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.

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.

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.

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.

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.

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.

Association of early-onset Alzheimer's disease with germline-generated high affinity self-antigen load.

Self-antigen presentation outside the central nervous system has crucial role regarding self-proteins tolerance and autoimmunity, leading to neuroinflammation. Self-antigen with strong-binding affinity is considered to be pathogenic. We aim to investigate whether strong-binding affinity self-antigen load is associated with early/late-onset Alzheimer's disease (AD). A total of 54 AD samples (22 early-onset, 32 late-onset) underwent next-generation sequencing (NGS) for whole-exome sequencing. Genotypes of HLA class I genes and germline mutations were obtained for estimation of the binding affinity and number of self-antigens. For each patient, self-antigen load was estimated by adding up the number of self-antigens with strong-binding affinity. Self-antigen load of early-onset AD was significantly higher than late-onset AD (mean ± SD: 6115 ± 2430 vs 4373 ± 2492; p = 0.011). An appropriate cutoff value 2503 for dichotomizing self-antigen load was obtained by receiver operating characteristic (ROC) curve analysis. Patients were then dichotomized into high or low self-antigen load groups in the binary multivariate logistic regression analysis. Adjusted odds ratio of the high self-antigen load (>2503) was 14.22 (95% CI, 1.22-165.70; p = 0.034) after controlling other covariates including gender, education, ApoE status, and baseline CDR score. This is the first study using NGS to investigate germline mutations generated self-antigen load in AD. As strong-binding affinity self-antigen is considered to be pathogenic in neuroinflammation, our finding indicated that self-antigen load did have a role in the pathogenesis of AD owing to its association with neuroinflammation. This finding may also contribute to further research regarding disease mechanism and development of novel biomarkers or treatment.

Immunoregulatory effects of very low density lipoprotein from healthy individuals and metabolic syndrome patients on glial cells.

Epidemiological studies have reported that elderly patients with metabolic syndrome (MetS) are significantly more likely to develop neuronal degenerative diseases than those without MetS. Our previous study showed that patients with MetS had significantly higher levels of negatively charged very low density lipoproteins (VLDLs) in the plasma than healthy controls. Highly electronegative VLDL is a key risk factor for endothelial dysfunction and atrial fibrillation. However, the impact of negatively charged VLDL in brain immunity remains unclear. In this study, VLDLs were isolated from normal healthy (nVLDL) individuals or patients with MetS (metVLDL). Primary astroglia and microglia mixed cell cultures as well as microglial-enriched cultures were used to test the effects of VLDLs. Microglia/astroglia activation as evidenced by their morphological changes and production of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2), were assessed by immunofluorescence staining and ELISA, respectively. Our results showed that metVLDLs mainly act on the microglia, and not the astroglia, with low concentration (0.05-0.5 µg/mL) inducing cell morphological changes and decreased cellular processes in the microglia. However, nVLDL treatment at these concentrations had no effects on microglia and astroglia. Most importantly, TNF-α and PGE2 levels significantly increased in the microglia treated with metVLDL via a dose-dependent manner. Together, our data indicate that metVLDLs can contribute to MetS-associated brain disorders through microglia activation and neuroinflammation.

Compensatory Neural Recruitment for Error-Related Cerebral Activity in Patients with Moderate-To-Severe Obstructive Sleep Apnea.

(1) Background: Although it is known that obstructive sleep apnea (OSA) impairs action-monitoring function, there is only limited information regarding the associated cerebral substrate underlying this phenomenon. (2) Methods: The modified Flanker task, error-related event-related potentials (ERPs), namely, error-related negativity (ERN) and error positivity (Pe), and functional magnetic resonance imaging (fMRI) were used to evaluate neural activities and the functional connectivity underlying action-monitoring dysfunction in patients with different severities of OSA. (3) Results: A total of 14 control (Cont) subjects, 17 patients with moderate OSA (mOSA), and 10 patients with severe OSA (sOSA) were enrolled. A significant decline in posterror correction rate was observed in the modified Flanker task when patients with mOSA were compared with Cont subjects. Comparison between patients with mOSA and sOSA did not reveal any significant difference. In the analysis of ERPs, ERN and Pe exhibited declined amplitudes in patients with mOSA compared with Cont subjects, which were found to increase in patients with sOSA. Results of fMRI revealed a decreased correlation in multiple anterior cingulate cortex functional-connected areas in patients with mOSA compared with Cont subjects. However, these areas appeared to be reconnected in patients with sOSA. (4) Conclusions: The behavioral, neurophysiological, and functional image findings obtained in this study suggest that mOSA leads to action-monitoring dysfunction; however, compensatory neural recruitment might have contributed to the maintenance of the action-monitoring function in patients with sOSA.

A 48-Week, Multicenter, Open-Label, Observational Study Evaluating Oral Rivastigmine in Patients with Mild-to-Moderate Alzheimer's Disease in Taiwan.

INTRODUCTION: Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer's type. This study assessed the short- and long-term effectiveness and safety of rivastigmine in patients with mild-to-moderate Alzheimer's disease (AD) in a real-world clinical setting in Taiwan. METHODS: This was a 48-week, single-arm, open-label, prospective, observational, post-marketing surveillance, multicenter study. The primary outcomes were change from baseline to week 48 in the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scores. One-year persistence to treatment, effect on activities of daily living, and incidence of adverse events (AEs) were also assessed. RESULTS: Overall, 151 patients were enrolled in the study, of which 91 (60.26%) completed this study. At the end of the study, the mean rivastigmine dose received by the patients was 6.59 mg/day. At week 48, the changes in mean [standard deviation (SD)] MMSE and CDR scores in the intent-to-treat (ITT) population from baseline were - 1.00 (3.8; p = 0.0344) and 0.07 (0.29; p = 0.0403), respectively. The most frequently reported AEs by preferred term were dizziness (12.58%) and nausea (9.27%). No new or unexpected AEs were observed, and 30 (20.13%) patients in the ITT population were on rivastigmine therapy for 1 year without treatment discontinuation. CONCLUSION: Despite the low 1-year persistence rate, rivastigmine showed a stabilizing effect on declining cognition in patients with mild-to-moderate AD in a real-world scenario. Rivastigmine is well tolerated at 6.0-9.0 mg/day with no unexpected safety concerns. FUNDING: Novartis Co. Ltd., Taipei, Taiwan.

REST rs3796529 Genotype and Rate of Functional Deterioration in Alzheimer's Disease.

Recently, REST (RE1-silencing transcription factor) gene has been shown to be lost in Alzheimer's disease (AD), and a missense minor REST allele rs3796529-T has been shown to reduce the rate of hippocampal volume loss. However, whether the REST rs3796529 genotype is associated with the rate of functional deterioration in AD is unknown. A total of 584 blood samples from Taiwanese patients with AD were collected from January 2002 to December 2013. The diagnosis of AD was based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. The allele frequency of rs3796529-T was compared between the AD cohort and 993 individuals from the general population in Taiwan. Kaplan-Meier analysis, the log rank test and a multivariate Cox model were then used to evaluate the association between rs3796529-T and functional deterioration in the AD cohort. The allele frequency of rs3796529-T was significantly lower in the AD cohort compared to the general population cohort (36.82% vs. 40.73%, p=0.029). Kaplan-Meier analysis and the log rank test showed that the AD patients carrying the rs3796529 T/T genotype had a longer progression-free survival than those with the C/C genotype (p=0.012). In multivariate analysis, the rs3796529 T/T genotype (adjusted HR=0.593, 95% CI: 0.401-0.877, p=0.009) was an independent protective factor for functional deterioration. The rs3796529 T/T genotype was associated with slower functional deterioration in patients with AD. This finding may lead to a to better understanding of the molecular pathways involved, and prompt further development of novel biomarkers to monitor AD.

Acute glucose fluctuation impacts microglial activity, leading to inflammatory activation or self-degradation.

Diabetes mellitus is associated with an increased risk of Alzheimer's dementia and cognitive decline. The cause of neurodegeneration in chronic diabetic patients remains unclear. Changes in brain microglial activity due to glycemic fluctuations may be an etiological factor. Here, we examined the impact of acute ambient glucose fluctuations on BV-2 microglial activity. Biochemical parameters were assayed and showed that the shift from normal glucose (NG; 5.5 mM) to high glucose (HG; 25 mM) promoted cell growth and induced oxidative/inflammatory stress and microglial activation, as evidenced by increased MTT reduction, elevated pro-inflammatory factor secretion (i.e., TNF-α and oxygen free radicals), and upregulated expression of stress/inflammatory proteins (i.e., HSP70, HO-1, iNOS, and COX-2). Also, LPS-induced inflammation was enlarged by an NG-to-HG shift. In contrast, the HG-to-NG shift trapped microglia in a state of metabolic stress, which led to apoptosis and autophagy, as evidenced by decreased Bcl-2 and increased cleaved caspase-3, TUNEL staining, and LC3B-II expression. These stress episodes were primarily mediated through MAPKs, PI3K/Akt, and NF-κB cascades. Our study demonstrates that acute glucose fluctuation forms the stress that alters microglial activity (e.g., inflammatory activation or self-degradation), representing a novel pathogenic mechanism for the continued deterioration of neurological function in diabetic patients.

Association of hyperglycemia episodes on long-term mortality in type 2 diabetes mellitus with vascular dementia: A population-based cohort study.

AIM: This study investigated the effect of severe hyperglycemia episodes on survival and associated factors related to risk of mortality in type 2 diabetes mellitus (DM) patients with dementia. METHODS: We enrolled all type 2 DM patients newly diagnosed as having dementia in Taiwan from 1998 to 2005. These patients were categorized into those who had hyperglycemia episodes and those who did not based on whether or not they had been hospitalized for hyperglycemia after dementia diagnosis. Factors independently associated with mortality were evaluated. RESULTS: Of 5314 patients identified, 303 (5.7%) had at least one hyperglycemia hospitalization. Patients with at least one hyperglycemia hospitalization had a 30% greater risk of mortality than those who had no such admissions (adjusted hazard ratio: 1.30, 95% confidence interval: 1.09-1.55). Other variables, including age, sex, geographical region, insurance amount, patient with congestive heart failure, cerebrovascular disease, renal disease, use of anti-hypertensive drugs, use of anti-lipid drugs, and use of insulin were independently associated with risk of mortality. CONCLUSION: Severe hyperglycemia is common in type 2 DM patients with dementia and it substantially shortens their life. The findings of this study suggest a great need to improve care in DM patients with dementia.

Seroprevalence of dengue virus in two districts of Kaohsiung City after the largest dengue outbreak in Taiwan since World War II.

Dengue virus (DENV) is the leading cause of arboviral diseases in humans worldwide. In this study, we investigated the seroprevalence of DENV infection in two districts of Kaohsiung City, a metropolis in southern Taiwan, where major dengue outbreaks have occurred in the past three decades. We enrolled 1,088 participants from the Sanmin and Nanzih districts after the dengue outbreak of 2015, the largest in Taiwan since World War II, and found an overall DENV seroprevalence of 12.4% (95% confidence interval: 10.5-13.4%) based on the InBios DENV IgG ELISA kit. The ratios of clinically inapparent to symptomatic infections were 2.86 and 4.76 in Sanmin and Nanzih districts, respectively. Consistent with higher case numbers during recent outbreaks, the DENV seroprevalence was higher in Sanmin district (16.4%) than in Nanzih district (6.9%), suggesting district differences in seroprevalence and highlighting the importance of screening the DENV immune status of each individual before using the currently available DENV vaccine, Dengvaxia. In the two districts, the seroprevalence rates increased from 2.1% (in the 30-39-year age group) to 17.1% (60-69) and 50% (70-79). The pattern of a sharp and significant increase in seroprevalence in the 70-79-year age group correlated with a dramatic increase in the proportion of clinically severe DENV infections among total dengue cases in that age group. This differed from observations in the Americas and Southeast Asia and suggested that a large proportion of monotypically immune individuals together with other risk factors may contribute to clinically severe dengue among the elderly in Taiwan.

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.

Differences in the frequency of Alzheimer's disease-associated genomic variations in populations of different races.

AIM: The general genetic background is important when studying major common diseases, such as Alzheimer's disease (AD). Determining the underlying genetic factors in populations of different races might allow for the tailored management of such diseases. The aim of the present study was to identify potential single-nucleotide polymorphisms (SNP) and genes associated with racial differences. METHODS: We identified AD-associated SNP with different carrier frequencies among races through the National Human Genome Research Institute and 1000 Genome Project databases. We generated heatmaps and carried out principle component analysis and pathway analysis. A total of 99 AD-associated SNP from genome-wide association studies were found to have different frequencies among races. Principle component analysis showed that specific SNP had higher or lower frequencies in specific races, and that similar races were clustered together. RESULTS: Pathway analysis showed that a total of 15 pathways involving intracellular endocytosis, inflammation, immune response and lipid metabolism were significant, and that apolipoprotein E was involved in the most significant pathways. A literature review showed that 16 genes were involved in the pathogenesis of AD, and that the identified SNP could be used to cluster different races, suggesting that these SNP represented different genomic backgrounds of races. CONCLUSIONS: As disease-associated genes might have several functional variants across different populations, these genes could be candidates for further studies, such as target gene sequencing or functional follow up of putative loci regarding racial differences. Geriatr Gerontol Int 2017; 17: 2184-2193.

Sensitivity and specificity of executive function tests for Alzheimer's disease.

Decline in executive function (EF) occurs early in Alzheimer's disease (AD) and can interfere with daily functioning. Unfortunately, little is known about the relative ability of traditional EF tests to detect these cognitive changes. Given that timely diagnosis and intervention are essential to improving functional outcome in this population, our aim was to identify the specific EF measures that best differentiated mild dementia from normal aging. Thirty-one patients with mild AD and 31 controls were administered 7 EF tests. Findings indicated significant between-group differences on all measures except Wisconsin Card Sorting Test. The remaining 6 tests displayed fair to good accuracy discriminating between AD cases and controls. Only category fluency and Tower of London test remained in the final regression model that yielded the highest AUC of 0.90, which was not statistically different from that of either test alone. Overall, most of the tests employed were valid for assessing mild EF disturbances. Specifically, the two measures can be used in isolation for quick screening or in combination to facilitate a more in-depth evaluation of EF performance. This study contributes to clinical field by testifying to the validity of various EF tests to identify AD-related compromises in this cognitive domain.

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.