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）是最常见的老年神经退行性疾病，影响约540万人