Search

Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n = 330) and AD-conversion group (n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR = 1.96, 95% CI: 1.07-2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD. [ABSTRACT FROM AUTHOR]

Background Although sildenafil has been shown to be safe and effective in idiopathic pulmonary arterial hypertension (PAH) and PAH related to connective tissue disease, its effects in Eisenmenger syndrome are less clear. Objective To investigate whether long-term treatment (12 months) with the phosphodiesterase type 5 inhibitor sildenafil improves clinical and haemodynamic parameters in patients with Eisenmenger syndrome. Design Prospective, open-label, multicentre study. Setting Four pulmonary hypertension centres in China. Patients 84 Eisenmenger syndrome functional class II-IV patients. Interventions Oral sildenafil 20 mg orally three times a day. Outcome measures 6-min walk distance (6MWD) test, resting systemic arterial blood oxygen saturation (SaO2) in room air, haemodynamic parameters assessed by right heart catheterisation, safety and tolerability. Results The overall treatment effects at 12 months versus baseline (mean changes with 95% CIs) were 56 m increase (42 to 69, p<0.0001) in 6MWD, and 2.4% increase (1.8% to 2.9%, p<0.0001) in resting room air SaO2. Improvements were also seen in mean pulmonary arterial pressure and pulmonary vascular resistance index (-4.7 mm Hg (-7.5 to -1.9), p=0.001; and -474 dyn×s×cm-5×m2 (-634 to -314), p<0.0001, respectively). Sildenafil was well tolerated. Most adverse events were mild and transient, and occurred in the first 2 weeks of treatment. Conclusions Twelve months of oral sildenafil treatment was well tolerated and appeared to improve exercise capacity, systemic arterial oxygen saturation and haemodynamic parameters in patients with Eisenmenger syndrome. [ABSTRACT FROM AUTHOR]