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

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，并可能在健康衰老过程中认知和感觉功能下降中发挥作用。然而，没有直接的活体证据表明大脑线粒体功能发生了改变。在过去的十年中，我们开发了非侵入性13C磁共振波谱（MRS）方法，结合稳定的13C同位素标记底物，研究人类的脑代谢。MRS具有独特的非侵入性测量神经元和胶质细胞TCA循环速率的能力，这是体内线粒体氧化能产生的直接测量方法。利用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%，胶质TCA循环增加30%。我们的一般假设是，在健康衰老中，神经元线粒体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)这些代谢变化是否存在于前额叶皮层中，这与认知功能的丧失有关？2)神经元TCA循环损伤的严重程度是否与执行功能测试的表现相关？ 3)神经胶质线粒体代谢的改变是否与谷氨酸氧化和回补增强有关，这可能反映了突触谷氨酸清除受损。回答这些问题将对理解线粒体功能在与正常衰老相关的认知能力下降中的作用具有直接意义，有可能为这一过程提供新的、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。

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.