营养状况和认知功能在APOE ε4与阿尔茨海默病精神行为症状相关性的中介效应

目的 探讨营养状况和认知功能在载脂蛋白E等位基因4(APOE ε4)与阿尔茨海默病(AD)精神行为症状(NPS)及其亚型相关性的中介效应。方法 连续性收集2021年6月至2023年1月首都医科大学附属北京天坛医院阿尔茨海默病生物标志物与生活方式研究(CIBL)队列中293例AD疾病谱[包括遗忘型轻度认知障碍(aMCI)和AD痴呆期]患者,根据是否携带APOE ε4将患者分为携带组(107例)和非携带组(186例)。对各NPS亚型患者分别进一步分析入组年龄、性别、体质量指数(BMI)、简易精神状态评价量表(MMSE)、蒙特利尔认知评估量表(MoCA)和微型营养评估量表(MNA)评分等差异。采用SPSS 26.0统计软件进行数据处理。根据数据类型,分别采用t检验、Mann-Whitney U检验或χ²检验进行组间比较。将假设检验中有统计学意义的因素定为后面中介效应分析的混杂因素,采用简单中介效应模型分析营养状况和认知功能在APOE ε4与NPS及其亚型中的潜在中介作用。结果 与对照组相比,携带组患者出现幻觉、淡漠和异常运动行为的比例更高,差异有统计学意义(P＜0.05)。对NPS亚型患者分别进行分析,与非幻觉组相比,幻觉组年龄更大,受教育年限更少,携带APOE ε4比例更高,MMSE、MoCA和 MNA 评分均更低;与非淡漠组相比,淡漠组男性比例更高,携带APOE ε4比例更高,MMSE、MoCA和MNA评分均更低;与非异常运动行为组相比,异常运动行为组年龄更大,高脂血症比例更低,携带APOE ε4比例更低,MMSE、MoCA及MNA评分更低,差异有统计学意义(P<0.05)。校正混杂因素后,MNA评分介导了29.80%(95%CI 0.062~0.522)APOE ε4与淡漠的相关性,19.95%(95%CI 0.011~0.419)APOE ε4与异常运动行为的相关性。MMSE评分介导APOE ε4与幻觉、淡漠和异常运动行为的相关性分别是24.21%(95%CI 0.078~0.573),39.01%(95%IC 0.155~0.914)和23.37%(95%CI 0.068~0.576)。结论 对于aMCI和AD患者而言,营养状况和认知功能部分介导了APOE ε4和淡漠或异常运动行为的相关性,而认知功能还部分介导了APOE ε4和幻觉的相关性。     

Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms

BACKGROUND AND AIMS: Several nonsteroidal anti-inflammatory drugs (NSAIDs) are metabolized by the cytochrome P450 2C9 (CYP2C9). Two common variants of the CYP2C9 gene (CYP2C9*2 and *3) were reported to significantly affect the activity of the CYP2C9 enzyme. The aim of this study was to evaluate the impact of CYP2C9 polymorphisms on the risk of gastroduodenal bleeding in acute NSAID users. METHODS: This case-control study included 26 patients with endoscopically documented NSAID-related gastroduodenal bleeding lesions and 52 age-, sex- and NSAID use-matched controls with no lesions at endoscopy. Both cases and controls were Helicobacter pylori negative and acute users of an NSAID or cycloxygenase-2 inhibitor that undergoes CYP2C9 metabolism (ie, celecoxib, diclofenac, ibuprofen, naproxen, or piroxicam). Two marker single nucleotide polymorphisms in the CYP2C9 gene, identifying the CYP2C9 *2 and *3 allele, were evaluated in all subjects. RESULTS: Setting the CYP2C9*1/*1 wild type as reference, significantly higher frequencies of CYP2C9*1/*3 (34.6% vs 5.8%; P < .001; odds ratio [OR], 12.9; 95% confidence interval [CI], 2.917-57.922) and CYP2C9*1/*2 (26.9% vs 15.4%; P = .036; OR, 3.8; 95% CI, 1.090-13.190) were identified in bleeding versus control patients, whereas no differences between bleeding and controls were observed in the distribution of CYP2C9*2/*3 heterozygotes. Considering allele carriers, the presence of CYP2C9*3 allele was associated with a significant high risk of bleeding (adjusted OR, 7.3; 95% CI, 2.058-26.004). CONCLUSIONS: CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C9. Further studies that evaluate the effectiveness of a strategy using CYP2C9 genotyping in NSAID users are needed before genotyping is introduced into clinical practice.     

Association of Apolipoprotein E Polymorphisms in Patients with Non-Alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of alcohol abuse worldwide. Non-alcoholic steatohepatitis (NASH) is the most progressive form of NAFLD. The aim of this study was to investigate the role of apolipoprotein E (APOE) polymorphisms in the development of NASH. We analysed 57 NASH patients and 245 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a case–control study. The diagnosis of the patients was based on liver biopsy. The serum levels of glucose, lipids, vitamin B12, folic acid, homocysteine, insulin, total biluribin, total protein, albumin, ferritin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined in all of the subjects. Body mass index (BMI), waist circumference (WC), AST, ALT, fasting blood sugar (FBS), total cholesterol, triglyceride (TG), low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, insulin and ferritin levels were significantly higher in the 57 patients with NASH compared with the 245 healthy controls. The APOE ε3 allele was overrepresented in the whole group of NASH patients (ε3=97.37% in NASH versus 82.45% in controls). The APOE polymorphism was statistically significantly associated with NASH (χ²=15.741; p=0.008). The APOE3/3 genotype (odds ratio [OR]=7.941; p=0.000) was strongly associated with increased risk for NASH in all NASH patients. Consequently, the APOE3/3 genotype may play a role in the aetiopathogenesis of NASH.     

Apolipoprotein-E gene variants associated with cardiovascular risk factors in antipsychotic recipients

Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors.     

Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. METHODS: We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. RESULTS: When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01). CONCLUSIONS: The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.     

Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer

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