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：
8088177
负责人：
Douglas Lyle Rothman
金额：
$ 46.83万
依托单位：
YALE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/8088177
关键词：
Acetates Address Age Aging Aging-Related Process Alzheimer&apos s Disease Animals Autopsy Behavioral Biological Markers Brain Cell Respiration Cells Citric Acid Cycle Cognitive Consumption Couples Data Development Elderly Energy Metabolism Enrollment Epilepsy Etiology Functional Magnetic Resonance Imaging Glucose Glutamates Glutamine Human Impaired cognition Impairment Individual Differences Infusion procedures Isotope Labeling Lead Left Magnetic Resonance Spectroscopy Measures Memory Metabolic Metabolism Methods Mitochondria Mitochondrial DNA Modeling Neurodegenerative Disorders Neuroglia Neurons Neurotransmitters Occipital lobe Patients Performance Play Positron-Emission Tomography Prefrontal Cortex Process Production Pyruvate Carboxylase Recycling Research Resolution Role Sensory Sensory Process Severities Signal Transduction Synapses Synaptic Cleft Testing Time Tissue Model Update age related base brain metabolism brain tissue cognitive function cohort executive function extracellular frontal lobe glucose uptake gray matter healthy aging in vivo loss of function mitochondrial dysfunction nervous system disorder neuron loss neurotransmitter release normal aging novel oxidation prefrontal lobe public health relevance research study

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，并可能在健康衰老的认知和感觉功能下降中发挥作用。但是，没有直接的体内证据证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13C磁共振光谱（MRS）方法，以及稳定的13C同位素标记为底物的方法，以研究人类的脑代谢。 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，这是对体内线粒体氧化能产生的直接测量。使用13C MRS，我们发现健康老年受试者的枕叶中能量代谢的深刻改变，包括神经元TCA周期降低28％，谷氨酸/谷氨酰胺循环降低了24％，而胶质性TCA降低了30％循环。我们的总体假设是，在健康衰老中，神经元线粒体能够支持大脑功能能量需求的能力丧失。我们将在拟议的研究中解决三个问题 - 1）前额叶皮层中是否存在这些代谢变化，这与衰老的认知功能丧失有关？ 2）神经元TCA循环的严重程度是否与既定的执行功能测试和3）的性能相关，而3）由于神经胶质线粒体代谢而导致谷氨酸氧化和厌氧性增强引起的改变，这可能反映出受损的突触乳木酸盐清除率。回答这些问题将在理解线粒体功能在与正常衰老相关的认知下降中的作用方面具有直接意义线粒体功能障碍在阿尔茨海默氏症和其他神经退行性疾病的发展中的作用。公共卫生相关性：拟议的研究将使用13C MRS在人脑中研究人脑中的线粒体氧化代谢和谷氨酸神经递质循环是否在健康的老年受试者的前额叶皮层中改变。他们将直接测试线粒体代谢是否与衰老的认知功能丧失有关。如果发现关联，将为线粒体功能障碍在与衰老过程相关的认知下降的病因中的关键作用提供进一步的证据。尽管没有提出过患者研究，但这些发现将构成表征线粒体代谢异常改变的基础，这可能在阿尔茨海默氏病和其他神经系统疾病的病因中起作用。