Nicotinamide riboside supplementation for treating arterial stiffness and elevated systolic blood pressure in patients with moderate to severe CKD

项目总结 此应用程序是对NIH针对阿尔茨海默氏症的NOT-AG-22-025管理补充剂的响应 不专注于阿尔茨海默病(AD)的赠款。轻度认知障碍(MCI)，特征为 情节记忆、执行功能和其他流畅认知功能领域以外的减少 正常衰老会导致个人患上与年龄相关的神经退行性疾病， 包括阿尔茨海默病(AD)和相关的痴呆症。慢性肾脏疾病(CKD)患者 患有MCI的风险很高，患病率大约是年龄匹配的普通人口的2倍。存在以下风险 CKD的MCI部分是由大的弹性动脉(即主动脉)僵硬和收缩血增加所介导的 血压(SBP)，导致脑血管功能下降(例如，搏动性血液增加 血流和脑血管反应性降低，部分原因是血管氧化应激)，这是先于 痴呆症的临床发作。用常规药物治疗降低SBP可降低MCI和 然而，绝大多数慢性肾脏病患者未能实现充分的血压控制。 提高NAD+在衰老和AD小鼠模型中的生物利用度改善认知危险因素 减损。在一项初步研究中，我们发现通过口服补充烟酰胺来增强NAD+ 核糖苷降低中老年人的SBP和主动脉僵硬，提示烟酰胺核苷 补充改善轻度认知损害和阿尔茨海默病的多种危险因素。然而， 烟酰胺核苷改善成人慢性肾脏病脑健康的疗效及机制， 谁是高风险或MCI/痴呆症，是未知的，但已被确定为高度优先的研究主题。 利用我们资助的父母奖临床试验，我们建议评估口服烟酰胺的疗效 核糖苷通过增加认知表现指标来增强3-4期慢性肾脏病成人的脑健康 和脑血管功能。为了评估作用机制，我们还将使用参与者血清来 确定补充烟酰胺核苷的益处是否由循环变化所介导 减少脑血管内皮细胞(CECs)线粒体ROS产生的代谢物。 因此，我们建议扩大我们的父母奖试验，将这些临床和机械标记纳入其中 在这个高危人群中大脑健康的问题。这项研究与阿尔茨海默病和相关痴呆症高度相关 因为它将评估一种新的膳食补充剂改善认知功能和建立MCI/AD 3-4期慢性肾脏病成人的危险因素。利用正在进行的试验将通过以下方式刺激AD领域的研究 使我们能够迅速收集和传播关于饮食补充剂功效的结果 烟酰胺核苷可降低轻度认知障碍、阿尔茨海默病和相关痴呆的风险 临床相关的高危人群。因此，这一行政补充将加速翻译一份高度 有望为预防中重度CKD患者的AD和相关痴呆提供干预措施。

PROJECT SUMMARY This application is in response to NOT-AG-22-025, Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease (AD). Mild cognitive impairment (MCI), characterized by reductions in episodic memory, executive function, and other domains of fluid cognitive function beyond what is expected with normal aging, predisposes individuals to age-related neurodegenerative diseases, including Alzheimer’s disease (AD) and related dementias. Individuals with chronic kidney disease (CKD) are at high risk of MCI, with a prevalence approximately 2x the age-matched general population. The risk for MCI in CKD is in part mediated by large elastic artery (i.e. aortic) stiffness and increased systolic blood pressure (SBP), contributing to reductions in cerebral vascular function (e.g., increased pulsatile blood flow and reduced cerebrovascular reactivity, in part due to vascular oxidative stress), which precedes the clinical onset of dementia. Lowering SBP with conventional pharmacotherapy decreases risk for MCI and dementia; however, the vast majority of patients with CKD fail to achieve adequate BP control. Boosting NAD+ bioavailability in mouse models of aging and AD improves risk factors for cognitive impairment. In a pilot study, we found that boosting NAD+ via oral supplementation with nicotinamide riboside reduced SBP and aortic stiffness in midlife and older adults, suggesting that nicotinamide riboside supplementation improves multiple risk factors for mild cognitive impairment and AD. However, the efficacy and underlying mechanisms of nicotinamide riboside for improving brain health in adults with CKD, who are at high risk or MCI/dementia, are unknown but has been identified as high-priority research topics. Leveraging our funded parent award clinical trial, we propose to assess the efficacy of oral nicotinamide riboside to enhance brain health in adults with stage 3-4 CKD by adding measures of cognitive performance and cerebrovascular function. To assess mechanisms of action, we also will use participant serum to determine if the benefits of nicotinamide riboside supplementation are mediated by changes in circulating metabolites that reduce mitochondrial ROS production in cerebrovascular endothelial cells (CECs). Therefore, we are proposing to expand our parent award trial to include these clinical and mechanistic markers of brain health in this high-risk population. This research is highly relevant to AD and related dementias because it will evaluate a novel dietary supplement for improving cognitive function and established MCI/AD risk factors in adults with stage 3-4 CKD. Leveraging an ongoing trial will stimulate research in the AD field by allowing us to rapidly collect and disseminate results on the efficacy of dietary supplementation with nicotinamide riboside for decreasing the risk for mild cognitive impairment, AD and related dementias in a clinically-relevant, at-risk group. Thus, this administrative supplement will speed translation of a highly promising intervention for preventing AD and related dementias in patients with moderate-to-severe CKD.