Alcohol and Metabolic-associated Fatty Liver Disease.

The diagnosis of metabolic-associated fatty liver disease is based on the detection of liver steatosis together with the presence of metabolic dysfunction. According to this new definition, the diagnosis of metabolic-associated fatty liver disease is independent of the amount of alcohol consumed. Actually, alcohol and its metabolites have various effects on metabolic-associated abnormalities during the process of alcohol metabolism. Studies have shown improved metabolic function in light to moderate alcohol drinkers. There are several studies focusing on the role of light to moderate alcohol intake on metabolic dysfunction. However, the results from studies are diverse, and the conclusions are often controversial. This review systematically discusses the effects of alcohol consumption, focusing on light to moderate alcohol consumption, obesity, lipid and glucose metabolism, and blood pressure.

Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-ß [Aß], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aß1 - 42 (p = 0.019) and Aß1 - 42/Aß1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aß1 - 42 (p = 0.009) and t-Tau/Aß1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

Metabolically healthy obesity and risk of stroke: a meta-analysis of prospective cohort studies.

BACKGROUND: Metabolic healthy obesity (MHO) is a unique subgroup of overweight and obese individuals with normal metabolic characteristics. Its association with the risk of stroke remains unclear. We aimed to examine the risk of stroke in MHO individuals and the further associations between stroke and metabolic abnormalities under different bodyweight conditions. METHODS: We systematically searched PubMed, Embase and Cochrane Library from December 1946 to January 2019, and only included prospective cohort studies. Random effects models were used to evaluate the pooled risk ratios (RR) and 95% confidence intervals (95% CI) of incident stroke. RESULTS: A total of eight studies comprising 4,256,888 participants were included in the meta-analysis. MHO individuals had an increased risk of stroke compared with metabolically healthy normal weight (MH-NW) individuals (RR =1.17, 95% CI: 1.11-1.23). However, the stroke risk of metabolically healthy overweight individuals was the same (RR =1.02, 95% CI: 0.84-1.23). All groups with unhealthy metabolism had a similarly elevated risk: normal weight (RR =1.83, 95% CI: 1.57-2.14), overweight (RR =1.93, 95% CI: 1.44-2.58), and obesity (RR =2.00, 95% CI: 1.40-2.87). CONCLUSIONS: The meta-analysis confirms a positive association between MHO phenotype and the risk of stroke. Individuals with metabolic abnormalities under different bodyweight conditions are at elevated risk.

Associations of the neutrophil to lymphocyte ratio with intracranial artery stenosis and ischemic stroke.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has emerged as an inflammatory marker. However, the associations of NLR with intracranial artery stenosis (ICAS) and ischemic stroke remain unclear. This study aimed to examine the associations of NLR with ICAS and ischemic stroke among a large and high-risk population. METHODS: Participants with records of clinical characteristics were prospectively recruited from the Neurology Department and Health & Physical Examination Center of Qingdao Municipal Hospital. Logistic regression analysis was used to examine the associations of NLR with ICAS and ischemic stroke. Moreover, we also conducted parametric mediation analysis to estimate the effect of NLR on the risk of ischemic stroke mediated through ICAS. RESULTS: A total of 2989 participants were enrolled in this study. After adjusting for covariates, NLR (OR = 1.125, 95%CI 1.070-1.183) and ICAS (OR = 1.638, 95%CI 1.364-1.967) were significantly associated with ischemic stroke. Compared with the first quartile NLR, the second, third and fourth quartiles NLR were independent risk predictors for ischemic stroke (P for trend < 0.001); the third and fourth quartiles were independent predictors for ICAS (P for trend < 0.001). The mediation analysis showed that ICAS partially mediated the association between NLR and ischemic stroke, accounting for 14.4% of the total effect (P < 0.001). CONCLUSIONS: NLR was significantly associated with ICAS and ischemic stroke. Besides, ICAS partially mediated the association between NLR and ischemic stroke.

Sleep Characteristics and Cerebrospinal Fluid Progranulin in Older Adults: The CABLE Study.

Cerebrospinal fluid (CSF) progranulin (PGRN) is related to various neurodegeneration diseases. And sleep problems can cause abnormality in protein metabolism in vivo. We aim to explore the potential associations between the self-reported sleep characteristics and CSF PGRN in cognitively intact older adults. Our study recruited 747 participants (mean (standard deviation (SD)) age, 61.99 (10.52) years, 329 (42.89%) females) who had normal cognition from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF PGRN and sleep characteristics measured. The multiple linear regression and nonlinear regression adjusted for age, gender, education, and apolipoprotein E-epsilon 4 gene (APOE4) status were used to assess the associations between sleep characteristics and PGRN. Interaction effects were explored between APOE4 status and sleep characteristics on CSF PGRN level. Sleep disturbances indicated lower CSF PGRN (ß = - 0.0186, p = 0.0160). For detailed items in sleep disturbances, lower CSF PGRN was found in males who woke up during sleep (ß = - 0.0121, p = 0.0062) and in females who had breathing difficulties (ß = - 0.0258, p = 0.0271). Meanwhile, sleep efficiency was associated with CSF PGRN (ß = - 0.0512, p = 0.0497). No significant interaction effects between sleep characteristics and APOE4 status were found. Meanwhile, we did not find a nonlinear relationship between nocturnal sleep duration and CSF PGRN. Sleep problems may influence the metabolism of PGRN, thus attenuating the protective effects of PGRN on neurodegeneration diseases.

High pulse pressure is a risk factor for prodromal Alzheimer's disease: a longitudinal study.

It has been increasingly evident that pulse pressure (PP) is associated with Alzheimer's disease (AD) but whether PP increases AD risk and the mechanism responsible for this association remains unclear. To investigate the effects of PP in the process of AD, we have evaluated the cross-sectional and longitudinal associations of PP with AD biomarkers, brain structure and cognition and have assessed the effect of PP on AD risk in a large sample (n= 1,375) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Multiple linear regression and mixed-model regression were employed in cross-sectional and longitudinal analyses respectively. Clinical disease progression was assessed using Cox proportional hazards models. High PP was associated with lower ß-amyloid 42 (Aß42) (P= .015), and higher total tau (T-tau) (P= .011), phosphorylated tau (P-tau) (P= .003), T-tau/Aß42 (P= .004) and P-tau/Aß42 (P = .001), as well as heavier cortical amyloid-beta burden (P= .011). Longitudinally, baseline high PP was significantly associated with hippocampal atrophy (P= .039), entorhinal atrophy (P= .031) and worse memory performance (P= .058). Baseline high PP showed more rapid progression than those with normal PP (P <.001). These results suggest PP elevation could increase AD risk, which may be driven by amyloid plaques and subclinical neurodegeneration.

Weight Loss is a Preclinical Signal of Cerebral Amyloid Deposition and Could Predict Cognitive Impairment in Elderly Adults.

BACKGROUND: Higher late-life body mass index (BMI) was associated with reduced risk of Alzheimer's disease (AD), which might be explained by a reverse causal relationship. OBJECTIVE: To investigate whether weight loss was a preclinical manifestation of AD pathologies and could be a predictor of cognitive impairment. METHODS: A total of 1,194 participants (mean age = 73.2 [range: 54 to 91] years, female = 44.5%) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped according to AD biomarker profile as indicated by amyloid (A) and tau (TN) status and clinical stage by clinical dementia rating (CDR). BMI across the biomarker-defined clinical stages was compared with Bonferroni correction. Pearson correlation analysis was performed to test the relationship between the amyloid change by PET and the BMI change. Multiple regression models were used to explore the influences of amyloid pathologies on BMI change as well as the effects of weight loss on longitudinal changes of global cognitive function. RESULTS: BMI was significantly decreased in AD preclinical stage (amyloid positive [A+] and CDR = 0) and dementia stage (A+/TN+ and CDR = 0.5 or 1), compared with the healthy controls (A-/TN-and CDR = 0, p < 0.005), while no significant differences were observed between preclinical AD and AD dementia. Amyloid PET change was inversely correlated with BMI change (p = 0.023, ß= -14). Individuals in amyloid positive group exhibited faster weight loss (time×group interaction p = 0.019, ß= -0.20) compared to the amyloid negative group. Greater weight loss predicted higher risk of developing cognitive disorders. CONCLUSION: Elders who experienced greater weight loss might belong to preclinical stage of AD and could be targeted for primary prevention of the disease.

A Systematic Review and Meta-analysis of the Therapeutic Effect of Acupuncture on Migraine.

Background: Migraine is an intractable headache disorder, manifesting as periodic attacks. It is highly burdensome for patients and society. Acupuncture treatment can be beneficial as a supplementary and preventive therapy for migraine. Objectives: This systematic review and meta-analysis aimed to investigate the efficacy and safety of acupuncture for migraine, and to examine transcranial doppler changes after acupuncture. Methods: Reports, conference, and academic papers published before March 15, 2019 in databases including PubMed, Cochrane library, Embase, China National Knowledge Infrastructure, WANFANG Database, Chinese journal of Science and Technology, and China Biomedical were searched. Randomized controlled trials (RCTs) involving acupuncture, sham acupuncture, and medication in migraine were included. The Cochrane Collaboration software, RevMan 5.3, was used for data processing and migration risk analysis. Results: Twenty-eight RCTs were included. 15 RCTs included medication only, 10 RCTs included sham acupuncture only, and 3 RCTs included both. The study included 2874 patients, split into 3 groups: acupuncture treatment group (n = 1396), medication control group (n = 865), and sham acupuncture control group (n = 613). The results showed that treatment was more effective in the acupuncture group than in the sham acupuncture group (MD = 1.88, 95% CI [1.61, 2.20], P < 0.00001) and medication group (MD = 1.16, 95% CI [1.12, 1.21], P < 0.00001). Improvement in visual analog scale (VAS) score was greater in the acupuncture group than in the sham acupuncture group (MD = -1.00, 95% CI [-1.27,-0.46], P < 0.00001; MD = -0.59, 95% CI [-0.81,-0.38], P < 0.00001), and their adverse reaction rate was lower than that of the medication group (RR = 0.16, 95% CI [0.05, 0.52], P = 0.002). The improvement of intracranial blood flow velocity by acupuncture is better than that by medication, but the heterogeneity makes the result unreliable. Conclusions: Acupuncture reduced the frequency of migraine attacks, lowered VAS scores, and increased therapeutic efficiency compared with sham acupuncture. Compared with medication, acupuncture showed higher effectiveness with less adverse reactions and improved intracranial blood circulation. However, owing to inter-study heterogeneity, a prospective, multicenter RCT with a large sample is required to verify these results.

Association of cerebrospinal fluid neurogranin levels with cognition and neurodegeneration in Alzheimer's disease.

Accumulating data suggest cerebrospinal fluid (CSF) neurogranin (Ng) as a potential biomarker for cognitive decline and neurodegeneration in Alzheimer disease (AD). To investigate whether the CSF Ng can be used for diagnosis, prognosis, and monitoring of AD, we examined 111 cognitively normal (CN) controls, 193 mild cognitive impairment (MCI) patients and 95 AD patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Correlations were tested between baseline CSF Ng levels and baseline core AD biomarkers and longitudinal glucose metabolism, brain atrophy and cognitive decline. We detected that CSF Ng levels increased with disease severity, and correlated with phosphorylated tau and total tau levels within each diagnostic group. High baseline CSF Ng levels correlated with longitudinal reductions in cortical glucose metabolism within each diagnostic group and hippocampal volume within MCI group during follow-up. In addition, high baseline CSF Ng levels correlated with cognitive decline as reflected by decreased cognitive scale scores. The CSF Ng levels predicted future cognitive impairment (adjusted hazard ratio:3.66, 95%CI: 1.74-7.70, P = 0.001) in CN controls. These data demonstrate that CSF Ng offers diagnostic utility for AD and predicts future cognitive impairment in CN individuals and, therefore, may be a useful addition to the current AD biomarkers.

Serum Uric Acid Levels and Risk of Intracranial Atherosclerotic Stenosis: A Cross-Sectional Study.

Elevated serum uric acid (SUA) has been reported to be associated with an increased risk of cardiovascular diseases, but the role of SUA in intracranial atherosclerosis remains unclear. To investigate the association between SUA and intracranial atherosclerotic stenosis (ICAS), we evaluated 1522 subjects (305 with ICAS, 1217 without ICAS) with magnetic resonance angiography (MRA). Subjects were classified into ten groups according to the deciles of the SUA level. The rate of ICAS reached a minimum in the seventh decile (6.0-6.3 mg/dL; reference group). After adjusting for confounding factors, multivariate logistic regression analysis demonstrated that both low SUA level (≤ 3.8 mg/dL; OR, 2.34; 95% CI, 1.29-4.39; p = 0.006) and high SUA level (≥ 7.8 mg/dL; OR, 2.10; 95% CI, 1.15-3.92; p = 0.017) conferred greater risk for ICAS. In multivariable analysis with a quadratic model which used SUA as a continuous variable, a U-shaped association between SUA and the rate of ICAS was confirmed (α > 0; p < 0.001). The estimated SUA level associated with the lowest rate of ICAS was 6.2 mg/dL. In conclusion, our findings suggest a U-shaped association between ICAS and SUA.

Late-life obesity is a protective factor for prodromal Alzheimer's disease: a longitudinal study.

Higher body mass index (BMI) in late-life has recently been considered as a possible protective factor for Alzheimer's disease (AD), which yet remains conflicting. To test this hypothesis, we have evaluated the cross-sectional and longitudinal associations of BMI categories with CSF biomarkers, brain ß-amyloid (Aß) load, brain structure, and cognition and have assessed the effect of late-life BMI on AD risk in a large sample (n = 1,212) of non-demented elderly from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. At baseline, higher late-life BMI categories were associated with higher levels of CSF Aß42 (p=0.037), lower levels of CSF total-tau (t-tau, p=0.026) and CSF t-tau/Aß42 (p=0.008), lower load of Aß in the right hippocampus (p=0.030), as well as larger volumes of hippocampus (p<0.0001), entorhinal cortex (p=0.009) and middle temporal lobe (p=0.040). But no association was found with CSF phosphorylated-tau (p-tau) or CSF p-tau/Aß42. Longitudinal studies showed that higher BMI individuals experienced a slower decline in cognitive function. In addition, Kaplan-Meier survival analysis revealed that higher late-life BMI had a reduced risk of progression to AD over time (p = 0.009). Higher BMI in late-life decreased the risk of AD, and this process may be driven by AD-related biomarkers.

Elevated Hs-CRP Levels Are Associated with Higher Risk of Intracranial Arterial Stenosis.

Correlation between the level of high-sensitivity C-reactive protein (hs-CRP) and the incidence of intracranial arterial stenosis (ICAS) is unclear. We aim to investigate the relationship between hs-CRP levels and ICAS. A total of 1458 patients aged ≥ 40 years were enrolled in this study. All the participants had a magnetic resonance angiography (MRA) examination for the evaluation of ICAS. Participants were classified into four groups according to stroke and ICAS. Multivariable logistic regression models were used to assess the relationship of hs-CRP levels and ICAS status. A total of 432 (29.63%) subjects had ICAS. The levels of hs-CRP in stroke group were significantly higher than those in non-stroke group (p < 0.001). Patients with ICAS tend to have higher hs-CRP levels (p < 0.001). In multivariate analysis, the fourth hs-CRP quartile had the strongest association with ICAS in both stroke group and non-stroke group (OR 2.512, 95% CI 1.651-3.853, p < 0.001 for stroke group, and OR 2.534, 95% CI 1.435-4.595, p = 0.002 for non-stroke group) among the four quartiles of hs-CRP levels. Our study suggests that elevated serum hs-CRP levels are associated with higher risk of ICAS, in both stroke patients and non-stroke participants.

Apolipoprotein B/AI ratio as an independent risk factor for intracranial atherosclerotic stenosis.

To investigate the relation of higher apolipoprotein B/apolipoprotein AI (apoB/AI) ratio with the risk of suffering intracranial atherosclerotic stenosis (ICAS) in both stroke and non-stroke population, we enrolled 1138 patients with acute ischemic stroke (359 with ICAS, 779 without ICAS) and 1072 non-stroke controls (239 with ICAS, 833 without ICAS) into the study. ICAS was defined as atherosclerotic stenosis >50% or the occlusion of the several main intracranial arteries. ApoB/AI ratio of patients with ICAS was significantly higher than those of individuals without ICAS in both stroke group and non-stroke groups. Increased ratio of apoB/AI was an independent risk factor for ICAS in both stroke group (OR 2.80, 95% CI 1.45-5.42, p=0.002) and non-stroke groups (OR 3.38, 95% CI 1.61-7.12, p<0.001). Compared with the lowest quartile, the third (Stroke OR=1.71, 95%CI, 1.11-2.63, p=0.014; Non-stroke OR=1.71, 95%CI, 1.04-2.82, p=0.033) and forth quartiles (Stroke OR=2.06, 95%CI, 1.27-3.35, p=0.003; Non-stroke OR=2.00, 95%CI, 1.16-3.49, p=0.012) were independent risk factors for ICAS in both stroke (p value for trend=0.001)) and non-stroke (p value for trend=0.006) groups. In summary, increased apoB/AI ratio was a valuable independent risk factor for ICAS in stroke patients as well as in non-stroke controls.

Elevated homocysteine as an independent risk for intracranial atherosclerotic stenosis.

To investigate the association of homocysteine concentration with intracranial atherosclerotic stenosis (ICAS), we assessed 933 acute ischemic stroke patients (346 with ICAS, 587 without ICAS) and 798 non-stroke controls (175 with ICAS, 623 without ICAS) with magnetic resonance angiography (MRA). Homocysteine concentration was found to be significantly higher in participants with ICAS than those without ICAS. In logistic regression analyses, homocysteine concentration was significantly associated with ICAS both in patients (OR: 1.04; 95% CI: 1.01-1.08; P=0.008) and controls (OR: 1.10; 95% CI: 1.06-1.15; P<0.001) for 1 µmol/L increment in homocysteine. Compared with the lowest quartile, the second (OR:1.53; 95% CI: 1.01-2.33), third (OR:1.71; 95% CI: 1.14 -2.60) and fourth (OR:2.48; 95%CI: 1.63-3.81) quartiles were independent predictors of ICAS in patients (P for trend<0.001); the third (OR:1.99; 95% CI: 1.18-3.40) and fourth (OR:2.36; 95%CI: 1.38-4.10) quartiles were independent predictors of ICAS in controls (P for trend<0.001). Hence, elevated homocysteine might be an independent risk for ICAS.

The role of UNC5C in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease in adults characterized by the deposition of extracellular plaques of ß-amyloid protein (Aß), intracellular neurofibrillary tangles (NFTs), synaptic loss and neuronal apoptosis. AD has a strong and complex genetic component that involving into multiple genes. With recent advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS) technology, UNC5C was identified to have association with AD. Emerging studies on cell and animal models identified that aberrant UNC5C may contribute to AD by activating death-associated protein kinase 1 (DAPK1) which is a new component involved in AD pathogenesis with an extensive involvement in aberrant tau, Aß and neuronal apoptosis/autophagy. In this review, we briefly summarize the biochemical properties, genetics, epigenetics, and the speculative role of UNC5C in AD. We hope our review would bring comprehensive understandings of AD pathogenesis and provide new therapeutic targets for AD.

Tau in neurodegenerative disease.

Tau, a microtubule-associated protein, is the main component of the intracellular filamentous inclusions that are involved in neurodegenerative diseases known as tauopathies, including Alzheimer disease (AD), frontotemporal dementia with parkinsonism-17 (FTDP-17), Pick disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Hyperphosphorylated, aggregated tau proteins form the core of neurofibrillary tangles (NFTs), which are shown to be one of the pathological hallmarks of AD. The discovery of mutations in the microtubule-associated protein tau (MAPT) gene in patients with FTDP-17 also contributes to a better understanding of the dysfunctional tau as a cause of diseases. Although recent substantial progress has been made in the tau pathology of tauopathies, the mechanisms underlying tau-induced neurodegeneration remain unclear. Here, we present an overview of the biochemical properties of tau protein and the pathogenesis underlying tau-induced neurodegenerative diseases. Meanwhile, we will discuss the tau-related biomarkers and ongoing tau-targeted strategies for therapeutic modulation.

Association of HLA-DRB1 polymorphism with Alzheimer's disease: a replication and meta-analysis.

Genome-wide association studies (GWAS) have identified one single-nucleotide polymorphism (SNP) rs9271192 within HLA-DRB1 as a risk factor for Alzheimer's disease (AD) in Caucasians. The effect of rs9271192 on AD needed to be verified in other ethnic cohorts. In order to evaluate the association between HLA-DRB1 rs9271192 polymorphism and late-onset AD (LOAD) in the Northern Han Chinese population, we recruited 982 LOAD patients and 1344 sex- and age-matched healthy controls. The results showed that HLA-DRB1 rs9271192 was associated with LOAD (genotype P = 0.015, allele P = 0.04). The results of logistic regression revealed the C allele homozygosity strongly increased the risk of LOAD under a recessive model in the total sample (P = 0.004, OR =2.069, 95% CI = 1.262-3.434). When these data were stratified by apolipoprotein E (APOE) ε4 status, the observed association was confined to APOE ε4 non-carriers (additive model: P=0.048, OR =1.191, 95% CI =1.001-1.417; recessive model: P < 0.001, OR = 2.601, 95% CI =1.519-4.566). Furthermore, meta-analysis after sensitive analysis confirmed that rs9271192 within HLA-DRB1 increased the risk of LOAD (OR = 1.12, 95% CI = 1.08-1.15). To summarize, the C allele in HLA-DRB1 rs9271192 may be an independent risk factor for LOAD.

The Association of MME microRNA Binding Site Polymorphism with the Risk of Late Onset Alzheimer's Disease in Northern Han Chinese.

BACKGROUND: Although ß-amyloid (Aß) degradation has been normally implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) through cellular biological studies, the genetic studies linking Aß degradation and LOAD are still scarce. Neprilysin (NEP), one of the most crucial Aß-degrading enzymes in AD, is the metalloendopeptidase which particularly participates in the monomeric Aß species degradation. MicroRNAs (miRNAs) exert post-transcriptional dysregulation and their target sequence on the 3' untranslated regions (3'UTR) may be regulated by single nucleotide polymorphisms (SNPs). OBJECTIVE: To investigate the potential risk of common locus within NEP gene (MME) with LOAD in Northern Han Chinese population. METHOD: We screened a locus (rs6665) in 3' UTR of NEP gene (MME) which sequence was specially regulated by miRNA-187, and further investigated its possible association with LOAD onset in a large case-control study (984 LOAD patients and 1354 healthy controls) in Northern Han Chinese. RESULTS: The distribution of rs6665 genotype (P=0.003) and allele A/C (P=0.001) showed significant difference between LOAD and controls (Odds Ratio (OR) =1.255, 95% Confidence Interval (CI) =1.102-1.429). After adjusting for age, gender and Apolipoprotein (ApoE) ε4 status, the minor C allele of rs6665 showed significant association with LOAD in all three genotypic models (Dominant: P=0.003, OR=1.291, 95%CI=1.092-1.526; Recessive: P=0.030, OR =1.425, 95%CI =1.035- 1.961; Additive: P=0.001, OR=1.249,95%CI=1.093-1.427). After stratifying by ApoE ε4 status, rs6665 polymorphism was found to elevate the LOAD risk in ApoE ε4 carriers (P=0.002, OR=1.846, 95%CI=1.264-2.697). CONCLUSION: Our study firstly confirmed the association of MME miRNA binding site polymorphism with the risk of LOAD. However, the association results warrant further validation.

Potential Regulators Driving the Transition in Nonalcoholic Fatty Liver Disease: a Stage-Based View.

BACKGROUND AND AIM: The incidence of nonalcoholic fatty liver disease (NAFLD), ranging from mild steatosis to hepatocellular injury and inflammation, increases with the rise of obesity. However, the implications of transcription factors network in progressive NAFLD remain to be determined. METHODS: A co-regulatory network approach by combining gene expression and transcription influence was utilized to dissect transcriptional regulators in different NAFLD stages. In vivo, mice models of NAFLD were used to investigate whether dysregulated expression be undertaken by transcriptional regulators. RESULTS: Through constructing a large-scale co-regulatory network, sample-specific regulator activity was estimated. The combinations of active regulators that drive the progression of NAFLD were identified. Next, top regulators in each stage of NAFLD were determined, and the results were validated using the different experiments and bariatric surgical samples. In particular, Adipocyte enhancer-binding protein 1 (AEBP1) showed increased transcription activity in nonalcoholic steatohepatitis (NASH). Further characterization of the AEBP1 related transcription program defined its co-regulators, targeted genes, and functional organization. The dynamics of AEBP1 and its potential targets were verified in an animal model of NAFLD. CONCLUSIONS: This study identifies putative functions for several transcription factors in the pathogenesis of NAFLD and may thus point to potential targets for therapeutic interventions.

Impacts of CD33 Genetic Variations on the Atrophy Rates of Hippocampus and Parahippocampal Gyrus in Normal Aging and Mild Cognitive Impairment.

The cluster of differentiation 33 (CD33) has been proved as a susceptibility locus associated with late-onset Alzheimer's disease (LOAD) based on recent genetic studies. Numerous studies have shown that multiple neuroimaging measures are potent predictors of AD risk and progression, and these measures are also affected by genetic variations in AD. Figuring out the association between CD33 genetic variations and AD-related brain atrophy may shed light on the underlying mechanisms of CD33-related AD pathogenesis. Thus, we investigated the influence of CD33 genotypes on AD-related brain atrophy to clarify the possible means by which CD33 impacts AD. A total of 48 individuals with probable AD, 483 mild cognitive impairment, and 281 cognitively normal controls were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We investigated the influence of CD33 SNPs on hippocampal volume, parahippocampal gyrus volume, posterior cingulate volume, middle temporal volume, hippocampus CA1 subregion volume, and entorhinal cortex thickness. We found that brain regions significantly affected by CD33 genetic variations were restricted to hippocampal and parahippocampal gyrus in hybrid population, which were further validated in subpopulation (MCI and NC) analysis. These findings reaffirm the importance of the hippocampal and parahippocampal gyrus in AD pathogenesis, and present evidences for the CD33 variations influence on the atrophy of specific AD-related brain structures. Our findings raise the possibility that CD33 polymorphisms contribute to the AD risk by altering the neuronal degeneration of hippocampal and parahippocampal gyrus.