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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：
8490267
负责人：
Douglas Lyle Rothman
金额：
$ 47.56万
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/8490267
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.

描述(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。然而，没有直接的体内证据表明大脑线粒体功能发生了变化。在过去的十年里，我们开发了非侵入性的13C磁共振波谱(MRS)方法，结合稳定的13C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细胞TCA周期的速率的独特能力--这是对体内线粒体氧化能量产生的直接测量。使用13C MRS，我们发现健康老年人枕叶的能量代谢发生了深刻的变化，包括神经元TCA循环减少28%，谷氨酸/谷氨酰胺循环减少24%，神经胶质TCA循环增加30%。我们的一般假设是，在健康的衰老过程中，神经元线粒体失去了支持大脑功能能量需求的能力。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质，这与认知功能的衰老有关？2)神经元TCA周期的损害程度是否与既定执行功能测试的表现相关，以及3)神经胶质线粒体代谢的变化是由于谷氨酸氧化和细胞减退的增强，这可能反映了突触谷氨酸清除的受损。回答这些问题将对了解线粒体功能在与正常衰老相关的认知衰退中的作用具有直接意义，可能提供这一过程的新的、非侵入性的生物标志物，也将为应用这些方法研究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发展中的作用提供关键的基线信息。