13C MRS Studies of Human Brain Mitochondrial Metabolism in Healthy Aging

健康老龄化过程中人脑线粒体代谢的 13C MRS 研究

基本信息

  • 批准号:
    7984654
  • 负责人:
  • 金额:
    $ 47.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2014-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been implicated in age-related neurodegenerative diseases and may play a role in the decline of cognitive and sensory function with healthy aging. However there is no direct in vivo evidence for altered brain mitochondrial function. Over the last decade we have developed non invasive 13C Magnetic Resonance Spectroscopy (MRS) methods, in conjunction with stable 13C isotope labeled substrates, to study brain metabolism in humans. MRS has the unique ability to non-invasively measure the rates of the neuronal and glial TCA cycles - a direct measure of in vivo mitochondrial oxidative energy production. Using 13C MRS we found profound alterations in energy metabolism in the occipital lobe of healthy elderly subjects including a 28% reduction in the neuronal TCA cycle, a parallel 24% reduction in the glutamate/glutamine cycle, and a 30% increase in the glial TCA cycle. Our general hypothesis is that in healthy aging there is a loss of capacity of neuronal mitochondria to support brain functional energetic requirements. We will address three questions in the proposed research - 1) Are these metabolic changes present in the prefrontal cortex, which has been implicated in the loss of cognitive function with aging? 2) Does the severity of impairment of the neuronal TCA cycle correlate with performance on an established test of executive function and 3) are the alterations in glial mitochondrial metabolism due to enhanced glutamate oxidation and anaplerosis, which may reflect impaired synaptic glutamate clearance. Answering these questions will have immediate significance in understanding the role of mitochondrial function in the cognitive declines associated with normal aging, potentially provide novel, non-invasive biomarkers of this process, and also will provide critical baseline information for the application of these methods to study the role of mitochondrial dysfunction in the development of Alzheimer's and other neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: The proposed studies will use 13C MRS to study in human brain whether mitochondrial oxidative metabolism and glutamate neurotransmitter cycling are altered in the prefrontal cortex of healthy elderly subjects. They will test directly whether altered mitochondrial metabolism is associated with loss of cognitive function with aging. If an association is found it will provide further evidence for a key role of mitochondrial dysfunction in the etiology of the cognitive declines associated with the aging process. Although there are no patient studies proposed, these findings will form the basis for characterizing abnormal alterations in mitochondrial metabolism that may play a role in the etiology of Alzheimer's and other neurological diseases.
描述(由申请人提供):线粒体功能障碍与年龄相关的神经退行性疾病有关,并可能在健康老龄化的认知和感觉功能下降中发挥作用。然而,没有直接的体内证据表明脑线粒体功能改变。在过去的十年中,我们开发了非侵入性的13 C磁共振波谱(MRS)方法,结合稳定的13 C同位素标记底物,研究人类的大脑代谢。MRS具有非侵入性测量神经元和神经胶质TCA循环速率的独特能力-直接测量体内线粒体氧化能量产生。使用13 C MRS,我们发现健康老年受试者枕叶能量代谢发生了深刻的变化,包括神经元三羧酸循环减少28%,谷氨酸/谷氨酰胺循环平行减少24%,以及胶质细胞三羧酸循环增加30%。我们的一般假设是,在健康的老龄化有一个神经元线粒体的能力,以支持大脑功能的能量需求的损失。我们将在拟议的研究中解决三个问题- 1)这些代谢变化是否存在于前额叶皮层中,这与随着年龄的增长认知功能的丧失有关?2)神经元TCA循环受损的严重程度是否与执行功能的既定测试中的表现相关,以及3)由于谷氨酸氧化和回补增强而导致的神经胶质线粒体代谢的改变,这可能反映了突触谷氨酸清除受损。阐明这些问题将对理解线粒体功能在与正常衰老相关的认知下降中的作用具有直接意义,可能提供这一过程的新的非侵入性生物标志物,并且还将为应用这些方法研究线粒体功能障碍在阿尔茨海默病和其他神经退行性疾病发展中的作用提供关键的基线信息。 公共卫生关系:拟议的研究将使用13 C MRS来研究健康老年受试者的前额叶皮层中的线粒体氧化代谢和谷氨酸神经递质循环是否改变。他们将直接测试线粒体代谢的改变是否与衰老引起的认知功能丧失有关。如果发现相关性,将进一步证明线粒体功能障碍在与衰老过程相关的认知能力下降病因学中的关键作用。虽然没有提出患者研究,但这些发现将成为表征线粒体代谢异常改变的基础,这些异常改变可能在阿尔茨海默氏症和其他神经系统疾病的病因学中发挥作用。

项目成果

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Douglas Lyle Rothman其他文献

Douglas Lyle Rothman的其他文献

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{{ truncateString('Douglas Lyle Rothman', 18)}}的其他基金

Console and gradient upgrade for a 9.4 T 16 cm in vivo MR system
9.4 T 16 cm 体内 MR 系统的控制台和梯度升级
  • 批准号:
    8826292
  • 财政年份:
    2015
  • 资助金额:
    $ 47.43万
  • 项目类别:
Console for 4T Human MR System
4T 人体 MR 系统控制台
  • 批准号:
    8246539
  • 财政年份:
    2012
  • 资助金额:
    $ 47.43万
  • 项目类别:
13C MRS Studies of Human Brain Mitochondrial Metabolism in Healthy Aging
健康老龄化过程中人脑线粒体代谢的 13C MRS 研究
  • 批准号:
    8088177
  • 财政年份:
    2010
  • 资助金额:
    $ 47.43万
  • 项目类别:
13C MRS Studies of Human Brain Mitochondrial Metabolism in Healthy Aging
健康老龄化过程中人脑线粒体代谢的 13C MRS 研究
  • 批准号:
    8293136
  • 财政年份:
    2010
  • 资助金额:
    $ 47.43万
  • 项目类别:
13C MRS Studies of Human Brain Mitochondrial Metabolism in Healthy Aging
健康老龄化过程中人脑线粒体代谢的 13C MRS 研究
  • 批准号:
    8490267
  • 财政年份:
    2010
  • 资助金额:
    $ 47.43万
  • 项目类别:
Core Center for Quantitative Neuroscience with magnetic Resonance (QNMR)
磁共振定量神经科学 (QNMR) 核心中心
  • 批准号:
    7434780
  • 财政年份:
    2007
  • 资助金额:
    $ 47.43万
  • 项目类别:
Acquisition of a 7T human MR system for the development of ultra high resolution
购置7T人体MR系统,用于开发超高分辨率
  • 批准号:
    7127961
  • 财政年份:
    2006
  • 资助金额:
    $ 47.43万
  • 项目类别:
7T HUMAN MR SYSTEM, ULTRA HIGH RESOLUTION: NEUROSCIENCE
7T 人体 MR 系统,超高分辨率:神经科学
  • 批准号:
    7335350
  • 财政年份:
    2006
  • 资助金额:
    $ 47.43万
  • 项目类别:
MRS Studies of Brain Mitochondrial Function in Metabolic Syndrome
代谢综合征脑线粒体功能的 MRS 研究
  • 批准号:
    6844967
  • 财政年份:
    2004
  • 资助金额:
    $ 47.43万
  • 项目类别:
CORE--MRS/MRI Core
CORE--MRS/MRI 核心
  • 批准号:
    6844970
  • 财政年份:
    2004
  • 资助金额:
    $ 47.43万
  • 项目类别:

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