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

补充烟酰胺核苷可治疗中度至重度 CKD 患者的动脉僵硬度和收缩压升高

• 批准号: 10711872
• 负责人: Michel Benjamin Chonchol
• 金额: $ 36.01万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-23 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711872
• 关键词: Acute; Administrative Supplement; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Aorta; Arteries; Award; Biological Availability; Biomedical Research; Blood; Blood Pressure; Blood Vessels; Blood flow; Brain; Cardiovascular system; Cephalic; Cerebrovascular Disorders; Chronic Kidney Failure; Clinical; Clinical Trials; Cognitive; Dementia; Dietary Supplementation; Elasticity; Elderly; Endothelial Cells; Endothelium; Episodic memory; Femur; Funding; General Population; Grant; Human; Hypercapnia; Hypertension; Impaired cognition; Individual; Intervention; Link; Liquid substance; Measures; Mediating; Mitochondria; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Oral; Outcome; Oxidative Stress; Parents; Participant; Patients; Persons; Pharmacotherapy; Physiologic pulse; Pilot Projects; Placebos; Plasma; Population; Populations at Risk; Prevalence; Production; Reactive Oxygen Species; Research; Research Priority; Rest; Risk; Risk Factors; Rodent; Serum; Speed; Superoxides; Supplementation; Translations; United States National Institutes of Health; age related neurodegeneration; arterial stiffness; blood pressure control; brain health; cardiovascular risk factor; cerebrovascular; clinically relevant; cognitive function; cognitive performance; dementia risk; dietary supplements; efficacy evaluation; executive function; high risk; high risk population; improved; indexing; insight; metabolomics; middle age; middle cerebral artery; mild cognitive impairment; mouse model; nicotinamide riboside supplementation; nicotinamide-beta-riboside; normal aging; novel; novel therapeutics; oral supplementation; prevent; randomized placebo-controlled clinical trial; response; symptomatic improvement; vascular risk factor

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.

项目摘要 本申请是对NOT-AG-22-025的回应，NIH以阿尔茨海默氏症为重点的行政补充 不专注于阿尔茨海默病（AD）的赠款。轻度认知障碍（MCI），特征为 情景记忆、执行功能和其他流体认知功能领域的减少， 正常衰老所预期的，使个体易患与年龄相关的神经退行性疾病， 包括阿尔茨海默病（AD）和相关痴呆。慢性肾脏病（CKD）患者 MCI的高风险，患病率约为年龄匹配的一般人群的2倍。的风险 CKD中的MCI部分由大弹性动脉（即主动脉）僵硬和收缩期血液增加介导 血压（SBP），导致脑血管功能降低（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），这在 痴呆症的临床发作。常规药物治疗降低SBP可降低MCI风险， 然而，绝大多数CKD患者无法实现充分的BP控制。 提高衰老和AD小鼠模型中NAD+的生物利用度可改善认知功能障碍的风险因素 损伤在一项初步研究中，我们发现通过口服补充烟酰胺来提高NAD+水平， 核苷降低中年和老年人的SBP和主动脉僵硬度，表明烟酰胺核苷 补充剂改善了轻度认知障碍和AD的多种风险因素。但 烟酰胺核苷改善成人CKD患者大脑健康的疗效和潜在机制， 处于高风险或MCI/痴呆的人，是未知的，但已被确定为高优先级的研究课题。 利用我们资助的母公司奖临床试验，我们建议评估口服烟酰胺的疗效 核苷通过增加认知表现指标来增强3-4期CKD成人的大脑健康 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， 确定烟酰胺核苷补充剂的益处是否是由循环系统的变化介导的。 在脑血管内皮细胞（CEC）中，线粒体ROS代谢物减少。 因此，我们建议扩大我们的父母奖试验，包括这些临床和机制标志物 大脑健康的风险。这项研究与AD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，用于改善认知功能和建立MCI/AD 3-4期CKD成人的危险因素。利用正在进行的试验将刺激AD领域的研究， 使我们能够快速收集和传播有关膳食补充剂功效的结果， 烟酰胺核苷用于降低轻度认知障碍、AD和相关痴呆的风险， 临床相关的高危人群因此，这一行政补充将加快翻译的高度 在中重度CKD患者中预防AD和相关痴呆的有希望的干预措施。