Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Dementia

口服烟酰胺核苷对轻度认知障碍和轻度阿尔茨海默氏痴呆患者生物能代谢、氧化应激和认知的影响

• 批准号: 10386819
• 负责人: FEI DU
• 金额: $ 88.63万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386819
• 关键词: ATP phosphohydrolase; Achievement; Address; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Animals; Antioxidants; Bioenergetics; Biological Process; Brain; Brain imaging; Cell Line; Cell Survival; Cerebrum; Circadian Rhythms; Clinical Trials; Clinical assessments; Cognition; Cognitive; Consumption; Creatine Kinase; Custom; Data; Development; Disease; Early Diagnosis; Electron Transport; Energy Metabolism; Equilibrium; Foundations; Free Radicals; Functional disorder; Glucose; Glutathione; Goals; Healthcare Systems; Human; Imaging Techniques; In Vitro; Individual; Inflammation; Literature; Magnetic Resonance Spectroscopy; Measurement; Measures; Medial; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; NADH; Neurobiology; Neurodegenerative Disorders; Neuronal Dysfunction; Nicotinamide adenine dinucleotide; Oral; Oral Administration; Oxidation-Reduction; Oxidative Stress; Oxides; Patients; Phase I Clinical Trials; Prefrontal Cortex; Process; Production; Publishing; RF coil; Resistance; Scanning; Schizophrenia; Signaling Molecule; Stress; Supplementation; Techniques; Testing; United States; Veins; age related; cerebrovascular; clinical effect; cognitive function; daily functioning; design; effective therapy; functional independence; functional outcomes; imaging approach; improved; in vivo; indexing; innovation; interest; mild cognitive impairment; mitochondrial dysfunction; neural repair; neurobiological mechanism; neuroimaging; neuroinflammation; nicotinamide riboside supplementation; nicotinamide-beta-riboside; normal aging; novel; novel strategies; open label; patient population; repaired; response; standardize measure; therapeutic target; treatment strategy

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disease of aging, affecting ~5.4 million individuals in the United States with a predicted increase to 13.8 million by 2050. This would be a substantial burden on healthcare systems. Thus, developing new and effective treatment strategies is imperative. In this vein, changes in metabolism and mitochondrial dysfunction have been identified as hallmarks of the aging process. The brain consumes ~20% of the body's glucose, of which ~80% is metabolized in mitochondria to generate ATP and support brain function. Mitochondrial dysfunction results in decreased ATP production and release of free radicals with elevated oxidative stress during aging. Mitochondrial function is mediated, in part, by nicotinamide adenine dinucleotide (NAD, including oxidizing and reducing forms, i.e. NAD+ and NADH). Unfortunately, decreases in NAD+ levels, and consequently the redox ratio (NAD+/NADH), are associated with normal aging, especially after age 45, and also with numerous diseases such as AD. Accumulating evidence suggests that nicotinamide riboside (NR), an orally bioavailable precursor of NAD+, can enhance mitochondrial function and help slow or reverse these age-related abnormalities. Currently, 30+ clinical trials, including two AD studies, are registered on clinicaltrials.gov using NR and related compounds. However, no studies to date have investigated in vivo metabolic and bioenergetic changes associated with NR supplementation because of the challenges in measuring NAD+/NADH, namely low concentration (<1mM) and overlapping resonances with other metabolites. Such measurement requires dedicated, state-of-the-art imaging approaches. To that end, we have developed novel neuroimaging approaches to measure in vivo NAD+ and NADH, as well as other markers of mitochondrial function, including creatine kinase (CK)/ATPase activity and the antioxidant glutathione (GSH)— a molecule essential for cellular repair that has functional ties to NAD. These technical achievements undergird our current proposal, which aims to investigate the neurobiological mechanisms and clinical effects of NR in patients with mild cognitive impairment (MCI)/mild AD using in vivo neuroimaging techniques. We propose a 12- week, open-label, proof of concept study to measure the effects of oral NR (1g/day) on brain energy metabolism, oxidative stress, and cognitive functioning in MCI/mild AD patients. This study may provide crucial information about NAD-related molecular mechanisms in MCI/AD, and facilitate the development and refinement of this promising treatment approach. In summary, our innovative theoretical framework, driven by our pilot data and published literature, includes three conceptual prongs: first, MCI/mild AD is associated with excessive redox dysregulation, oxidative stress and deficient mitochondrial function; second, these abnormalities could be remediated by NR; and third, the downstream effects of NR would accelerate CK/ATPase activities, thereby increasing GSH levels and, in turn, improving cognitive function. Thus, identifying the precise molecular mechanisms involved in MCI/AD-related bioenergetic dysfunction will provide important therapeutic targets.

阿尔茨海默病 (AD) 是最常见的衰老神经退行性疾病，影响约 540 万人 到 2050 年，美国的人口预计将增加到 1380 万。这将是一个巨大的数字 因此，开发新的有效治疗策略势在必行。 静脉、新陈代谢的变化和线粒体功能障碍已被确定为衰老的标志 大脑消耗约 20% 的身体葡萄糖，其中约 80% 在线粒体中代谢为葡萄糖。 产生 ATP 并支持大脑功能 线粒体功能障碍导致 ATP 产生减少和 衰老过程中氧化应激升高导致自由基释放，部分是由线粒体功能介导的。 由烟酰胺腺嘌呤二核苷酸（NAD，包括氧化形式和还原形式，即 NAD+ 和 NADH）组成。 不幸的是，NAD+ 水平的降低以及氧化还原比 (NAD+/NADH) 的降低与 正常衰老，尤其是 45 岁以后，也与许多疾病（如 AD）有关。 表明烟酰胺核苷 (NR) 是一种口服生物可利用的 NAD+ 前体，可以增强线粒体 目前，已有 30 多个临床试验，其中包括两项 AD。 使用 NR 和相关化合物在 ClinicalTrials.gov 上注册的研究，但迄今为止还没有研究。 研究了与 NR 补充相关的体内代谢和生物能变化，因为 测量 NAD+/NADH 的挑战，即低浓度 (<1mM) 和与其他物质重叠共振 为此，我们需要专门的、最先进的成像方法。 开发了新的神经影像方法来测量体内 NAD+ 和 NADH 以及其他标记物 线粒体功能，包括肌酸激酶 (CK)/ATP 酶活性和抗氧化剂谷胱甘肽 (GSH) — 一种与 NAD 具有功能联系的细胞修复必需分子。 我们目前的提案旨在研究 NR 的神经生物学机制和临床效果 我们建议使用体内神经影像技术对患有轻度认知障碍 (MCI)/轻度 AD 的患者进行 12- 一周，开放标签概念验证研究，测量口服 NR（1 克/天）对大脑能量代谢的影响， MCI/轻度 AD 患者的氧化应激和认知功能这项研究可能提供重要信息。 了解 MCI/AD 中 NAD 相关的分子机制，并促进该研究的发展和完善 总之，我们有前途的理论框架，由我们的试点数据和驱动。 已发表的文献，包括三个概念：首先，MCI/轻度 AD 与过度氧化还原有关 其次，这些异常可能与调节失调、氧化应激和线粒体功能缺陷有关。 通过 NR 修复；第三，NR 的下游效应会加速 CK/ATPase 活性，从而 增加 GSH 水平，进而改善认知功能，从而识别出精确的分子。 MCI/AD 相关生物能功能障碍的机制将提供重要的治疗靶点。