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: 10152493
• 负责人: FEI DU
• 金额: $ 55.5万
• 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/10152493
• 关键词: ATP phosphohydrolase; Achievement; Address; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Animals; Antioxidants; Bioavailable; 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; 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.

阿尔茨海默氏病（AD）是衰老的最普遍的神经退行性疾病，影响约540万 到2050年，美国的个人预计将增加到1380万。这将是一个实质性的 医疗保健系统负担。这是必须制定新的有效治疗策略。在这个 静脉，新陈代谢和线粒体功能障碍的变化已被确定为衰老的标志 过程。大脑消耗约20％的人体葡萄糖，其中约80％在线粒体中代谢 产生ATP并支持大脑功能。线粒体功能障碍可改善ATP的产生和 在衰老过程中释放自由基具有升高的氧化物应激。线粒体功能部分介导 由烟酰胺腺嘌呤二核苷酸（NAD，包括氧化和还原形式，即NAD+和NADH）。 不幸的是，NAD+水平下降，因此氧化还原比（NAD+/NADH）与 正常衰老，尤其是45岁之后，并且患有许多疾病，例如AD。积累证据 表明烟酰胺核苷（NR）是NAD+的口服生物利用前体，可以增强线粒体 功能并有助于减慢或逆转这些与年龄相关的异常。目前，有30多次临床试验，包括两个广告 研究使用NR和相关化合物在ClinicalTrials.gov上进行了注册。但是，迄今尚无研究 研究了与补充NR相关的体内代谢和生物能变化 测量NAD+/NADH的挑战，即低浓度（<1mm）和与其他的共振重叠 代谢物。这样的测量需要专门的最先进的成像方法。为此，我们有 开发了新型神经影像学方法，用于测量体内NAD+和NADH，以及其他标记 线粒体功能，包括Crectionine激酶（CK）/ATPase活性和抗氧化剂谷胱甘肽（GSH） - 与NAD具有功能关系的细胞修复必不可少的分子。这些技术成就基础 我们目前的提议旨在研究NR在 使用体内神经影像学技术的轻度认知障碍（MCI）/轻度AD患者。我们提出了一个12- 一周，开放标签，概念验证研究，以测量口服NR（1G/天）对脑能量代谢的影响， MCI/轻度AD患者的氧化应激和认知功能。这项研究可能提供关键信息 关于MCI/AD中NAD相关的分子机制，并促进了这一点的发展和完善 有希望的治疗方法。总而言之，我们的创新理论框架，由我们的试点数据和 已发表的文献包括三个概念插条：首先，MCI/温和广告与多余的氧化还原有关 失调，氧化应激和线粒体功能不足；第二，这些异常可能是 由NR修复；第三，NR的下游效应将加速CK/ATPase活动，从而 提高GSH水平，进而提高认知功能。那，识别精确的分子 与MCI/AD相关的生物能功能障碍有关的机制将提供重要的治疗靶标。