Arterial Stiffness, Cognition, and Equol (ACE)

项目概要/摘要 这项申请，“动脉硬化，认知和雌马酚（ACE），”是一项早期随机对照试验 (RCT)旨在测试10 mg/天雌马酚补充剂对认知功能的24个月干预效果， 在400名年龄在70岁以上的无痴呆的个体中，观察了脑功能减退、动脉硬化和白色病变（WML）。 日本最近的研究报告说，大豆和大豆异黄酮（ISF）含量高的饮食与下列因素呈负相关： 偶发性认知障碍和痴呆。美国妇女异黄酮大豆健康（WISH），一项随机对照试验， 然而，ISFs对认知没有显着影响。我们认为，不一致的结果是由于 雌马酚产生能力的差异。雌马酚，一种ISF大豆苷元在肠道中的代谢产物 在所有ISF及其代谢产物中，微生物组是最具生物活性的。50-70%的日本人将大豆黄酮转化为 雌马酚的比例为20-30%。WISH的亚组分析表明，雌马酚生产者 比对照组更好的认知能力，这表明雌马酚可以减缓认知能力的下降。此外，动脉 僵硬是认知能力下降的重要预测因素，在10的短期RCT中， 在中年受试者中补充雌马酚。最后，WML是与年龄相关的 认知能力下降和痴呆。我们报道了雌马酚产生状态与WML%的纵向相关性。 (WML体积归一化为总脑体积）在日本认知正常的老年人。血清雌马酚水平 使用成像研究前6-9年收集和储存的样本进行测量; 50%为非雌马酚 生产者和雌马酚生产者被分为两组（高和低）。非雌马酚生产者 WML%比高产者高>100%，这表明补充雌马酚可能会减缓 WML的进展。以前没有研究测试过雌马酚补充剂对认知能力下降的影响， 老年人的动脉僵硬度或WML。我们假设每天补充10毫克雌马酚 显著减缓认知下降（主要结局）和动脉僵硬的进展， WML%（次要结局）。我们试验的总体影响将是确定雌马酚的作用 补充维生素C可以改善老年人的认知和脑血管结局。如果一个积极的信号 在这个早期试验中确定，它不仅会导致3期试验，以测试一个假设， 补充剂可降低认知障碍和痴呆的风险，但也可用于富含ISF的饮食的RCT 马酚生产者和非生产者之间的关系，朝着精确的健康战略迈进。

Project Summary/Abstract This application, “Arterial stiffness, Cognition and Equol (ACE),” is an early stage randomized controlled trial (RCT) designed to test the effect of a 24-month intervention of 10 mg/day equol supplementation on cognitive decline, arterial stiffness, and white matter lesions (WMLs) among 400 individuals aged 70+ without dementia. Recent studies in Japan reported that a diet high in soy and soy isoflavones (ISFs) is inversely associated with incident cognitive impairment and dementia. The Women’s Isoflavone Soy Health (WISH) in the US, an RCT of ISFs, however, showed no significant effect of ISFs on cognition. We posit that the discrepant result is due to the difference in equol-producing capability. Equol, a metabolite of an ISF daidzein transformed by the gut microbiome, is most bioactive among all ISFs and their metabolites. 50-70% of Japanese convert daidzein to equol in contrast to 20-30% of Americans. The subgroup analysis of WISH showed that equol producers had better cognition than the control group, suggesting that equol may slow cognitive decline. In addition, arterial stiffness, a significant predictor of cognitive decline, is significantly improved in a short-duration RCT of 10 mg/day equol supplementation in middle-aged subjects. Finally, WMLs are a risk factor for age-related cognitive decline and dementia. We reported a longitudinal association of equol-producing status with WML% (WML volume normalized to total brain volume) in cognitively normal elderly in Japan. Serum equol levels were measured using samples collected and stored 6-9 years before the imaging study; 50% were non-equol producers and equol producers were divided into two groups (high and low). Non-equol producers had >100% greater WML% than high producers, suggesting that supplementation of equol may slow the progression of WMLs. No previous study has tested the effect of equol supplementation on cognitive decline, arterial stiffness or WMLs in older adults. We hypothesize that supplementation of 10 mg/day equol will significantly slows both cognitive decline (primary outcome), and the progression of arterial stiffness and WML% (secondary outcomes). The overall impact of our trial will be to determine the role of equol supplementation in improving cognitive and cerebrovascular outcomes in older adults. Should a positive signal be identified in this early-stage trial, it would not only lead to a phase 3 trial to test a hypothesis that equol supplementation reduces risk for cognitive impairment and dementia but also to an RCT of a diet rich in ISFs between equol producers and non-producers, moving toward a precision health strategy.