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

阿尔茨海默病(AD)是最常见的老年神经退行性疾病，影响约540万人 预计到2050年，美国的个人数量将增加到1380万。这将是一个实质性的 医疗系统的负担。因此，开发新的有效的治疗策略势在必行。在这 静脉、新陈代谢变化和线粒体功能障碍已被确认为衰老的标志 进程。大脑消耗约20%的身体葡萄糖，其中约80%在线粒体中代谢 产生三磷酸腺苷，支持大脑功能。线粒体功能障碍导致ATP产生减少和 随着衰老过程中氧化应激的增加，自由基的释放。线粒体的功能在一定程度上是由 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+水平的下降，以及由此导致的氧化还原比率(NAD+/NADH)与 正常衰老，特别是在45岁以后，也有许多疾病，如阿尔茨海默病。积累证据 提示NAD+的口服生物可利用前体-烟酰胺核苷(NR)可以增强线粒体 有助于延缓或逆转这些与年龄相关的异常。目前，30多项临床试验，包括两项AD 研究已在临床试验网站上注册，使用天然橡胶和相关化合物。然而，到目前为止，还没有研究表明 研究了与补充NR相关的体内代谢和生物能量变化，因为 测量NAD+/NADH的挑战，即低浓度(&lt；1 mM)和与其他 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 开发了新的神经成像方法来在体内测量NAD+和NADH以及其他标志物 线粒体功能，包括肌酸激酶(CK)/ATPase活性和抗氧化剂谷胱甘肽(GSH)- 一种对细胞修复至关重要的分子，与NAD有功能联系。这些技术成就为 我们目前的建议，旨在研究NR的神经生物学机制和临床疗效。 使用体内神经成像技术对轻度认知障碍(MCI)/轻度AD患者进行研究。我们建议12- 每周，开放标签，概念验证研究，以衡量口服NR(1g/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。这项研究可能会提供关键信息 关于NAD在MCI/AD中的相关分子机制，并促进这方面的发展和完善 前景看好的治疗方法。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方面：第一，MCI/轻度AD与过度氧化还原有关 调节失调、氧化应激和线粒体功能缺陷；第二，这些异常可能是 第三，NR的下游效应会加速CK/ATPase的活性，从而 提高谷胱甘肽水平，进而改善认知功能。因此，识别准确的分子 参与MCI/AD相关生物能障碍的机制将提供重要的治疗靶点。

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.