxylase-containing neurons in the substantia nigra and locus coeruleus of rats fed a HFD compared with rats fed a ND. However, hippocampal pyramidal neurons were not affected. Our findings indicate that the long-term consumption of a HFD may cause lipid metabolism overload in the brain and damage to glial cells. The decrease in astrocytes may lead to reduced protection of the brain and affect the survival of tyrosine hydroxylase-containing neurons but not pyramidal neurons of the hippocampus.

Angiotensin-converting enzyme gene and plasma protein level in Alzheimer's disease in Taiwanese.

BACKGROUND: angiotensin-converting enzyme (ACE) gene insertion/deletion (indel) polymorphism is considered a biomarker for Alzheimer's disease (AD). However, the associations of ACE gene and protein level to AD are undetermined among Taiwanese. METHODS: this study investigated 257 Taiwanese cases with AD and 137 ethnically matched controls using ACE gene indel genotype association methods with logistic regression adjusted for other variables. Besides, 65 out of 257 AD patients, 11 with D/D genotype, 28 with I/I genotype and 26 with I/D genotype were recruited. Their plasma ACE protein levels were measured by enzyme-linked immuno-sorbent assay and compared for their corresponding ACE gene indel polymorphism. RESULTS: patients with ACE-I/I homozygote were less likely to be associated with AD, compared with both I/D and D/D (OR: 0.601; 95% CI: 0.372-0.969; P = 0.037), or only I/D genotype (OR: 0.584; 95% CI: 0.349-0.976; P = 0.040). There were significantly different plasma ACE protein levels among these three different genotype groups (P = 0.023). The I/I genotype group had significantly lower ACE plasma levels [114.79 ± 31.32 ng/ml (mean ± SD)], compared with D/D (164.07 ± 86.36 ng/ml; P = 0.010), but not I/D (141.45 ± 51.50 ng/ml; P = 0.064). CONCLUSION: ACE-I/I homozygote corresponds to lower plasma ACE protein level and it is independently but less likely to be associated with AD. These findings signal the importance of ACE indel polymorphisms to their corresponding protein levels and to AD.

Intermittent Hypoxia Activates N-Methyl-D-Aspartate Receptors to Induce Anxiety Behaviors in a Mouse Model of Sleep-Associated Apnea.

Sleep apnea disrupts physiologic homeostasis and causes neuronal dysfunction. In addition to signs of mental disorders and cognitive dysfunction, patients with sleep apnea have a higher anxiety rate. Here, we examined the mechanisms underlying this critical health issue. We used a mouse model with sleep-associated chronic intermittent hypoxia (IH) to verify the effects of sleep apnea on neuronal dysfunction. To evaluate how IH alters neuronal function to yield anxiety-like behavior and cognitive dysfunction, we examined synaptic plasticity and neuronal inflammation in related brain areas, including the medial prefrontal cortex (mPFC), striatum, and hippocampus. Mice subjected to chronic IH for 10 days exhibited significant anxiety-like behaviors in the elevated plus maze test. IH mice spent less travel time in open arms and more travel time in enclosed arms compared to control mice. However, cognitive impairment was minimal in IH mice. Increased glutamate N-methyl-D-aspartate (NMDA) receptor subunits 2B (GluN2B) and phosphorylated-ERK1/2 were seen in the mPFC, striatum, and hippocampus of IH mice, but no significant microglial and astrocyte activation was found in these brain areas. Chronic IH in mice induced compensatory increases in GluN2B to disturb neuronal synaptic plasticity, without neuronal inflammation. The altered synaptic plasticity subsequently led to anxiety-like behavior in mice. Treatment with the NMDA receptor antagonist dextromethorphan attenuated chronic IH-induced anxiety-like behavior and GluN2B expression. Our findings provide mechanistic evidence of how IH may provoke anxiety and support for the importance of early intervention to alleviate anxiety-associated complications in patients with chronic sleep apnea.

Electronegative very-low-density lipoprotein induces brain inflammation and cognitive dysfunction in mice.

Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of cognitive dysfunction. We previously showed that patients with metabolic syndrome (MetS) had significantly higher plasma levels of electronegative very-low-density lipoprotein (VLDL) than did healthy controls. However, the effects of electronegative-VLDL on the brain and cognitive function remain unclear. In this study, VLDL isolated from healthy volunteers (nVLDL) or patients with MetS (metVLDL) was administered to mice by means of tail vein injection. Cognitive function was assessed by using the Y maze test, and plasma and brain tissues were analyzed. We found that mice injected with metVLDL but not nVLDL exhibited significant hippocampus CA3 neuronal cell loss and cognitive dysfunction. In mice injected with nVLDL, we observed mild glial cell activation in the medial prefrontal cortex (mPFC) and hippocampus CA3. However, in mice injected with metVLDL, plasma and brain TNF-α and Aß-42 levels and glial cell activation in the mPFC and whole hippocampus were higher than those in control mice. In conclusion, long-term exposure to metVLDL induced levels of TNF-α, Aß-42, and glial cells in the brain, contributing to the progression of cognitive dysfunction. Our findings suggest that electronegative-VLDL levels may represent a new therapeutic target for cognitive dysfunction.

Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis.

BACKGROUND: The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis. METHODS: Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 +/- 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index > or = 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect. RESULTS: In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index > or = 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index > or = 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27). CONCLUSIONS: The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.