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

基本信息

  • 批准号:
    10386819
  • 负责人:
  • 金额:
    $ 88.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
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.

项目成果

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FEI DU其他文献

FEI DU的其他文献

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{{ truncateString('FEI DU', 18)}}的其他基金

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:
    10394467
  • 财政年份:
    2020
  • 资助金额:
    $ 88.63万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 88.63万
  • 项目类别:
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:
    10653272
  • 财政年份:
    2020
  • 资助金额:
    $ 88.63万
  • 项目类别:
Molecular Mechanisms and Biomarkers for Disease Progression from Prodrome to Early Psychosis
从前驱症状到早期精神病的疾病进展的分子机制和生物标志物
  • 批准号:
    10065526
  • 财政年份:
    2019
  • 资助金额:
    $ 88.63万
  • 项目类别:
Molecular Mechanisms and Biomarkers for Disease Progression from Prodrome to Early Psychosis
从前驱症状到早期精神病的疾病进展的分子机制和生物标志物
  • 批准号:
    10312102
  • 财政年份:
    2019
  • 资助金额:
    $ 88.63万
  • 项目类别:
Molecular Mechanisms and Biomarkers for Disease Progression from Prodrome to Early Psychosis
从前驱症状到早期精神病的疾病进展的分子机制和生物标志物
  • 批准号:
    10529311
  • 财政年份:
    2019
  • 资助金额:
    $ 88.63万
  • 项目类别:
Oxidative Stress in First Episode Schizophrenia Assessed in vivo Using NAD+ and NADH Measurement
使用 NAD 和 NADH 测量在体内评估首发精神分裂症中的氧化应激
  • 批准号:
    9369156
  • 财政年份:
    2017
  • 资助金额:
    $ 88.63万
  • 项目类别:
Early Life Stress and Depression: Molecular and Functional Imaging Approaches
早期生活压力和抑郁:分子和功能成像方法
  • 批准号:
    10203785
  • 财政年份:
    2012
  • 资助金额:
    $ 88.63万
  • 项目类别:
Early Life Stress and Depression: Molecular and Functional Imaging Approaches
早期生活压力和抑郁:分子和功能成像方法
  • 批准号:
    10616773
  • 财政年份:
    2012
  • 资助金额:
    $ 88.63万
  • 项目类别:
Early Life Stress and Depression: Molecular and Functional Imaging Approaches
早期生活压力和抑郁:分子和功能成像方法
  • 批准号:
    10418734
  • 财政年份:
    2012
  • 资助金额:
    $ 88.63万
  • 项目类别:

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